@book{garey_computers_1997,
	address = {New York, {NY}},
	title = {Computers and intractability : a guide to the theory of {NP-completeness}},
	isbn = {0716710447 9780716710448 0716710455 9780716710455},
	shorttitle = {Computers and intractability},
	publisher = {Freeman},
	author = {Garey, Michael R and Johnson, David S},
	year = 1997
}


@Manual{iPAC,
    title = {iPAC: Identification of Protein Amino acid Clustering},
    author = {Gregory Ryslik and Hongyu Zhao},
    year = {2012},
    note = {R package version 1.2.0},
    howpublished = {\url{http://www.bioconductor.org/packages/2.12/bioc/html/iPAC.html}},
  }

@Manual{GraphPAC,
	title = {GraphPAC: Identification of Mutational Clusters in Proteins via a Graph Theoretical Approach},
	author = {Gregory Ryslik and Hongyu Zhao},
	year = {2012},
	note = {R package version 1.0.0},
	howpublished = {\url{http://bioconductor.org/packages/release/bioc/html/GraphPAC.html} } ,
}


@article{ye_2010,
	title = {Statistical method on nonrandom clustering with application to somatic mutations in cancer},
	volume = {11},
	issn = {1471-2105},
	url = {http://www.biomedcentral.com/1471-2105/11/11},
	doi = {10.1186/1471-2105-11-11},
	number = {1},	
	journal = {BMC Bioinformatics},
	author = {Ye, Jingjing and Pavlicek, Adam and Lunney, Elizabeth A and Rejto, Paul A and Teng, {Chi-Hse}},
	year = {2010},
	pages = {11}
}

@book{borg_modern_1997,
	address = {New York},
	title = {Modern multidimensional scaling : theory and applications},
	isbn = {0387948457 9780387948454},
	shorttitle = {Modern multidimensional scaling},
	publisher = {Springer},
	author = {Borg, Ingwer and Groenen, Patrick J. F},
	year = {1997}
}


@article{pdb,
	title = {The Protein Data Bank},
	volume = {28},
	issn = {13624962},
	url = {www.pdb.org},
	doi = {10.1093/nar/28.1.235},
	number = {1},
	journal = {Nucleic Acids Research},
	author = {Berman, H. M. and Westbrook, J. and Feng, Z. and Gilliland, G. and Bhat, T.N. and Weissig, H. and Shindyalov, I.N. and Bourne, P.E.},
	month = jan,
	year = {2000},
	pages = {235--242}
}

@article{vogelstein_cancer_2004,
	title = {Cancer genes and the pathways they control},
	volume = {10},
	issn = {1078-8956},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/15286780},
	doi = {10.1038/nm1087},
	abstract = {The revolution in cancer research can be summed up in a single sentence: cancer is, in essence, a genetic disease. In the last decade, many important genes responsible for the genesis of various cancers have been discovered, their mutations precisely identified, and the pathways through which they act characterized. The purposes of this review are to highlight examples of progress in these areas, indicate where knowledge is scarce and point out fertile grounds for future investigation.},
	number = {8},
	journal = {Nature Medicine},
	author = {Vogelstein, Bert and Kinzler, Kenneth W},
	month = aug,
	year = {2004},
	note = {{PMID:} 15286780},
	keywords = {Adenomatous Polyposis Coli Protein, Apoptosis, {DNA-Binding} Proteins, {DNA} Repair, Genes, Tumor Suppressor, Humans, {Hypoxia-Inducible} Factor 1, {Hypoxia-Inducible} Factor 1, alpha Subunit, Mutation, Neoplasms, Nuclear Proteins, Oncogenes, Phosphatidylinositol {3-Kinases}, Receptor {Protein-Tyrosine} Kinases, Retinoblastoma Protein, Signal Transduction, Smad Proteins, {Trans-Activators}, Transcription Factors, Tumor Suppressor Protein p53},
	pages = {789--799}
}

@article{weinstein_mechanisms_2006,
	title = {Mechanisms of disease: Oncogene addiction--a rationale for molecular targeting in cancer therapy},
	volume = {3},
	issn = {1743-4254},
	shorttitle = {Mechanisms of disease},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/16894390},
	doi = {10.1038/ncponc0558},
	abstract = {There has been considerable progress in the systemic treatment of cancer because of the rapid development and clinical application of molecular targeted agents. Although patients with a particular type and stage of cancer are often treated as a single group, more-specific therapy is being considered, as subsets of these patients who are more likely to benefit from treatment with particular agents are being identified. We previously introduced the concept of 'oncogene addiction' to explain how some cancers that contain multiple genetic, epigenetic, and chromosomal abnormalities are dependent on or 'addicted' to one or a few genes for both maintenance of the malignant phenotype and cell survival. Thus, reversal of only one or a few of these abnormalities can inhibit cancer cell growth and in some cases translate to improved survival rates. This review summarizes current experimental and clinical evidence for the concept of oncogene addiction and describes molecular mechanisms that may explain this phenomenon. In addition, we discuss how high-throughput screening methods, including gene-expression profiling and proteomics, and emerging methods for analyzing complex cellular networks can be used to identify the state of oncogene addiction, i.e. the {'Achilles'} heel,' in specific cancers. Finally, we discuss the use of molecular targeted agents in combination with other anticancer agents as a strategy to optimize therapy and prevent disease recurrence.},
	number = {8},
	journal = {Nature Clinical Practice. Oncology},
	author = {Weinstein, I Bernard and Joe, Andrew K},
	month = aug,
	year = {2006},
	note = {{PMID:} 16894390},
	keywords = {Animals, Antineoplastic Combined Chemotherapy Protocols, Cell Transformation, Neoplastic, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Targeting, Genes, Tumor Suppressor, Humans, Neoplasm Recurrence, Local, Neoplasm Staging, Neoplasms, Oncogenes},
	pages = {448--457}
}


@article{bardelli_mutational_2003,
	title = {Mutational Analysis of the Tyrosine Kinome in Colorectal Cancers},
	volume = {300},
	issn = {00368075, 10959203},
	url = {http://www.sciencemag.org/cgi/doi/10.1126/science.1082596},
	doi = {10.1126/science.1082596},
	number = {5621},
	journal = {Science},
	author = {Bardelli, A.},
	month = may,
	year = {2003},
	pages = {949--949}
}

@article{sjoeblom_consensus_2006,
	title = {The consensus coding sequences of human breast and colorectal cancers},
	volume = {314},
	issn = {1095-9203},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/16959974},
	doi = {10.1126/science.1133427},
	abstract = {The elucidation of the human genome sequence has made it possible to identify genetic alterations in cancers in unprecedented detail. To begin a systematic analysis of such alterations, we determined the sequence of well-annotated human protein-coding genes in two common tumor types. Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of approximately 90 mutant genes but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, we identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. These data define the genetic landscape of two human cancer types, provide new targets for diagnostic and therapeutic intervention, and open fertile avenues for basic research in tumor biology.},
	number = {5797},
	journal = {Science {(New} York, {N.Y.)}},
	author = {SjÃ¶blom, Tobias and Jones, SiÃ¢n and Wood, Laura D and Parsons, D Williams and Lin, Jimmy and Barber, Thomas D and Mandelker, Diana and Leary, Rebecca J and Ptak, Janine and Silliman, Natalie and Szabo, Steve and Buckhaults, Phillip and Farrell, Christopher and Meeh, Paul and Markowitz, Sanford D and Willis, Joseph and Dawson, Dawn and Willson, James K V and Gazdar, Adi F and Hartigan, James and Wu, Leo and Liu, Changsheng and Parmigiani, Giovanni and Park, Ben Ho and Bachman, Kurtis E and Papadopoulos, Nickolas and Vogelstein, Bert and Kinzler, Kenneth W and Velculescu, Victor E},
	month = oct,
	year = {2006},
	note = {{PMID:} 16959974},
	keywords = {Amino Acid Substitution, Breast Neoplasms, Cell Line, Tumor, Colorectal Neoplasms, Computational Biology, Consensus Sequence, Databases, Nucleic Acid, Female, Genes, Neoplasm, Genome, Human, Humans, Male, Mutation, Polymerase Chain Reaction, Sequence Analysis, {DNA}},
	pages = {268--274}
}		


