Synapse - The landscape of somatic genetic alterations in breast cancers from CHEK2 germline mutation carriers

The landscape of somatic genetic alterations in breast cancers from CHEK2 germline mutation carriers Journal Article

Authors:	Mandelker, D.; Kumar, R.; Pei, X.; Selenica, P.; Setton, J.; Arunachalam, S.; Ceyhan-Birsoy, O.; Brown, D. N.; Norton, L.; Robson, M. E.; Wen, H. Y.; Powell, S.; Riaz, N.; Weigelt, B.; Reis-Filho, J. S.
Article Title:	The landscape of somatic genetic alterations in breast cancers from CHEK2 germline mutation carriers
Abstract:	Pathogenic germline variants in checkpoint kinase 2 (CHEK2), which plays pivotal roles in DNA damage response and cell cycle regulation, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic and genomic characteristics of 33 BCs from CHEK2 germline mutation carriers (16 high-risk variants and 17 low-risk p.Ile157Thr variants). CHEK2-associated BCs from patients with high-risk germline variants were largely hormone receptor-positive (87%, 13/15), and 81% (13/16) exhibited loss of heterozygosity (LOH) of the CHEK2 wild-type allele. Conversely, CHEK2-associated BCs from patients with the low-risk p.Ile157Thr variant displayed less-frequent loss of heterozygosity (5/17, 29%) and higher levels of CHEK2 protein expression than those with high-risk germline variants. CHEK2-associated BCs lacked a dominant mutational signature 3, a genomics feature of homologous recombination DNA repair deficiency (HRD). Our findings indicate that CHEK2-associated BCs are generally hormone receptor-positive and lack HRD-related mutational signatures, recapitulating the features of ATM-associated BCs. Specific CHEK2 germline variants may have a distinct impact on tumor biology.
Keywords:	risk; tumor; susceptibility; variant; i157t
Journal Title:	JNCI Cancer Spectrum
Volume:	3
Issue:	2
ISSN:	2515-5091
Publisher:	Oxford University Press
Date Published:	2019-06-01
Start Page:	pkz027
Language:	English
ACCESSION:	WOS:000493383200002
DOI:	10.1093/jncics/pkz027
PROVIDER:	wos
PMCID:	PMC6649818
PUBMED:	31360903
Notes:	Source: Wos