Pathogenic variants (PVs) in ATM are relatively common, but the scope and magnitude of risk remains uncertain. This study aimed to estimate ATM PV cancer risks independent of family cancer history. This analysis included patients referred for hereditary cancer testing with a multi-gene panel ( N = 627,742). Cancer risks for ATM PV carriers ( N = 4,607) were adjusted for family history using multivariable logistic regression and reported as ORs with 95% confidence intervals (CIs). Subanalyses of the c.7271T>G missense PV were conducted. Moderate-to-high risks for pancreatic (OR, 4.21; 95% CI, 3.24–5.47), prostate (OR, 2.58; 95% CI, 1.93–3.44), gastric (OR, 2.97; 95% CI, 1.66–5.31), and invasive ductal breast (OR, 2.03; 95% CI, 1.89–2.19) cancers were estimated for ATM PV carriers. Notably, c.7271T>G was associated with higher invasive ductal breast cancer risk (OR, 3.76; 95% CI, 2.76–5.12) than other missense and truncating ATM PVs. Low-to-moderate risks were seen for ductal carcinoma in situ (OR, 1.80; 95% CI, 1.61–2.02), male breast cancer (OR, 1.72; 95% CI, 1.08–2.75), ovarian cancer (OR, 1.57; 95% CI, 1.35–1.83), colorectal cancer (OR, 1.49; 95% CI, 1.24–1.79), and melanoma (OR, 1.46; 95% CI, 1.18–1.81). ATM PVs are associated with multiple cancer risks and, while professional society guidelines support that carriers are eligible for increased breast and pancreatic cancer screening, increased screening for prostate and gastric cancer may also be warranted. c.7271T>G is associated with high risk for breast cancer, with a 3- to 4-fold risk increase that supports consideration of strategies for prevention and/or early detection. Prevention Relevance: This study estimated risks for multiple cancers associated with ATM pathogenic variants independent of family history. These results indicate that some common variants may be associated with higher breast cancer risks than previously appreciated and increased screening for prostate and gastric cancer may be warranted for carriers of ATM pathogenic variants.

中文翻译：

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共济失调毛细血管扩张症突变 (ATM) 基因的种系致病性变异与多种癌症的高风险和中度风险相关


ATM 的致病变异 (PV) 相对常见，但风险的范围和程度仍不确定。本研究旨在评估独立于家族癌症史的 ATM PV 癌症风险。该分析包括转诊进行多基因组遗传性癌症检测的患者 (N = 627,742)。 ATM PV 携带者 (N = 4,607) 的癌症风险使用多变量逻辑回归根据家族史进行调整，并报告为具有 95% 置信区间 (CI) 的 OR。对 c.7271T>G 错义 PV 进行了子分析。胰腺癌（OR，4.21；95% CI，3.24–5.47）、前列腺癌（OR，2.58；95% CI，1.93–3.44）、胃癌（OR，2.97；95% CI，1.66–5.31）的中度至高风险）和侵袭性导管乳腺癌（OR，2.03；95% CI，1.89-2.19）对 ATM PV 携带者进行了估计。值得注意的是，与其他错义和截短的 ATM PV 相比，c.7271T>G 与较高的浸润性导管乳腺癌风险相关（OR，3.76；95% CI，2.76–5.12）。导管原位癌（OR，1.80；95% CI，1.61–2.02）、男性乳腺癌（OR，1.72；95% CI，1.08–2.75）、卵巢癌（OR，1.57）的风险为低至中度。 ；95% CI，1.35–1.83）、结直肠癌（OR，1.49；95% CI，1.24–1.79）和黑色素瘤（OR，1.46；95% CI，1.18–1.81）。 ATM PV 与多种癌症风险相关，虽然专业协会指南支持携带者有资格增加乳腺癌和胰腺癌筛查，但也可能需要增加前列腺癌和胃癌筛查。 c.7271T>G 与乳腺癌高风险相关，风险增加 3 至 4 倍，支持考虑预防和/或早期检测策略。预防相关性：本研究评估了与 ATM 致病变异相关的多种癌症的风险，与家族史无关。 这些结果表明，一些常见变异可能与比以前认识的更高的乳腺癌风险相关，并且可能需要对 ATM 致病变异携带者增加前列腺癌和胃癌筛查。