Abstract P5-03-02: Cancer risks associated with pathogenic variants in the ataxia telangiectasia mutated (ATM) gene
Authors: Hall Michael J , Larson Katie , Bernhisel Ryan , Hughes Elisha , Rosenthal Eric , Singh Nanda , Lancaster Johnathan M , Kurian Allison W 
Published: March 2020

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&gt;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&gt;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 &gt;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&gt;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&gt;G and all other ATM PV carriersAll ATM PVs (excluding c.7271T&gt;G)c.7271T&gt;GCancer OR (95% CI)p-valueOR (95% CI)p-valueBreast, Invasive1.94 (1.79, 2.09)&lt;0.00013.80 (2.78, 5.19)&lt;0.0001Breast, DCIS1.83 (1.62, 2.05)&lt;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)&lt;0.00011.99 (0.99, 4.02)0.0532Colorectal1.51 (1.25, 1.82)&lt;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)&lt;0.00014.37 (0.70, 27.26)0.1146Pancreatic4.18 (3.17, 5.49)&lt;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.