Abstract P5-09-09: CHEK2: the third susceptibility BReast CAncer (BC) gene?

Abstract

Abstract INTRODUTION: Considered a medium penetrance gene, CHEK2 codes for a kinase that is a key component of the DNA damage-signaling pathway. CHEK2 pathogenic variants were previously associated with breast and colorectal families and also with Li-Fraumeni phenotypes. Next generation sequencing (NGS) allowed for systematic inclusion of CHEK2 into gene panels. In here, we characterize the growing subgroup of CHECK2 BC families identified through our multidisciplinary program. METHODS: Identification and review of CHEK2 families identified between 01/2000-06/2018 (until 2014 only the c.1100delC was tested (MLPA, MRC Holland); since 2014 NGS methods used were either,Trusight Cancer sequencing panel (Illumina, San Diego, CA, USA) or BRCA MASTR Dx (Multiplicom, Niel, Belgium). Carriers were included in a prospective follow up program. RESULTS: 3646 index pts consented on gene testing. Most hereditary families (HF) were BRCA1/2 (374) (92%) but among non-BRCA HF bigger subgroups were 16 CHEK2, 10 Tp53 and 5 PALB2 HF. All CHEK2 index pts were diagnosed with only 3 different pathogenic variants: c.1100delC (9) c.319+2T>A (6) and c.593-1G>T (1 case of the only male BC pt in all CHEK2 pedigrees). Index pts: mostly (93,8%) to females, with a mean age at first cancer diagnosis of 39 years (yrs) (30-52), 62,5% between 30-39yrs. With the exception of a Non Hodgking's Lymphoma index case, all index pts had BC(93,8%), 68,8% of which were ductal carcinomas and 12,5% of intraductal, all strongly positive for the estrogen receptor. With a mean follow up of 8,26yrs (3-15), secondary cancer cases occurred in 37,5% of index pts (mostly, 12,5%, BC at a mean of 53yrs (41-59). Family phenotypes: data form 98 relatives (53,5% females) revealed diagnoses of BC (31,6%), prostate (8,1%), colorectal (7,1%) cancers. Only 22,2% of family cancers were diagnosed before 50yrs. VUS: Among several complex variants of unknown significance, c.1036C>T;p.Arg346Cys co-segregates in a predominantly male family with 3 prostate, 1 male and 1 female BC. DISCUSSION AND CONCLUSIONS: In the Portuguese population, emerging recurrent pathogenic variants in the CHEK2 gene, make it the most important non-BRCA BC gene so far. Carriers are included in prospective follow up but non-CHEK2 relatives are a challenge to genetic testing, as well as pedigree review, that questions its classification as a medium penetrance gene (or suggest the role of modifier factors). Citation Format: Gomes VL, Machado P, Fragoso S, Santos S, Coelho I, Parreira J, Rodrigues P, Rodrigues F, Clara A, Bento S, Luís A, Opinião A, Vaz F. CHEK2: the third susceptibility BReast CAncer (BC) gene? [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-09.