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Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency

Title
Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency
Author
공구
Keywords
NONPOLYPOSIS COLORECTAL-CANCER; PD-1 BLOCKADE; COLON-CANCER; MICROSATELLITE INSTABILITY; MUTATIONAL PROCESSES; SIGNATURES; HOMOLOG; GENE; LANDSCAPE; TUMORS
Issue Date
2017-09
Publisher
AMER ASSOC CANCER RESEARCH
Citation
CANCER RESEARCH, v. 77, no. 18, page. 4755-4762
Abstract
Mismatch repair (MMR)-deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients. We identified 11 of 640 tumors as MMR deficient, but only 2 of 11 exhibited germline mutations in MMR genes or Lynch Syndrome. Two additional tumors had a substantially reduced proportion of mutations attributed to MMR deficiency, where the predominant mutational signatures were related to APOBEC enzymatic activity. Overall, 6 of 11 of the MMR-deficient cases in this cohort were confirmed genetically or epigenetically as having abrogation of MMR genes. However, IHC analysis of MMR-related proteins revealed all but one of 10 samples available for testing as MMR deficient. Thus, the mutational signatures more faithfully reported MMR deficiency than sequencing of MMR genes, because they represent a direct pathophysiologic readout of repair pathway abnormalities. As whole-genome sequencing continues to become more affordable, it could be used to expose individually abnormal tumors in tissue types where MMR deficiency has been rarely detected, but also rarely sought. (C) 2017 AACR.
URI
http://cancerres.aacrjournals.org/content/77/18/4755https://repository.hanyang.ac.kr/handle/20.500.11754/115521
ISSN
0008-5472; 1538-7445
DOI
10.1158/0008-5472.CAN-17-1083
Appears in Collections:
COLLEGE OF MEDICINE[S](의과대학) > MEDICINE(의학과) > Articles
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