@article{wagner_rapid_2007,
	title = {Rapid Detection of Positive Selection in Genes and Genomes Through Variation Clusters},
	volume = {176},
	issn = {0016-6731},
	url = {http://www.genetics.org/cgi/doi/10.1534/genetics.107.074732},
	doi = {10.1534/genetics.107.074732},
	number = {4},
	journal = {Genetics},
	author = {Wagner, A.},
	month = aug,
	year = {2007},
	pages = {2451--2463}
}


@article{kreitman_methods_2000,
	title = {Methods to detect selection in populations with applications to the human.},
	volume = {1},
	issn = {1527-8204, {1545-293X}},
	url = {http://www.annualreviews.org/doi/abs/10.1146/annurev.genom.1.1.539},
	doi = {10.1146/annurev.genom.1.1.539},
	number = {1},
	journal = {Annual Review of Genomics and Human Genetics},
	author = {Kreitman, Martin},
	month = sep,
	year = {2000},
	pages = {539--559}
}


@article{wang_prevalence_2002,
	title = {Prevalence of somatic alterations in the colorectal cancer cell genome},
	volume = {99},
	issn = {00278424, 10916490},
	url = {http://www.pnas.org/cgi/doi/10.1073/pnas.261714699},
	doi = {10.1073/pnas.261714699},
	number = {5},
	journal = {Proceedings of the National Academy of Sciences},
	author = {Wang, {T.-L.}},
	month = feb,
	year = {2002},
	pages = {3076--3080}
}

@article{wagner_computational_1997,
	title = {A computational genomics approach to the identification of gene networks},
	volume = {25},
	issn = {13624962},
	url = {http://www.nar.oupjournals.org/cgi/doi/10.1093/nar/25.18.3594},
	doi = {10.1093/nar/25.18.3594},
	number = {18},
	journal = {Nucleic Acids Research},
	author = {Wagner, A},
	month = sep,
	year = {1997},
	pages = {3594--3604}
}

@article{the_uniprot_consortium_reorganizing_2011,
	title = {Reorganizing the protein space at the Universal Protein Resource {(UniProt)}},
	volume = {40},
	issn = {0305-1048, 1362-4962},
	url = {http://www.nar.oxfordjournals.org/cgi/doi/10.1093/nar/gkr981},
	doi = {10.1093/nar/gkr981},
	number = {D1},
	journal = {Nucleic Acids Research},
	author = {The UniProt Consortium},
	month = nov,
	year = {2011},
	pages = {D71--D75}
}


@article{veldscholte_mutation_1990,
	title = {A mutation in the ligand binding domain of the androgen receptor of human {LNCaP} cells affects steroid binding characteristics and response to anti-androgens},
	volume = {173},
	issn = {{0006-291X}},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/2260966},
	abstract = {{LNCaP} prostate tumor cells contain an abnormal androgen receptor system. Progestagens, estradiol and anti-androgens can compete with androgens for binding to the androgen receptor and can stimulate both cell growth and excretion of prostate specific acid phosphatase. We have discovered in the {LNCaP} androgen receptor a single point mutation changing the sense of codon 868 {(Thr} to Ala) in the ligand binding domain. Expression vectors containing the normal or mutated androgen receptor sequence were transfected into {COS} or Hela cells. Androgens, progestagens, estrogens and anti-androgens bind the mutated androgen receptor protein and activate the expression of an androgen-regulated reporter gene construct {(GRE-tk-CAT).} The mutation therefore influences both binding and the induction of gene expression by different steroids and antisteroids.},
	number = {2},
	journal = {Biochemical and Biophysical Research Communications},
	author = {Veldscholte, J and {Ris-Stalpers}, C and Kuiper, G G and Jenster, G and Berrevoets, C and Claassen, E and van Rooij, H C and Trapman, J and Brinkmann, A O and Mulder, E},
	month = dec,
	year = {1990},
	note = {{PMID:} 2260966},
	keywords = {Binding Sites, Binding, Competitive, Gene Expression Regulation, Neoplastic, {HeLa} Cells, Humans, Ligands, Male, Mutation, Prostatic Neoplasms, Receptors, Androgen, Steroids, Transfection, Tumor Cells, Cultured},
	pages = {534--540}
},

@article{suzuki_androgen_1993,
	title = {Androgen receptor gene mutations in human prostate cancer},
	volume = {46},
	issn = {0960-0760},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/8274409},
	abstract = {To investigate the structural abnormality of the androgen receptor {(AR)} in human prostate cancers, exons {B-H} encoding {DNA-} and hormone-binding domains were examined by single-strand conformation polymorphism analysis of polymerase chain reaction products using originally designed oligoprimers. Tissues from 7 cases of untreated stage B prostate cancer surgically removed and from 8 cases of endocrine therapy-resistant cancers obtained at autopsy were used in the study. Two different mutations were identified in exons D and H in the different cancer foci of the same cancer death patient. One mutation in exon D (at codon 701, Leu to His) was detected in the prostate, and the other in exon H (at codon 877, Thr to Ala) was found in metastatic tissues. In untreated cancer tissues and the other autopsy samples, no mutations were detected. The mutation in exon H was identical to that reported in {LNCaP} cells. These results indicate that {AR} gene mutations occur in relation to endocrine therapy-resistance, although the mutation was found in 1 out of 8 resistant cases (12.5\%) at autopsy.},
	number = {6},
	journal = {The Journal of Steroid Biochemistry and Molecular Biology},
	author = {Suzuki, H and Sato, N and Watabe, Y and Masai, M and Seino, S and Shimazaki, J},
	month = dec,
	year = {1993},
	note = {{PMID:} 8274409},
	keywords = {Adenocarcinoma, Alanine, Amino Acid Sequence, Base Sequence, {DNA} Primers, {DNA}, Neoplasm, {DNA-Binding} Proteins, Exons, Genetic Variation, Histidine, Humans, Leucine, Male, Molecular Sequence Data, Point Mutation, Polymerase Chain Reaction, Polymorphism, Genetic, Prostatic Neoplasms, Receptors, Androgen, Threonine},
	pages = {759--765}
},

@article{suzuki_codon_1996,
	title = {Codon 877 mutation in the androgen receptor gene in advanced prostate cancer: relation to antiandrogen withdrawal syndrome},
	volume = {29},
	issn = {0270-4137},
	shorttitle = {Codon 877 mutation in the androgen receptor gene in advanced prostate cancer},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/8827083},
	abstract = {The growth of prostate cancer is androgen responsive, and androgen receptor {(AR)} is thought to play an important role in the development of this cancer. Recently, some reports demonstrated that {AR} gene mutations were detected in human prostate cancer tissues. We have previously reported that one of eight endocrine therapy-resistant prostate cancer cases showed {AR} gene mutation {[Suzuki} et al: J Steroid Biochem Mol Biol 46:759-765, 1993]. To further investigate structural abnormality of the {AR} in a large number of human prostate cancers, exons {B-H} encoding {DNA-and} hormone-binding domains were examined by single-strand conformation polymorphism analysis of polymerase chain reaction products and direct sequencing. Tissues surgically removed from 30 cases of stage B or C prostate cancer and from 22 cases of endocrine therapy-resistant cancers obtained at autopsy were used in the study. Three out of 22 cancer death cases (14\%) revealed {AR} gene mutations, one of which contained two different mutations-exon D in cancerous prostate and exon H in metastatic tissues. In the other two cases, {AR} gene mutations in exon H were found in metastatic tissues. All three cases in metastatic tissues showed the same mutation at codon 877 {(877Thr--{\textgreater}Ala).} In stage B or C cancer tissues and the other cancer death samples, no {AR} mutation was detected. The mutation in exon H was identical to that reported in a human prostate cancer cell line, {LNCaP.} These results indicate that {AR} gene mutation scarcely occurs in the early stage of prostate cancer and that the mutation is found in relation to endocrine therapy resistance. Two patients with an {AR} gene mutation at codon 877 revealed a remarkable fall in prostate-specific antigen after withdrawal of antiandrogen. Data on the other case were not available. These results indicate that a codon 877 mutation in the {AR} gene in advanced prostate cancer evokes the antiandrogen withdrawal syndrome. To our knowledge, this report is the first description of relationship between an {AR} mutation at codon 877 and the antiandrogen withdrawal syndrome.},
	number = {3},
	journal = {The Prostate},
	author = {Suzuki, H and Akakura, K and Komiya, A and Aida, S and Akimoto, S and Shimazaki, J},
	month = sep,
	year = {1996},
	note = {{PMID:} 8827083},
	keywords = {Aged, Amino Acid Sequence, Androgen Antagonists, Chlormadinone Acetate, Codon, Genes, Genetic Variation, Humans, Male, Mutation, Orchiectomy, Polymerase Chain Reaction, Polymorphism, {Single-Stranded} Conformational, {Prostate-Specific} Antigen, Prostatic Neoplasms, Receptors, Androgen, Substance Withdrawal Syndrome},
	pages = {153--158}
},

@article{bohl_crystal_2007,
	title = {Crystal structure of the {T877A} human androgen receptor ligand-binding domain complexed to cyproterone acetate provides insight for ligand-induced conformational changes and structure-based drug design},
	volume = {282},
	issn = {0021-9258},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/17311914},
	doi = {10.1074/jbc.M611711200},
	abstract = {Cyproterone acetate {(CPA)} is a steroidal antiandrogen used clinically in the treatment of prostate cancer. Compared with steroidal agonists for the androgen receptor {(AR)} (e.g. dihydrotestosterone, R1881), {CPA} is bulkier in structure and therefore seemingly incompatible with the binding pockets observed in currently available x-ray crystal structures of the {AR} ligand-binding domain {(LBD).} We solved the x-ray crystal structure of the human {AR} {LBD} bound to {CPA} at {1.8A} in the {T877A} variant, a mutation known to increase the agonist activity of {CPA} and therefore facilitate purification and crystal formation of the receptor.drug complex. The structure demonstrates that bulk from the 17alpha-acetate group of {CPA} induces movement of the Leu-701 side chain, which results in partial unfolding of the C-terminal end of helix 11 and displacement of the loop between helices 11 and 12 in comparison to all other {AR} {LBD} crystal structures published to date. This structural alteration leads to an expansion of the {AR} binding cavity to include an additional pocket bordered by Leu-701, Leu-704, Ser-778, Met-780, Phe-876, and Leu-880. Further, we found that {CPA} invokes transcriptional activation in the {L701A} {AR} at low nanomolar concentrations similar to the {T877A} mutant. Analogous mutations in the glucocorticoid receptor {(GR)} and progesterone receptor were constructed, and we found that {CPA} was also converted into a potent agonist in the {M560A} {GR.} Altogether, these data offer information for structure-based drug design, elucidate flexible regions of the {AR} {LBD}, and provide insight as to how {CPA} antagonizes the {AR} and {GR.}},
	number = {18},
	journal = {The Journal of Biological Chemistry},
	author = {Bohl, Casey E and Wu, Zengru and Miller, Duane D and Bell, Charles E and Dalton, James T},
	month = may,
	year = {2007},
	note = {{PMID:} 17311914},
	keywords = {Amino Acid Substitution, Amino Acids, Crystallography, {X-Ray}, Cyproterone Acetate, Drug Design, Humans, Ligands, Mutation, Missense, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, Receptors, Androgen, Receptors, Glucocorticoid, Receptors, Progesterone, Structural Homology, Protein, {Structure-Activity} Relationship},
	pages = {13648--13655}
},

@article{gaddipati_frequent_1994,
	title = {Frequent detection of codon 877 mutation in the androgen receptor gene in advanced prostate cancers},
	volume = {54},
	issn = {0008-5472},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/8187068},
	abstract = {Prostatic tissue specimens derived from transurethral resections of patients with metastatic prostate cancer were analyzed for genetic alterations in the hormone-binding domain of the androgen receptor {(AR)} gene. Direct sequencing of the polymerase chain reaction-derived {DNAs} of 6 of 24 specimens revealed a codon 877 mutation {(ACT--{\textgreater}GCT}, {Thr--{\textgreater}Ala)} in the hormone-binding domain of the {AR} gene. This same {AR} mutation has been reported previously in a metastatic prostate cancer cell line, {LNCaP}, where this mutation confers upon the {AR} an altered ligand-binding specificity which is stimulated by estrogens, progestagens, and antiandrogens. It is possible that analogous to an activated/altered growth factor receptor oncogene, codon 877 mutant {AR} with altered ligand binding may provide a selective growth advantage in the genesis of a subset of advanced prostate cancer. Although estrogens are used infrequently, antiandrogens are used increasingly in hormonal therapy for patients with advanced prostate cancer. The stimulatory effect of these therapeutic agents on the codon 877 mutant {AR} further suggests that this frequently observed {AR} mutation may contribute to the treatment refractory disease.},
	number = {11},
	journal = {Cancer Research},
	author = {Gaddipati, J P and {McLeod}, D G and Heidenberg, H B and Sesterhenn, I A and Finger, M J and Moul, J W and Srivastava, S},
	month = jun,
	year = {1994},
	note = {{PMID:} 8187068},
	keywords = {Codon, {DNA}, Neoplasm, Humans, Male, Molecular Sequence Data, Point Mutation, Prostatic Neoplasms, Receptors, Androgen, Sequence Analysis, {DNA}, Tumor Cells, Cultured},
	pages = {2861--2864}
},

@article{taplin_selection_1999,
	title = {Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist},
	volume = {59},
	issn = {0008-5472},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/10363963},
	abstract = {The role of androgen receptor {(AR)} mutations in androgen-independent prostate cancer {(PCa)} was determined by examining {AR} transcripts and genes from a large series of bone marrow metastases. Mutations were found in 5 of 16 patients who received combined androgen blockade with the {AR} antagonist flutamide, and these mutant {ARs} were strongly stimulated by flutamide. In contrast, the single mutant {AR} found among 17 patients treated with androgen ablation monotherapy was not flutamide stimulated. Patients with flutamide-stimulated {AR} mutations responded to subsequent treatment with bicalutamide, an {AR} antagonist that blocks the mutant {ARs.} These findings demonstrate that {AR} mutations occur in response to strong selective pressure from flutamide treatment.},
	number = {11},
	journal = {Cancer Research},
	author = {Taplin, M E and Bubley, G J and Ko, Y J and Small, E J and Upton, M and Rajeshkumar, B and Balk, S P},
	month = jun,
	year = {1999},
	note = {{PMID:} 10363963},
	keywords = {Androgen Antagonists, Anilides, Antineoplastic Agents, Hormonal, Biopsy, Bone Marrow, Bone Marrow Neoplasms, Codon, {DNA} Mutational Analysis, Flutamide, Humans, Male, Mutation, Neoplasms, {Hormone-Dependent}, Nitriles, Prostatic Neoplasms, Receptors, Androgen, Reverse Transcriptase Polymerase Chain Reaction, Tosyl Compounds},
	pages = {2511--2515}
},

