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Molecular pathology selected abstracts

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Editors: Donna E. Hansel, MD, PhD, chief, Division of Anatomic Pathology, and professor, Department of Pathology, University of California, San Diego; James Solomon, MD, PhD, resident, Department of Pathology, UCSD; Richard Wong, MD, PhD, molecular pathology fellow, Department of Pathology, UCSD; and Sounak Gupta, MBBS, PhD, molecular pathology fellow, Memorial Sloan Kettering Cancer Center, New York.

Evaluation of mutational processes and somatic driver mutations in cancer exomes

February 2019—As next-generation sequencing-based tumor profiling gains popularity, multiple informative variables other than single-gene alterations will continue to be added to clinical reports. Examples of metrics that are being incorporated into such reports are tumor mutational burden and parameters to assess microsatellite instability. Other important parameters include various mutational signatures. In this context, the authors conducted a study in which they evaluated somatic alterations from 7,815 cancer exomes from The Cancer Genome Atlas across 26 cancer types for oncogenic driver alterations and mutational signatures. Driver alterations are thought to confer a selective growth advantage to clonal tumor populations. For instance, a BRAF p.V600E alteration in a cutaneous melanoma is often considered to be a driver alteration when compared with passenger alterations that do not confer a relative selective advantage. In contrast to driver alterations, mutational signatures are rarely clinically reported. The Catalogue of Somatic Mutations in Cancer (COSMIC) database lists at least 30 curated signatures. Common environmental factors associated with specific signatures include smoking (signature four) and exposure to ultraviolet radiation (signature seven). On the other hand, mutations in various enzymes are associated with specific mutational signatures. For instance, deficient mismatch repair is characterized by fewer than 3bp insertions and deletions at mono/polynucleotide repeats (signatures six and 26). Some associations emphasized in this study include polymerase epsilon (POLE) exonuclease domain mutations, which are commonly encountered in a subset of endometrial carcinomas. These POLE proofreading domain mutations lead to hypermutated cancers that respond well to immunotherapeutic agents. For instance, mutations occurring in a T[C>T]G context (signature 10) were causally linked to downstream alterations in multiple oncogenes (PIK3CA p.R88Q) and tumor-suppressor genes (PTEN p.R130Q, ARID1A p.R1989*, and TP53 p.R213*). Similarly, BRAF p.V600E alterations were associated with only somatic (not germline) mismatch repair deficiency in colorectal carcinomas, supporting the hypothesis that this BRAF alteration might promote susceptibility to developing mismatch repair deficiency. Other interesting observations included tumors with isocitrate dehydrogenase 1 (IDH1 p.R132H) alterations that are known to lead to a repressive chromatin landscape secondary to increased methylation. These tumors showed an inverse correlation with signature one, thought to occur secondary to spontaneous deamination of 5-methylcytosine. In summary, this study identified 39 statistically significant associations between driver alterations and mutational signatures from nearly 8,000 tumor samples across 26 cancer types. These findings increase understanding of the mutational pathogenesis of varied tumor types.

Poulos RC, Wong YT, Ryan R, et al. Analysis of 7,815 cancer exomes reveals associations between mutational processes and somatic driver mutations. PLOS Genet. 2018;14(11):e1007779. doi:10.1371/journal.pgen.1007779.

Correspondence: Dr. Jason W. H. Wong at jwhwong@hku.hk

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