Expanded germline genetic testing of patients with hematologic malignancies to identify high proportion with hereditary cancer predisposition.

Abstract

10612 Background: Identifying hereditary cancer predisposition in patients with hematologic malignancies is critical for their clinical management, surveillance, donor selection, family, and reproductive counseling. However, genetic testing for patients with hematologic malignancies has been limited, largely due to the difficulty of obtaining suitable DNA samples for germline analysis. Heme Germline-MSK-IMPACT is a clinically validated assay for germline testing using nail or saliva DNA, depending on the patient’s cancer type, in a non-invasive, rapid, and high-throughput manner, with the matched tumor analysis supporting results interpretation. Methods: Genetic testing was performed on 1300 consecutive patients with a clinical diagnosis or suspicion of a hematologic malignancy on Heme Germline-MSK-IMPACT, targeting 82 hereditary cancer predisposition genes. All individuals receiving somatic testing via paired tumor-normal sequencing on MSK-IMPACT-Heme as part of their clinical care were eligible to consent for germline analysis. Results: Germline pathogenic or likely pathogenic variants (gPVs) in hereditary cancer predisposition genes were identified in 16.7% (217/1300) of patients, with 5.8% (76/1300) having high penetrance autosomal dominant gene variants. gPVs known to be associated with hematologic malignancies were detected in DDX41 (n = 14), POT1 (n = 3), RUNX1 (n = 2), ETV6 (n = 1), TP53 (n = 1). Additionally, four patients had biallelic variants in genes causing autosomal recessive disorders that confer increased risk for hematologic malignancies ( FANCA (n = 2), ATM , MSH6 ). Other high-risk cancer predisposition genes with gPVs identified in multiple patients were BRCA2 (n = 16), BRCA1 (n = 15), MSH6 (n = 4), RTEL1 (n = 4), CDKN2A (n = 3), and PALB2 (n = 3). Moderate penetrance gPVs were detected in 6.2% (81/1300) of patients in genes such as CHEK2 (n = 36), ATM (n = 24), and LZTR1 (n = 8). Twenty-four (1.8%) patients had two or more gPVs identified. Conclusions: Germline testing in a broad cohort of individuals with hematologic malignancies detected hereditary cancer predisposition in a substantial proportion of the patients. This ratio is comparable to the rate of cancer predisposition variants identified in patients with solid tumors in recent studies. Matched tumor data analysis is ongoing to uncover second hits and correlations for improving our understanding of the hereditary contribution to hematologic malignancies.