@article{bohl_structural_2005,
	title = {Structural basis for accommodation of nonsteroidal ligands in the androgen receptor},
	volume = {280},
	issn = {0021-9258},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/16129672},
	doi = {10.1074/jbc.M507464200},
	abstract = {The mechanism by which the androgen receptor {(AR)} distinguishes between agonist and antagonist ligands is poorly understood. {AR} antagonists are currently used to treat prostate cancer. However, mutations commonly develop in patients that convert these compounds to agonists. Recently, our laboratory discovered selective androgen receptor modulators, which structurally resemble the nonsteroidal {AR} antagonists bicalutamide and hydroxyflutamide but act as agonists for the androgen receptor in a tissue-selective manner. To investigate why subtle structural changes to both the ligand and the receptor (i.e. mutations) result in drastic changes in activity, we studied structure-activity relationships for nonsteroidal {AR} ligands through crystallography and site-directed mutagenesis, comparing bound conformations of R-bicalutamide, hydroxyflutamide, and two previously reported nonsteroidal androgens, S-1 and R-3. These studies provide the first crystallographic evidence of the mechanism by which nonsteroidal ligands interact with the wild type {AR.} We have shown that changes induced to the positions of Trp-741, Thr-877, and Met-895 allow for ligand accommodation within the {AR} binding pocket and that a water-mediated hydrogen bond to the backbone oxygen of Leu-873 and the ketone of hydroxyflutamide is present when bound to the {T877A} {AR} variant. Additionally, we demonstrated that R-bicalutamide stimulates transcriptional activation in {AR} harboring the {M895T} point mutation. As a whole, these studies provide critical new insight for receptor-based drug design of nonsteroidal {AR} agonists and antagonists.},
	number = {45},
	journal = {The Journal of Biological Chemistry},
	author = {Bohl, Casey E and Miller, Duane D and Chen, Jiyun and Bell, Charles E and Dalton, James T},
	month = nov,
	year = {2005},
	note = {{PMID:} 16129672},
	keywords = {Androgen Receptor Antagonists, Androgens, Animals, Binding Sites, Cell Line, Drug Design, Humans, Ligands, Models, Molecular, Molecular Conformation, Mutation, Protein Binding, Receptors, Androgen, {Structure-Activity} Relationship, Transcriptional Activation},
	pages = {37747--37754}
},

@article{veldscholte_androgen_1992,
	title = {The androgen receptor in {LNCaP} cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiandrogens},
	volume = {41},
	issn = {0960-0760},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/1562539},
	abstract = {The human prostate tumor cell line {LNCaP} contains an abnormal androgen receptor system with broad steroid binding specificity. Progestagens, estradiol and several antiandrogens compete with androgens for binding to the androgen receptor in the cells to a higher extent than in other androgen sensitive systems. Optimal growth of {LNCaP} cells is observed after addition of the synthetic androgen R1881 (0.1 {nM).} In addition, estrogens, progestagens and several antiandrogens do not inhibit androgen responsive growth, but have striking growth stimulatory effects and increase {EGF} receptor level and acid phosphatase secretion. We have found that the androgen receptor in the {LNCaP} cells contains a single point mutation changing the sense of codon 868 {(Thr} to Ala) in the ligand binding domain. Expression vectors containing the normal or mutated androgen receptor sequence were transfected into {COS} or {HeLa} cells. Androgens, progestagens, estrogens and several antiandrogens bind the mutated androgen receptor protein and activate the expression of an androgen-regulated reporter gene {(GRE-tk-CAT)}, indicating that the mutation directly affects both binding specificity and the induction of gene expression. Interestingly, the antiandrogen casodex showed antiandrogenic properties in growth studies of {LNCaP} cells and did not induce reporter gene activity in Hela cells transfected with the mutant receptor. The mutated androgen receptor of {LNCaP} cells is therefore a useful tool in the elucidation of different levels of action of steroids and antisteroids.},
	number = {3-8},
	journal = {The Journal of Steroid Biochemistry and Molecular Biology},
	author = {Veldscholte, J and Berrevoets, C A and {Ris-Stalpers}, C and Kuiper, G G and Jenster, G and Trapman, J and Brinkmann, A O and Mulder, E},
	month = mar,
	year = {1992},
	note = {{PMID:} 1562539},
	keywords = {Binding Sites, Cell Division, Chloramphenicol {O-Acetyltransferase}, Estrogen Antagonists, {HeLa} Cells, Hormones, Humans, Male, Mutation, Prostatic Neoplasms, Receptors, Androgen, Steroids, Transfection},
	pages = {665--669}
},

@article{zhao_two_1999,
	title = {Two mutations identified in the androgen receptor of the new human prostate cancer cell line {MDA} {PCa} 2a},
	volume = {162},
	issn = {0022-5347},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/10569618},
	abstract = {{PURPOSE}

We have characterized the androgen receptor {(AR)} in a new human prostate cancer cell line, {MDA} {PCa} 2a, that has recently been established from a bone metastasis of a patient whose cancer exhibited androgen-independent growth.


{MATERIALS} {AND} {METHODS}

Androgen responsiveness of these cells was assessed by measuring the effect of {DHT} and R1881 on cell growth and {PSA} secretion. Scatchard analysis was used to characterize the affinity and abundance of {AR} protein. Using a {PCR} based strategy, genomic {DNA} of the entire coding region of {AR} gene was sequenced to identify possible mutations.


{RESULTS}

These cells express abundant {AR} {(Nmax} = 685 +/- 149 fmol./mg. protein), but the {AR} binding affinity {(Kd)} for {DHT} is only 25 {nM}, approximately 50-fold lower affinity than the mutated {AR} in {LNCaP} prostate cancer cells {(Kd} = 0.5 {nM)} or the wildtype {AR} in {MCF-7} breast cancer cells {(Kd} = 0.4 {nM).} Two mutations, {L701H} and {T877A}, were identified in the ligand binding domain of the {AR} gene. Compared with {LNCaP} cells, the new cell line is significantly less responsive to {DHT} and R1881 as well as to other androgens such as testosterone, androstenedione, and {DHEA.} Similar to {LNCaP} cells, the ligand specificity of the {AR} in {MDA} {PCa} 2a cells appears to be relaxed and non-androgens such as progesterone and estradiol act as agonists although with less potency than in {LNCaP} cells. Interestingly, in the absence of androgens, the new cell line expresses 15-fold higher baseline levels of {PSA} than {LNCaP.}


{CONCLUSIONS}

Two mutations were identified in the {AR} gene of the {MDA} {PCa} 2a cell line that are likely responsible for the decreased androgen sensitivity and altered ligand specificity observed in these cells. Thus, this new cell line with partial androgen responsiveness and {PSA} expression can serve as a functionally relevant model system of bone metastatic prostate cancer, and can be used to investigate the role of {AR} mutations in prostate cancer and its progression to androgen independence.},
	number = {6},
	journal = {The Journal of Urology},
	author = {Zhao, X Y and Boyle, B and Krishnan, A V and Navone, N M and Peehl, D M and Feldman, D},
	month = dec,
	year = {1999},
	note = {{PMID:} 10569618},
	keywords = {Cell Division, Humans, Male, Mutation, {Prostate-Specific} Antigen, Prostatic Neoplasms, Receptors, Androgen, Tumor Cells, Cultured},
	pages = {2192--2199}
}

