Background and aims

Heterozygous truncating pathogenic variants (PVs) in CHEK2 confer a 1.5 to 3-fold increased risk for breast cancer and may elevate colorectal cancer risks. Less is known regarding missense variants. Here we compared the cancer associations with truncating and missense PVs in CHEK2 across breast and colorectal cancer.

Methods

This was a retrospective analysis of 705,797 patients who received single laboratory multigene panel testing between 2013 and 2020. Multivariable logistic regression models determined cancer risk associated with CHEK2 variants as odds ratios (ORs) and 95% confidence intervals (CIs) after adjusting for age at diagnosis, cancer history, and ancestry. Breast and colorectal cancer analyses were performed using 6255 CHEK2 PVs, including truncating PVs (N = 4505) and missense PVs (N = 1750).

Results

CHEK2 PVs were associated with an increased risk of ductal invasive breast cancer (p < 0.001) and ductal carcinoma in situ (DCIS) (p < 0.001), with no statistically significant differences when truncating PVs (p < 0.001) and missense PVs (p < 0.001) were evaluated separately. All CHEK2 variants assessed conferred little to no risk of colorectal cancer.

Conclusions

In our large cohort, CHEK2 truncating and missense PVs conferred similar risks for breast cancer and did not seem to elevate risk for colorectal cancer.

中文翻译：

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超过 6,000 名 CHEK2 致病性变异携带者的乳腺癌和结直肠癌风险：错义变异与截短变异的比较

背景和目标

CHEK2中的杂合截短致病性变异 (PV)会使患乳腺癌的风险增加 1.5 至 3 倍，并可能增加结直肠癌的风险。关于错义变异我们知之甚少。在这里，我们比较了乳腺癌和结直肠癌中CHEK2中截短和错义 PV 与癌症的关联。

方法

这是对 2013 年至 2020 年间接受过单一实验室多基因小组测试的 705,797 名患者进行的回顾性分析。在调整年龄后，多变量逻辑回归模型将与CHEK2变异相关的癌症风险确定为比值比 (OR) 和 95% 置信区间 (CI)。诊断、癌症病史和血统。使用 6255 个CHEK2 PV进行乳腺癌和结直肠癌分析，包括截短 PV ( N  = 4505) 和错义 PV ( N  = 1750)。

结果

CHEK2 PV 与导管浸润性乳腺癌 ( p  < 0.001) 和导管原位癌 (DCIS) ( p < 0.001) 的风险增加相关，截短 PV ( p < 0.001  ) 和错义 PV ( p < 0.001) 时没有统计学显着差异。 < 0.001) 单独评估。所有评估的CHEK2变异几乎没有甚至没有结直肠癌风险。

结论

在我们的大型队列中，CHEK2截短和错义 PV 会带来类似的乳腺癌风险，但似乎不会增加结直肠癌的风险。