Abstract PS8-18: Describing the cancer spectrum in families with CHEK2 pathogenic and likely pathogenic variants by mutation type

Abstract

Abstract Background: Deleterious CHEK2 variants have well-defined risks for breast and colorectal cancers. Some studies have also suggested association with a variety of other cancers, including leukemia, kidney, prostate, thyroid and gastric cancers. However, most CHEK2 studies are based on European founder mutations, and there is a lack of data on non-founder mutations. Here, we describe the cancer family histories of patients with both founder and non-founder CHEK2 mutations. Methods: This is a retrospective review of patients who underwent germline testing of 31 cancer risk genes. All pathogenic (P) and likely pathogenic (LP) variants in CHEK2 were selected from our database and categorized as founder or non-founder mutations. Personal and family histories of cancer reported by the ordering provider were recorded for each case. Cancer rates were calculated as the number of patients with a personal and/or family history of each cancer divided by the total number of patients. Ethnicities in our CHEK2+ cohort and our overall database were calculated as a percentage. Results: A total of 132 patients were found to have P/LP variants in CHEK2. This CHEK2+ cohort was largely Caucasian (79.5%), despite our overall database being ethnically diverse (56% Caucasian). Nineteen different mutations were identified, 75% of which were founder and 25% were non-founder mutations. Personal histories of cancer were identified in 7% of patients. Twenty-eight different cancers were reported in patients’ personal/family histories. The rates of select cancers in the total cohort, founder mutation group and non-founder mutation group are reported in Table 1. Discussion: These findings support previous reports that prostate, gastric and kidney cancers may be part of the CHEK2 cancer spectrum, which has typically only included breast and colorectal cancer. We also identify ovarian and pancreatic cancer as potential CHEK2-associated cancers. Cancer rates are similar between CHEK2 patients with founder and non-founder mutations. Differences in cancer rates were observed between these two groups, but this cohort was too small to determine significance. Additional studies are needed to understand the overlap of cancer risk with non-founder mutations and those well-described for founder mutations. Table 1: Select cancer rates by CHEK2 mutation typeBreast FemaleOvarianProstateColorectalPancreaticUterineGastricKidneyAll80.3%39.4%25%23.5%13.6%8.3%8.3%6.1%Founder81.8%40.4%30.3%23.2%18.2%9.1%9.1%8.1%Non-founder75.8%36.3%9.1%24.2%0%6%6%0% Citation Format: Julia G Moroney, Michele S Basiliere. Describing the cancer spectrum in families with CHEK2 pathogenic and likely pathogenic variants by mutation type [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-18.