@article{narayan_role_2003,
	title = {Role of {APC} and {DNA} mismatch repair genes in the development of colorectal cancers},
	volume = {2},
	issn = {1476-4598},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/14672538},
	doi = {10.1186/1476-4598-2-41},
	abstract = {Colorectal cancer is the third most common cause of cancer-related death in both men and women in the western hemisphere. According to the American Cancer Society, an estimated 105,500 new cases of colon cancer with 57,100 deaths will occur in the {U.S.} in 2003, accounting for about 10\% of cancer deaths. Among the colon cancer patients, hereditary risk contributes approximately 20\%. The main inherited colorectal cancers are the familial adenomatous polyposis {(FAP)} and the hereditary nonpolyposis colorectal cancers {(HNPCC).} The {FAP} and {HNPCC} are caused due to mutations in the adenomatous polyposis coli {(APC)} and {DNA} mismatch repair {(MMR)} genes. The focus of this review is to summarize the functions of {APC} and {MMR} gene products in the development of colorectal cancers.},
	journal = {Molecular Cancer},
	author = {Narayan, Satya and Roy, Deodutta},
	month = dec,
	year = {2003},
	note = {{PMID:} 14672538},
	keywords = {Adenomatous Polyposis Coli Protein, Base Pair Mismatch, Colorectal Neoplasms, Disease Progression, {DNA} Repair, Humans},
	pages = {41}
}

@article{luechtenborg_apc_2004,
	title = {{APC} mutations in sporadic colorectal carcinomas from The Netherlands Cohort Study},
	volume = {25},
	issn = {0143-3334},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/14976131},
	doi = {10.1093/carcin/bgh117},
	abstract = {The adenomatous polyposis coli {(APC)} gene is considered to be a gatekeeper in colorectal tumourigenesis. Inactivating mutations in {APC} have been reported in 34-70\% of sporadic colorectal cancer patients, the majority of which occur in the mutation cluster region {(MCR).} In this study, tumour tissue from 665 incident colorectal cancer patients, who originate from 120 852 men and women (55-69 years of age at baseline) participating in The Netherlands Cohort Study, was evaluated for the occurrence and type of {APC} mutations with regard to age at diagnosis, gender, family history of colorectal cancer, Dukes' stage, tumour differentiation and sub-localization. Mutation analysis of the {MCR}, which spans codons 1286-1513, was performed on archival adenocarcinoma samples using macrodissection, nested {PCR} and direct sequencing of purified {PCR} fragments. A large number of genetic aberrations (n = 978), including point mutations (n = 833), deletions (n = 126) and insertions (n = 19) was detected in the {MCR} in 72\% of patients (479/665). In particular, we observed a large number of missense mutations, more than reported previously. This may indicate involvement in colorectal carcinogenesis, although their significance for {APC} functions is unclear. Truncating mutations were found in 37\% of patients (248/665). Patients with rectosigmoid and rectum tumours relatively more frequently harboured C {\textgreater} T nonsense mutations and truncating frameshift mutations as compared with patients with proximal and distal colon tumours {(P} = 0.009 and P = 0.045, respectively). Differences in occurrence of truncating mutations with regard to tumour sub-localization suggest a different aetiology of tumourigenesis in colon and rectum.},
	number = {7},
	journal = {Carcinogenesis},
	author = {LÃ¼chtenborg, Margreet and Weijenberg, Matty P and Roemen, Guido M J M and de BruÃ¯ne, Adriaan P and van den Brandt, Piet A and Lentjes, Marjolein H F M and Brink, Mirian and van Engeland, Manon and Goldbohm, R Alexandra and de Goeij, Anton F P M},
	month = jul,
	year = {2004},
	note = {{PMID:} 14976131},
	keywords = {Adenomatous Polyposis Coli Protein, Aged, Amino Acid Sequence, Base Sequence, Carcinoma, Colorectal Neoplasms, Female, Frameshift Mutation, Humans, Male, Middle Aged, Sequence Deletion},
	pages = {1219--1226}
}

@article{forbes_catalogue_2008,
	title = {The Catalogue of Somatic Mutations in Cancer {(COSMIC)}},
	volume = {Chapter 10},
	issn = {1934-8258},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/18428421},
	doi = {10.1002/0471142905.hg1011s57},
	abstract = {{COSMIC} is currently the most comprehensive global resource for information on somatic mutations in human cancer, combining curation of the scientific literature with tumor resequencing data from the Cancer Genome Project at the Sanger Institute, {U.K.} Almost 4800 genes and 250000 tumors have been examined, resulting in over 50000 mutations available for investigation. This information can be accessed in a number of ways, the most convenient being the Web-based system which allows detailed data mining, presenting the results in easily interpretable formats. This unit describes the graphical system in detail, elaborating an example walkthrough and the many ways that the resulting information can be thoroughly investigated by combining data, respecializing the query, or viewing the results in different ways. Alternate protocols overview the available precompiled data files available for download.},
	journal = {Current Protocols in Human Genetics / Editorial Board, Jonathan L. Haines ... [et Al.]},
	author = {Forbes, S A and Bhamra, G and Bamford, S and Dawson, E and Kok, C and Clements, J and Menzies, A and Teague, J W and Futreal, P A and Stratton, M R},
	month = apr,
	year = {2008},
	note = {{PMID:} 18428421},
	keywords = {Catalogs as Topic, Computer Graphics, Databases, Genetic, Genetics, Medical, Humans, Internet, Mutation, Neoplasms, Oncogenes, Phenotype},
	pages = {Unit 10.11}
}


@article{durbin_map_2010,
	title = {A map of human genome variation from population-scale sequencing},
	volume = {467},
	issn = {0028-0836, 1476-4687},
	url = {http://www.nature.com/doifinder/10.1038/nature09534},
	doi = {10.1038/nature09534},
	number = {7319},
	journal = {Nature},
	author = {Durbin, Richard M. and Altshuler, David L. and Durbin, Richard M. and others},
	month = oct,
	year = {2010},
	pages = {1061--1073}
}

@article{suzuki_three-dimensional_2004,
	title = {{Three-Dimensional} Window Analysis for Detecting Positive Selection at Structural Regions of Proteins},
	volume = {21},
	issn = {0737-4038, 1537-1719},
	url = {http://mbe.oupjournals.org/cgi/doi/10.1093/molbev/msh249},
	doi = {10.1093/molbev/msh249},
	number = {12},
	journal = {Molecular Biology and Evolution},
	author = {Suzuki, Y.},
	month = aug,
	year = {2004},
	pages = {2352--2359}
}


