My early work, performed in collaboration with my mentor Dr. Matthew Meyerson, included a meta-analysis of approximately 500 human lung adenocarcinoma expression arrays generated by the National Cancer Institute’s Director’s Challenge Program. We successfully reconciled discordant previous reports by demonstrating three reproducible molecular tumor subtypes of lung adenocarcinoma that are otherwise indistinguishable by routine clinical evaluation. The subtypes have statistically significant survival differences, independent of disease stager and are comprised of tumors with differing underlying rates of mutations in key lung cancer genes including KRAS and EGFR. Similar reports for squamous cell carcinoma of the lung are forthcoming, as are reports of clinically applicable diagnostic tests.
a. Hayes DN, Monti S, Parmigiani G, Gilks CB, Naoki Ki, Bhattacharjee A, Socinski MA, Perou C, Meyerson M. (2006). Gene Expression Profiling Reveals Reproducible Human Lung Adenocarcinoma Subtypes in Multiple Independent Patient Cohorts. J Clin Oncol, 24(31), 5079-90. PMID: 17075127.
In collaboration with Kwok Wong, Ned Sharpless, Buddy Weissman, and Ben Major, I have documented the frequent mutation of the gene STK11/LKB1 in human lung cancers, including squamous cell carcinoma and mutations in KEAP1/NRF2 pathway.
a. Ji H, Ramsey MR, Hayes DN, Fan C, McNamara K, Kozlowski P, Torrice C, Wu MC, Shimamura T, Perera SA, Liang MC, Cai D, Naumov GN, Bao L, Contreras CM, Li D, Chen L, Krishnamurthy J, Koivunen J, Chirieac LR, Padera RF, Bronson RT, Lindeman NI, Christiani DC, Lin X, Shapiro GI, Jänne PA, Johnson BE, Meyerson M. Kwiatkowski DJ, Castrillon DH, Bardeesy N, Sharpless NE, Wong KK. (2007). LKB1 Modulates Lung Cancer Differentiation and Metastasis. Nature, 448(7155), 807-10. PMID: 17676035.
b. Carretero J, Shimamura T, Rikova K, Jackson AL, Wilkerson MD, Borgman CL, Buttarazzi MS, Sanofsky BA, McNamara KL, Brandstetter KA, Walton ZE, Gu TL, Silva JC, Crosby K, Shapiro GI, Maira SM, Ji H, Castrillon DH, Kim CF, García-Echeverría C, Bardeesy N, Sharpless NE, Hayes DN, Kim WY, Engelman JA, Wong KK. (2010). Integrative Genomic and Proteomic Analyses Identify Targets for LKB1-Deficient Metastatic Lung Tumors. Cancer Cell, 17(6), 547-59. PMCID: 2901842.
c. Nakada Y, Stewart TG, Peña CG, Zhang S, Zhao N, Bardeesy N, Sharpless NE, Wong KK, Hayes DN, Castrillon DH. (2013). The LKB1 Tumor Suppressor as a Biomarker in Mouse and Human Tissues. PLoS One, 8(9), e73449. PMCID: 3783464.
d. Hast BE, Cloer EW, Goldfarb D, Li H, Siesser PF, Yan F, Walter V, Zheng N, Hayes DN, Major MB. (2014). Cancer-Derived Mutations in KEAP1 Impair NRF2 Degradation but not Ubiquitination. Cancer Res, 74(3), 808-17. PMCID: 3932503.
Progress in two key areas of science has provided the foundation for the work in my group. First, the advent of personal computers along with associated progress in the field of statistical computing greatly accelerated the development of data-rich models of human disease behavior. Second, collaborative efforts across biomedical science have made available the building blocks of normal (i.e. The Human Genome Project) and aberrant genomes (i.e. The Cancer Genome Atlas, TCGA). To leverage the power of computers to assess alterations in the genome associated with cancer, a host of molecular technologies have become commercially available in recent years. The primary targets of these assays have been nucleic acids (DNA and RNA), although a limited number of protein assays are also included. The technologies allow labs such as ours to make broad and inclusive measurements in samples of alterations in gene expression (RNA), gene dosage (DNA amplification and deletions), gene structure (normal population variants, mutations, alternate splices, fusion genes, and epigenetic modifications), protein abundance and other events such as presence of a pathogen. Primary technologies used in my lab include array-based approaches (gene expression arrays, methylation profiling, SNP chips, CGH, miRNA arrays), sequencing (targeted and deep sequencing / “NextGen”), and immunohistochemistry (including tissue microarrays).
a. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O’Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN. (2010). Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell, 17(1), 98-110. PMCID: 2818769.
b. Comprehensive Genomic Characterization of Squamous Cell Lung Cancers. (2012). Nature, 489(7417), 519-25. PMCID: 3466113.
c. Walter V, Yin X, Wilkerson MD, Cabanski CR, Zhao N, Du Y, Ang MK, Hayward MC, Salazar AH, Hoadley KA, Fritchie K, Sailey CJ, Weissler MC, Shockley WW, Zanation AM, Hackman T, Thorne LB, Funkhouser WD, Muldrew KL, Olshan AF, Randell SH, Wright FA, Shores CG, Hayes DN. (2013). Molecular Subtypes in Head and Neck Cancer Exhibit Distinct Patterns of Chromosomal Gain and Loss of Canonical Cancer Genes. PLoS One, 8(2):e56823. PMCID: 3579892.
d. Comprehensive Genomic Characterization of Head and Neck Squamous Cell Carcinomas. (2015). Nature, 517(7536), 576-82. PMCID: 4311405.
