目标:种系赋予的癌症风险,杂合子,ATM致病性/可能的致病性变体(PSV)尚未一致地确定。当前的研究通过分析使用多基因小组(MGP)测试的ATM杂合子功能丧失(LOF)和错义PSV携带者的大型数据集来评估这些风险。
方法:回顾了2015年10月至2020年2月期间接受ATM测序作为MGP一部分的所有个体的去识别数据。在癌症病例中,将六种最普遍的变异以及所有LOF和错义PSV组合的比率与种族匹配的相同PSV的比率进行比较,健康的人口控制。统计分析包括卡方检验和比值比计算。
结果:对于女性乳腺癌病例,与gnomAD非癌症对照相比,LOF)1794/219,269)和错义(301/219,269)ATMPSV的发生率更高(n=157/56,001,n=27/61,208;p<0.00001,分别)。值得注意的是,对照组的c.103C>T变异率高于乳腺癌病例[p=0.001;OR0.31(95%CI0.1-0.6)].对于所有癌症病例,与非癌症人群对照相比,在这两个数据集中报告的LOF(n=143)和错义(n=15)PSV在癌症病例中明显更普遍[ORLOF1.7(95%1.5-1.9)或错义3.0(95%CI2.3-4);p=0.0001]。
结论:LOF和错义杂合ATMPSV在几种癌症类型(乳腺癌,卵巢,前列腺,肺,胰腺)与健康人群对照相比。然而,并非所有ATMPSV都会增加癌症风险(例如,breast).
OBJECTIVE: Cancer risks conferred by germline, heterozygous, ATM pathogenic/likely pathogenic variants (PSVs) are yet to be consistently determined. The current study assessed these risks by analysis of a large dataset of ATM heterozygote loss of function (LOF) and missense PSV carriers tested with a multigene panel (MGP).
METHODS: De-identified data of all individuals who underwent ATM sequencing as part of MGP between October 2015 and February 2020 were reviewed. In cancer cases, rates for the six most prevalent variants and for all LOF and missense PSV combined were compared with rates of the same PSV in ethnically matched, healthy population controls. Statistical analysis included Chi-square tests and odds ratios calculations.
RESULTS: For female breast cancer cases, LOF )1794/219,269) and missense (301/219,269) ATM PSVs were seen at higher rates compared to gnomAD non-cancer controls (n = 157/56,001 and n = 27/61,208; p < 0.00001, respectively). Notably, the rate of the c.103C > T variant was higher in controls than in breast cancer cases [p = 0.001; OR 0.31 (95% CI 0.1-0.6)]. For all cancer cases combined, compared with non-cancer population controls, LOF (n = 143) and missense (n = 15) PSVs reported in both datasets were significantly more prevalent in cancer cases [ORLOF 1.7 (95% 1.5-1.9) ORmissense 3.0 (95% CI 2.3-4); p = 0.0001].
CONCLUSIONS: Both LOF and missense heterozygous ATM PSVs are more frequently detected in cases of several cancer types (breast, ovarian, prostate, lung, pancreatic) compared with healthy population controls. However, not all ATM PSVs confer an increased cancer risk (e.g., breast).