TY - JOUR
T1 - Whole-genome sequencing reveals breast cancers with mismatch repair deficiency
AU - Davies, Helen
AU - Morganella, Sandro
AU - Purdie, Colin A.
AU - Jang, Se Jin
AU - Borgen, Elin
AU - Russnes, Hege
AU - Glodzik, Dominik
AU - Zou, Xueqing
AU - Viari, Alain
AU - Richardson, Andrea L.
AU - Børresen-Dale, Anne Lise
AU - Thompson, Alastair
AU - Eyfjord, Jorunn E.
AU - Kong, Gu
AU - Stratton, Michael R.
AU - Nik-Zainal, Serena
N1 - Publisher Copyright:
©2017 American Association for Cancer Research.
PY - 2017/9/15
Y1 - 2017/9/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-17-1083
DO - 10.1158/0008-5472.CAN-17-1083
M3 - Article
C2 - 28904067
AN - SCOPUS:85031797398
SN - 0008-5472
VL - 77
SP - 4755
EP - 4762
JO - Cancer Research
JF - Cancer Research
IS - 18
ER -