@article{suzuki_method_1999,
	title = {A method for detecting positive selection at single amino acid sites},
	volume = {16},
	issn = {0737-4038},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/10563013},
	abstract = {A method was developed for detecting the selective force at single amino acid sites given a multiple alignment of protein-coding sequences. The phylogenetic tree was reconstructed using the number of synonymous substitutions. Then, the neutrality was tested for each codon site using the numbers of synonymous and nonsynonymous changes throughout the phylogenetic tree. Computer simulation showed that this method accurately estimated the numbers of synonymous and nonsynonymous substitutions per site, as long as the substitution number on each branch was relatively small. The false-positive rate for detecting the selective force was generally low. On the other hand, the true-positive rate for detecting the selective force depended on the parameter values. Within the range of parameter values used in the simulation, the true-positive rate increased as the strength of the selective force and the total branch length (namely the total number of synonymous substitutions per site) in the phylogenetic tree increased. In particular, with the relative rate of nonsynonymous substitutions to synonymous substitutions being 5.0, most of the positively selected codon sites were correctly detected when the total branch length in the phylogenetic tree was {\textgreater} or = 2.5. When this method was applied to the human leukocyte antigen {(HLA)} gene, which included antigen recognition sites {(ARSs)}, positive selection was detected mainly on {ARSs.} This finding confirmed the effectiveness of the present method with actual data. Moreover, two amino acid sites were newly identified as positively selected in {non-ARSs.} The three-dimensional structure of the {HLA} molecule indicated that these sites might be involved in antigen recognition. Positively selected amino acid sites were also identified in the envelope protein of human immunodeficiency virus and the influenza virus hemagglutinin protein. This method may be helpful for predicting functions of amino acid sites in proteins, especially in the present situation, in which sequence data are accumulating at an enormous speed.},
	number = {10},
	journal = {Molecular Biology and Evolution},
	author = {Suzuki, Y and Gojobori, T},
	month = oct,
	year = {1999},
	note = {{PMID:} 10563013},
	keywords = {Amino Acid Substitution, Amino Acids, Animals, Codon, Computer Simulation, Evolution, Molecular, Hemagglutinin Glycoproteins, Influenza Virus, {HIV} Envelope Protein gp120, {HLA} Antigens, Humans, Models, Genetic, Phylogeny, Protein Conformation, Selection, Genetic},
	pages = {1315--1328}
}

@article{suzuki_new_2004,
	title = {New Methods for Detecting Positive Selection at Single Amino Acid Sites},
	volume = {59},
	issn = {0022-2844, 1432-1432},
	url = {http://springerlink.metapress.com/openurl.asp?genre=article&id=doi:10.1007/s00239-004-2599-6},
	doi = {10.1007/s00239-004-2599-6},
	number = {1},
	journal = {Journal of Molecular Evolution},
	author = {Suzuki, Yoshiyuki},
	month = jul,
	year = {2004}
}

@article{yang_codon-substitution_2000,
	title = {Codon-substitution models for heterogeneous selection pressure at amino acid sites},
	volume = {155},
	issn = {0016-6731},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/10790415},
	abstract = {Comparison of relative fixation rates of synonymous (silent) and nonsynonymous (amino acid-altering) mutations provides a means for understanding the mechanisms of molecular sequence evolution. The nonsynonymous/synonymous rate ratio (omega = {d(N)d(S))} is an important indicator of selective pressure at the protein level, with omega = 1 meaning neutral mutations, omega {\textless} 1 purifying selection, and omega {\textgreater} 1 diversifying positive selection. Amino acid sites in a protein are expected to be under different selective pressures and have different underlying omega ratios. We develop models that account for heterogeneous omega ratios among amino acid sites and apply them to phylogenetic analyses of protein-coding {DNA} sequences. These models are useful for testing for adaptive molecular evolution and identifying amino acid sites under diversifying selection. Ten data sets of genes from nuclear, mitochondrial, and viral genomes are analyzed to estimate the distributions of omega among sites. In all data sets analyzed, the selective pressure indicated by the omega ratio is found to be highly heterogeneous among sites. Previously unsuspected Darwinian selection is detected in several genes in which the average omega ratio across sites is {\textless}1, but in which some sites are clearly under diversifying selection with omega {\textgreater} 1. Genes undergoing positive selection include the beta-globin gene from vertebrates, mitochondrial protein-coding genes from hominoids, the hemagglutinin {(HA)} gene from human influenza virus A, and {HIV-1} env, vif, and pol genes. Tests for the presence of positively selected sites and their subsequent identification appear quite robust to the specific distributional form assumed for omega and can be achieved using any of several models we implement. However, we encountered difficulties in estimating the precise distribution of omega among sites from real data sets.},
	number = {1},
	journal = {Genetics},
	author = {Yang, Z and Nielsen, R and Goldman, N and Pedersen, A M},
	month = may,
	year = {2000},
	note = {{PMID:} 10790415},
	keywords = {Amino Acid Substitution, Amino Acids, Animals, Codon, Drosophila, Gene Products, vif, Genes, pol, Globins, Hemagglutinin Glycoproteins, Influenza Virus, {HIV} Envelope Protein gp120, Humans, Membrane Glycoproteins, Mitochondria, Models, Genetic, Peptide Fragments, Selection, Genetic, Vertebrates, Viral Envelope Proteins, Viral Nonstructural Proteins},
	pages = {431--449}
}

@article{berglund_tertiary_2005,
	title = {Tertiary Windowing to Detect Positive Diversifying Selection},
	volume = {60},
	issn = {0022-2844, 1432-1432},
	url = {http://www.springerlink.com/index/10.1007/s00239-004-0223-4},
	doi = {10.1007/s00239-004-0223-4},
	number = {4},
	journal = {Journal of Molecular Evolution},
	author = {Berglund, {Ann-Charlotte} and Wallner, BjÃ¶rn and Elofsson, Arne and Liberles, David A.},
	month = apr,
	year = {2005},
	pages = {499--504}
}

@article{canutescu_graph-theory_2003,
	title = {A graph-theory algorithm for rapid protein side-chain prediction},
	volume = {12},
	issn = {09618368, {1469896X}},
	url = {http://doi.wiley.com/10.1110/ps.03154503},
	doi = {10.1110/ps.03154503},
	number = {9},
	journal = {Protein Science},
	author = {Canutescu, Adrian A. and Shelenkov, Andrew A. and Dunbrack, Roland L.},
	month = sep,
	year = {2003},
	pages = {2001--2014}
}


@article{zhang_algorithm_1994,
	title = {An algorithm based on graph theory for the assembly of contigs in physical mapping of {DNA}},
	volume = {10},
	issn = {1367-4803, 1460-2059},
	url = {http://bioinformatics.oxfordjournals.org/cgi/doi/10.1093/bioinformatics/10.3.309},
	doi = {10.1093/bioinformatics/10.3.309},
	number = {3},
	journal = {Bioinformatics},
	author = {Zhang, Peisen and Schon, Eric A. and Fischer, Stuart G. and Cayanis, Eftihia and Weiss, Janie and Kistler, Susan and Bourne, Philip E.},
	year = {1994},
	pages = {309--317}
}


@article{pevzner_eulerian_2001,
	title = {An Eulerian path approach to {DNA} fragment assembly},
	volume = {98},
	issn = {00278424, 10916490},
	url = {http://www.pnas.org/cgi/doi/10.1073/pnas.171285098},
	doi = {10.1073/pnas.171285098},
	number = {17},
	journal = {Proceedings of the National Academy of Sciences},
	author = {Pevzner, P. A.},
	month = aug,
	year = {2001},
	pages = {9748--9753}
}

@article{kras,
title = {Human K-Ras in complex with a GTP analogue},
doi = {10.2210/pdb3gft/pdb},
author = {Tong, Y. and Tempel, W., and Shen, L, and Arrowsmith, C.H, 
and Edwards, A.M. and Sundstrom, M., and Weigelt, J., and Bockharev, A., and Park, H.},
note ={PDB ID:3gft. http://www.rcsb.org/pdb/explore.do?structureId=3GFT.},
url = {http://www.rcsb.org/pdb/explore.do?structureId=3GFT},
month = Mar,
year = {2009},

}

@unpublished{PyMOL,
	note = {PyMOL, The PyMOL Molecular Graphics System, Version 1.3, Schr{\"o}dinger, LLC.},
	Author = {{Schr\"odinger, LLC}},
	Date-Added = {2010-08-19 17:29:55 -0400},
	Date-Modified = {2010-08-19 18:08:54 -0400},
	Month = {August},
	Title = {The {PyMOL} Molecular Graphics System, Version~1.3r1},
	Year = {2010}
}

