Somatic mutation load of estrogen receptor-positive breast tumors predicts overall survival: an analysis of genome sequence data.
Breast cancer is one of the most commonly diagnosed cancers in women. While there are several effective therapies for breast cancer and important single gene prognostic/predictive markers, more than 40,000 women die from this disease every year. The increasing availability of large-scale genomic datasets provides opportunities for identifying factors that influence breast cancer survival in smaller, well-defined subsets. The purpose of this study was to investigate the genomic landscape of various breast cancer subtypes and its potential associations with clinical outcomes. We used statistical analysis of sequence data generated by the Cancer Genome Atlas initiative including somatic mutation load (SML) analysis, Kaplan-Meier survival curves, gene mutational frequency, and mutational enrichment evaluation to study the genomic landscape of breast cancer. We show that ER(+), but not ER(-), tumors with high SML associate with poor overall survival (HR = 2.02). Further, these high mutation load tumors are enriched for coincident mutations in both DNA damage repair and ER signature genes. While it is known that somatic mutations in specific genes affect breast cancer survival, this study is the first to identify that SML may constitute an important global signature for a subset of ER(+) tumors prone to high mortality. Moreover, although somatic mutations in individual DNA damage genes affect clinical outcome, our results indicate that coincident mutations in DNA damage response and signature ER genes may prove more informative for ER(+) breast cancer survival. Next generation sequencing may prove an essential tool for identifying pathways underlying poor outcomes and for tailoring therapeutic strategies.
Department of Clinical Cancer Prevention, Unit 1360, The University of Texas M.D. Anderson Cancer Center, P.O. Box 301439, Houston, TX, 77030-1439, USA, sharicharan@mdanderson.org.
Svasti
S
Haricharan
Matthew N
MN
Bainbridge
Paul
P
Scheet
Powel H
PH
Brown
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D019295:Computational Biology / Q000379:methods; D004249:DNA Damage; D004260:DNA Repair; D030561:Databases, Nucleic Acid; D005260:Female; D056726:Genetic Association Studies; D023281:Genomics; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D011960:Receptors, Estrogen / Q000235:genetics*; D047368:Tumor Burden
D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen