Abstract P5-03-02: Cancer risks associated with pathogenic variants in the ataxia telangiectasia mutated (ATM) gene

Abstract

Background: Germ-line pathogenic variants (PV) in ATM are often considered low-to-moderate penetrance risk factors for breast cancer (BC), conferring a two-fold increased BC risk among heterozygous PV carriers. Several other cancers have been associated with ATM PV such as melanoma, thyroid cancer, prostate cancer, pancreatic cancer, gastro-esophageal cancers, colorectal cancer, and ovarian cancer. Estimating the diverse cancer risks attributable to ATM PVs may present challenges due to the low-to-moderate penetrance of ATM PV for some cancers, requiring large samples of tested patients to estimate risk with precision, and the potential for substantial variability in penetrance of particular ATM PV such as the c.7271T>G PV reported by previous studies. We investigated cancer risks with ATM PV in a large clinical testing dataset. Methods: Results of 614,344 individuals undergoing clinical analysis of ATM as part of a multi-gene hereditary cancer gene panel between 09/2013 and 06/2019 were reviewed. Patient age, sex, ancestry, personal and family cancer history were extracted from a test requisition form. PV included variants classified as suspected deleterious or deleterious (hereafter referred to as pathogenic). Risk estimates are estimated using multivariate logistic regression and are reported as odds ratios (OR) with 95% confidence intervals (CI). Results: PV in ATM were identified in 4,372/614,344 (0.7%) individuals: 4,155/592,881 (0.7%) females and 217/21,463 (1.0%) males. 1,603/4,155 (38.6%) of female ATM PV carriers had invasive BC or DCIS. Overall, ATM PV were associated with a 2-fold increased risk for invasive BC [OR 2.01, 95% CI 1.86-2.16] and DCIS [OR 1.82, 95% CI 1.62-2.04]. A prevalent missense PV c.7271T>G, predicted to lead to inactivation of ATM kinase activity and that has previously been described as high penetrance (Goldgar DE et al, Breast Cancer Res 2011), represented 5.1% (n=223) of all ATM PV, and was associated with a particularly high risk of invasive BC [OR 3.80, 95% CI 2.78-5.19] but no increased risk of DCIS. Significantly elevated risks of pancreatic cancer, gastric cancer, prostate cancer, ovarian cancer, colon cancer and melanoma were also observed among ATM PV carriers (see Table 1). Median age of invasive BC diagnosis was similar in carriers and non-carriers of ATM PV. Conclusions: ATM PV are associated with 1.5-fold to >4-fold increased cancer risks across a variety of disease sites, including invasive BC (2-fold increased risk). Cancer risks also demonstrate mutation-specific variability, as suggested by the 4-fold increased risk of invasive BC in carriers of the ATM PV c.7271T>G. Larger and/or pooled studies are critical to further refine the breadth and magnitude of ATM-associated cancer risk and to improve clinical management guidelines for ATM PV carriers. Table 1: Odds ratios for cancer risks in c.7271T>G and all other ATM PV carriersAll ATM PVs (excluding c.7271T>G)c.7271T>GCancer OR (95% CI)p-valueOR (95% CI)p-valueBreast, Invasive1.94 (1.79, 2.09)<0.00013.80 (2.78, 5.19)<0.0001Breast, DCIS1.83 (1.62, 2.05)<0.00011.63 (0.97, 2.74)0.0624Breast, Lobular invasive0.94 (0.73, 1.21)0.62330.84 (0.27, 2.64)0.7671Breast, Male1.44 (0.86, 2.42)0.16884.24 (0.46, 39.15)0.2032Ovarian1.55 (1.32, 1.82)<0.00011.99 (0.99, 4.02)0.0532Colorectal1.51 (1.25, 1.82)<0.00011.67 (0.67, 4.18)0.2693Endometrial1.10 (0.88, 1.39)0.39610.89 (0.28, 2.81)0.8401Melanoma1.44 (1.14, 1.81)0.00182.16 (1.00, 4.64)0.0491Prostate2.61 (1.93, 3.52)<0.00014.37 (0.70, 27.26)0.1146Pancreatic4.18 (3.17, 5.49)<0.00012.50 (0.34, 18.21)0.3660Gastric3.09 (1.73, 5.53)0.0001—— Citation Format: Michael J Hall, Katie Larson, Ryan Bernhisel, Elisha Hughes, Eric Rosenthal, Nanda Singh, Johnathan M Lancaster, Allison W Kurian. Cancer risks associated with pathogenic variants in the ataxia telangiectasia mutated (ATM) gene [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-03-02.

Heterozygous Pathogenic Nonsense ATM Variant Resulting in Unusually High Gastric Cancer Susceptibility

“…Other prevention options are left to the clinician's choice. A recent study demonstrated a moderate-to-high risk for pancreatic, prostatic, gastric and female breast malignancies, and a low-to-moderate risk for breast ductal carcinoma in situ, ovarian, colorectal, male breast cancers and melanoma (Hall 2021). These data support considering surveillance also for other tumors.…”

“…For most cancers and variants, no assumption can be made. Some missense variants appear to determine ahigher risk for breast cancer compared to truncating mutations (Hall 2021) We believe the nonsense variant identi ed in the family might correlate with a speci cally higher gastric cancer risk, but further research is needed to provide an assertion.…”

“…The study of these variants is hindered by their frequency in the general population, from 0.3% to 1% (Choi 2016;Hall 2021) the reduced penetrance for cancer susceptibility and the overall frequency of the implied malignancies. The National Comprehensive Cancer Network guidelines quantify risks and suggest surveillance only for breast cancer (Daly 2021).…”

“…These data support considering surveillance also for other tumors. The authors also suggest that genotype-phenotype assumption can be made for some mutations (Hall 2021).…”

Multi-gene panel testing increases germline predisposing mutations’ detection in a cohort of breast/ovarian cancer patients from Southern Italy

“…She showed also a case of ovarian cancer (maternal cousin) (Figure 3). This variant is predicted to cause loss of normal protein function through the protein truncation or nonsense-mediated mRNA decay; loss-of-function variants in ATM gene are known in the literature to be pathogenic (21,22).…”