@article{shepard_stimulus_1957,
	title = {Stimulus and response generalization: A stochastic model relating generalization to distance in psychological space},
	volume = {22},
	issn = {0033-3123, 1860-0980},
	shorttitle = {Stimulus and response generalization},
	url = {http://www.springerlink.com/index/10.1007/BF02288967},
	doi = {10.1007/BF02288967},
	number = {4},
	journal = {Psychometrika},
	author = {Shepard, Roger N.},
	month = dec,
	year = {1957},
	pages = {325--345}
}

@inproceedings{Garey_1974,
 author = {Garey, M. R. and Johnson, D. S. and Stockmeyer, L.},
 title = {Some simplified NP-complete problems},
 booktitle = {Proceedings of the sixth annual ACM symposium on Theory of computing},
 series = {STOC '74},
 year = {1974},
 location = {Seattle, Washington, United States},
 pages = {47--63},
 numpages = {17},
 url = {http://doi.acm.org/10.1145/800119.803884},
 doi = {http://doi.acm.org/10.1145/800119.803884},
 acmid = {803884},
 publisher = {ACM},
 address = {New York, NY, USA},
} 

@book{zelterman_models_2006,
	address = {Oxford; New York},
	title = {Models for discrete data},
	isbn = {0198567014 9780198567011},
	publisher = {Oxford University Press},
	author = {Zelterman, Daniel},
	year = {2006}
}

@book{lehmann_theory_1998,
	address = {New York},
	edition = {2nd},
	title = {Theory of point estimation},
	isbn = {0387985026 9780387985022},
	publisher = {Springer},
	author = {Lehmann, E. L and Casella, George},
	year = {1998}
}

@article{Breslow_1981,
     jstor_articletype = {research-article},
     title = {Odds Ratio Estimators When the Data are Sparse},
     author = {Breslow, Norman},
     journal = {Biometrika},
     jstor_issuetitle = {},
     volume = {68},
     number = {1},
     jstor_formatteddate = {Apr., 1981},
     pages = {pp. 73-84},
     url = {http://www.jstor.org/stable/2335807},
     ISSN = {00063444},
     abstract = {The properties of four commonly used estimators of the odds ratio are studied under a large-sample scheme in which the number of 2 × 2 tables increases but the possible marginal configurations remain fixed. Neither the unconditional maximum likelihood nor the empirical logit estimators converge to the true odds ratio; their asymptotic bias is computed for certain special cases of interest. The conditional maximum likelihood and Mantel-Haenszel estimators, which are consistent, have asymptotic variances whose ratio tends to one under the null hypothesis. Even for moderately large odds ratios the simple Mantel-Haenszel estimator maintains remarkably good efficiency.},
     language = {English},
     year = {1981},
     publisher = {Biometrika Trust},
     copyright = {Copyright © 1981 Biometrika Trust},
    }

    @article{Breslow_1982,
     jstor_articletype = {research-article},
     title = {The Variance of the Mantel-Haenszel Estimator},
     author = {Breslow, N. E. and Liang, K. Y.},
     journal = {Biometrics},
     jstor_issuetitle = {},
     volume = {38},
     number = {4},
     jstor_formatteddate = {Dec., 1982},
     pages = {pp. 943-952},
     url = {http://www.jstor.org/stable/2529874},
     ISSN = {0006341X},
     abstract = {Four variances for the logarithm of the Mantel-Haenszel estimator of the common odds ratio in a series of 2 X 2 tables are studied by means of Monte Carlo experiments. One variance is appropriate when the sample sizes in each table are large, while another is derived with the assumption that the number of tables increases. Neither is adequate when the underlying assumptions are violated. However, a weighted average of the two, as well as a jackknife variance, perform well and lead to reasonably accurate tests and confidence intervals over a range of different sampling schemes. Inferences based on the empirical logit estimator are shown to be distorted in comparison, due to bias when the true odds ratio departs from unity.},
     language = {English},
     year = {1982},
     publisher = {International Biometric Society},
     copyright = {Copyright © 1982 International Biometric Society},
    }

    @article{lowess_1988,
     jstor_articletype = {research-article},
     title = {Locally Weighted Regression: An Approach to Regression Analysis by Local Fitting},
     author = {Cleveland, William S. and Devlin, Susan J.},
     journal = {Journal of the American Statistical Association},
     jstor_issuetitle = {},
     volume = {83},
     number = {403},
     jstor_formatteddate = {Sep., 1988},
     pages = {pp. 596-610},
     url = {http://www.jstor.org/stable/2289282},
     ISSN = {01621459},
     abstract = {Locally weighted regression, or loess, is a way of estimating a regression surface through a multivariate smoothing procedure, fitting a function of the independent variables locally and in a moving fashion analogous to how a moving average is computed for a time series. With local fitting we can estimate a much wider class of regression surfaces than with the usual classes of parametric functions, such as polynomials. The goal of this article is to show, through applications, how loess can be used for three purposes: data exploration, diagnostic checking of parametric models, and providing a nonparametric regression surface. Along the way, the following methodology is introduced: (a) a multivariate smoothing procedure that is an extension of univariate locally weighted regression; (b) statistical procedures that are analogous to those used in the least-squares fitting of parametric functions; (c) several graphical methods that are useful tools for understanding loess estimates and checking the assumptions on which the estimation procedure is based; and (d) the M plot, an adaptation of Mallow's C<sub>p</sub> procedure, which provides a graphical portrayal of the trade-off between variance and bias, and which can be used to choose the amount of smoothing.},
     language = {English},
     year = {1988},
     publisher = {American Statistical Association},
     copyright = {Copyright © 1988 American Statistical Association},
    }

@book{hastie_generalized_1991,
	address = {London},
	title = {Generalized additive models},
	isbn = {0412343908 9780412343902},
	publisher = {Chapman \& Hall},
	author = {Hastie, T. J and Tibshirani, R. J},
	year = {1991}
}

@article{cleveland_robust_1979,
	title = {Robust Locally Weighted Regression and Smoothing Scatterplots},
	volume = {74},
	issn = {01621459},
	url = {http://www.jstor.org/stable/2286407?origin=crossref},
	doi = {10.2307/2286407},
	number = {368},
	journal = {Journal of the American Statistical Association},
	author = {Cleveland, William S.},
	month = dec,
	year = {1979},
	pages = {829}
}

@book{hastie_elements_2001,
	address = {New York},
	title = {The elements of statistical learning : data mining, inference, and prediction : with 200 full-color illustrations},
	isbn = {0387952845 9780387952840},
	shorttitle = {The elements of statistical learning},
	publisher = {Springer},
	author = {Hastie, Trevor and Tibshirani, Robert and Friedman, J. H},
	year = {2001}
}

@article{yue_inferring_2010,
	title = {Inferring the functional effects of mutation through clusters of mutations in homologous proteins},
	volume = {31},
	issn = {10597794, 10981004},
	url = {http://doi.wiley.com/10.1002/humu.21194},
	doi = {10.1002/humu.21194},
	number = {3},
	journal = {Human Mutation},
	author = {Yue, Peng and Forrest, William F. and Kaminker, Joshua S. and Lohr, Scott and Zhang, Zemin and Cavet, Guy},
	month = mar,
	year = {2010},
	pages = {264--271}
}

@book{graur_fundamentals_2000,
	address = {Sunderland, Mass.},
	title = {Fundamentals of molecular evolution},
	isbn = {0878932666 9780878932665},
	publisher = {Sinauer Associates},
	author = {Graur, Dan and Li, {Wen-Hsiung}},
	year = {2000}
}

@article{bardelli_mutational_2003,
	title = {Mutational analysis of the tyrosine kinome in colorectal cancers},
	volume = {300},
	issn = {1095-9203},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/12738854},
	doi = {10.1126/science.1082596},
	number = {5621},
	journal = {Science {(New} York, {N.Y.)}},
	author = {Bardelli, Alberto and Parsons, D Williams and Silliman, Natalie and Ptak, Janine and Szabo, Steve and Saha, Saurabh and Markowitz, Sanford and Willson, James K V and Parmigiani, Giovanni and Kinzler, Kenneth W and Vogelstein, Bert and Velculescu, Victor E},
	month = may,
	year = {2003},
	note = {{PMID:} 12738854},
	keywords = {Amino Acid Sequence, Colorectal Neoplasms, Computational Biology, {DNA} Mutational Analysis, Exons, Fusion Proteins, gag-onc, Guanylate Cyclase, Humans, Molecular Sequence Data, Mutation, Polymerase Chain Reaction, Protein Structure, Tertiary, {Protein-Tyrosine} Kinases, Receptor, {EphA3}, Receptor, {trkB}, Receptor, {trkC}, Sequence Analysis, {DNA}, Vascular Endothelial Growth Factor Receptor-2},
	pages = {949}
}


@article{torkamani_prediction_2008,
	title = {Prediction of cancer driver mutations in protein kinases},
	volume = {68},
	issn = {1538-7445},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/18339846},
	doi = {10.1158/0008-5472.CAN-07-5283},
	abstract = {A large number of somatic mutations accumulate during the process of tumorigenesis. A subset of these mutations contribute to tumor progression (known as "driver" mutations) whereas the majority of these mutations are effectively neutral (known as "passenger" mutations). The ability to differentiate between drivers and passengers will be critical to the success of upcoming large-scale cancer {DNA} resequencing projects. Here we show a method capable of discriminating between drivers and passengers in the most frequently cancer-associated protein family, protein kinases. We apply this method to multiple cancer data sets, validating its accuracy by showing that it is capable of identifying known drivers, has excellent agreement with previous statistical estimates of the frequency of drivers, and provides strong evidence that predicted drivers are under positive selection by various sequence and structural analyses. Furthermore, we identify particular positions in protein kinases that seem to play a role in oncogenesis. Finally, we provide a ranked list of candidate driver mutations.},
	number = {6},
	journal = {Cancer Research},
	author = {Torkamani, Ali and Schork, Nicholas J},
	month = mar,
	year = {2008},
	note = {{PMID:} 18339846},
	keywords = {Cell Line, Tumor, Cell Transformation, Neoplastic, Humans, Models, Genetic, Models, Molecular, Mutation, Neoplasms, Polymorphism, Single Nucleotide, Protein Kinases},
	pages = {1675--1682}
}

@article{greenman_patterns_2007,
	title = {Patterns of somatic mutation in human cancer genomes},
	volume = {446},
	issn = {0028-0836, 1476-4687},
	url = {http://www.nature.com/doifinder/10.1038/nature05610},
	doi = {10.1038/nature05610},
	number = {7132},
	journal = {Nature},
	author = {Greenman, Christopher and Stephens, Philip and Smith, Raffaella and Dalgliesh, Gillian L. and Hunter, Christopher and Bignell, Graham and Davies, Helen and Teague, Jon and Butler, Adam and Stevens, Claire and Edkins, Sarah and {O’Meara}, Sarah and Vastrik, Imre and Schmidt, Esther E. and Avis, Tim and Barthorpe, Syd and Bhamra, Gurpreet and Buck, Gemma and Choudhury, Bhudipa and Clements, Jody and Cole, Jennifer and Dicks, Ed and Forbes, Simon and Gray, Kris and Halliday, Kelly and Harrison, Rachel and Hills, Katy and Hinton, Jon and Jenkinson, Andy and Jones, David and Menzies, Andy and Mironenko, Tatiana and Perry, Janet and Raine, Keiran and Richardson, Dave and Shepherd, Rebecca and Small, Alexandra and Tofts, Calli and Varian, Jennifer and Webb, Tony and West, Sofie and Widaa, Sara and Yates, Andy and Cahill, Daniel P. and Louis, David N. and Goldstraw, Peter and Nicholson, Andrew G. and Brasseur, Francis and Looijenga, Leendert and Weber, Barbara L. and Chiew, {Yoke-Eng} and {deFazio}, Anna and Greaves, Mel F. and Green, Anthony R. and Campbell, Peter and Birney, Ewan and Easton, Douglas F. and {Chenevix-Trench}, Georgia and Tan, {Min-Han} and Khoo, Sok Kean and Teh, Bin Tean and Yuen, Siu Tsan and Leung, Suet Yi and Wooster, Richard and Futreal, P. Andrew and Stratton, Michael R.},
	month = mar,
	year = {2007},
	pages = {153--158}
}

@misc{pi3k,
	title = {{PI3K} - Source {BioScience} Healthcare},
	url = {http://healthcare.sourcebioscience.com/diagnostic-tests/pi3k},
	howpublished = {http://healthcare.sourcebioscience.com/diagnostic-tests/pi3k}
}

@article{cully_beyond_2006,
	title = {Beyond {PTEN} mutations: the {PI3K} pathway as an integrator of multiple inputs during tumorigenesis},
	volume = {6},
	issn = {{1474-175X}, 1474-1768},
	shorttitle = {Beyond {PTEN} mutations},
	url = {http://www.nature.com/doifinder/10.1038/nrc1819},
	doi = {10.1038/nrc1819},
	number = {3},
	journal = {Nature Reviews Cancer},
	author = {Cully, Megan and You, Han and Levine, Arnold J. and Mak, Tak W.},
	month = feb,
	year = {2006},
	pages = {184--192}
}

@article{croce_oncogenes_2008,
	title = {Oncogenes and cancer},
	volume = {358},
	issn = {1533-4406},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/18234754},
	doi = {10.1056/NEJMra072367},
	number = {5},
	journal = {The New England Journal of Medicine},
	author = {Croce, Carlo M},
	month = jan,
	year = {2008},
	note = {{PMID:} 18234754},
	keywords = {Animals, Cell Transformation, Neoplastic, Gene Amplification, Gene Expression Regulation, Humans, {MicroRNAs}, Mutation, Neoplasms, Oncogenes},
	pages = {502--511}
}

  
@Article{igraph,
    title = {The igraph software package for complex network research},
    author = {Gabor Csardi and Tamas Nepusz},
    journal = {InterJournal},
    volume = {Complex Systems},
    pages = {1695},
    year = {2006},
    url = {http://igraph.sf.net},
}

@Manual{TSP,
    title = {Traveling Salesperson Problem (TSP)},
    author = {Michael Hahsler and Kurt Hornik},
    year = {2011},
    note = {R package version 1.0-7},
}
 
@Manual{RMallow,
    title = {RMallow: Fit Multi-Modal Mallows' Models to ranking data.},
    author = {Erik Gregory},
    year = {2012},
    note = {R package version 1.0},
    url = {http://CRAN.R-project.org/package=RMallow},
  }
  
@article{KendallTau,
author = {Kendall, M. G.}, 
title = {A New Measure of Rank Correlation},
volume = {30}, 
number = {1-2}, 
pages = {81-93}, 
year = {1938}, 
doi = {10.1093/biomet/30.1-2.81}, 
URL = {http://biomet.oxfordjournals.org/content/30/1-2/81.short}, 
eprint = {http://biomet.oxfordjournals.org/content/30/1-2/81.full.pdf+html}, 
journal = {Biometrika} 
}
