十万女性乳腺癌风险易感基因关联

　　乳腺癌易感基因检测虽然已被广泛采用，但是对于许多基因而言，与乳腺癌的关联证据薄弱，潜在风险推算不精准，并且缺乏可靠的亚型相关风险推算。

　　2021年1月20日，国际四大医学期刊之首、美国麻省医学会《新英格兰医学杂志》在线发表国际乳腺癌学会联盟的研究报告，对25个国家超过11.3万例女性34个基因与乳腺癌风险的关联进行了分析。

　　该人群病例对照研究利用34个可能易感基因的大规模并行测序平台，对25个国家6万0466例乳腺癌女性和5万3461例无乳腺癌对照女性的标本进行测序。对这些基因蛋白质截断变异和罕见错义变异进行单独分析，比较全部乳腺癌和各个亚型乳腺癌的比例。根据区域和致病分类，对错义变异关联进行评估。

　　结果，全部乳腺癌女性与对照女性相比：

• 5个基因（ATM、BRCA1、BRCA2、CHEK2、PALB2）蛋白质截短变异比例显著较高（P<0.0001）

• 4个基因（BARD1、RAD51C、RAD51D、TP53）蛋白质截短变异比例相对较高（P<0.05，贝叶斯错误发现概率<0.05）

• 19个基因蛋白质截断变异比值比95%置信区间上限小于2.0

　　雌激素受体阳性与雌激素受体阴性乳腺癌女性相比，ATM、CHEK2基因蛋白质截断变异比例显著较高；雌激素受体阴性与雌激素受体阳性乳腺癌女性相比，BARD1、BRCA1、BRCA2、PALB2、RAD51C、RAD51D基因蛋白质截断变异比例显著较高。

　　全部乳腺癌女性与对照女性相比：

• 3个基因（ATM、CHEK2、TP53）罕见错义变异比例显著较高（P<0.001）

• 3个基因（BRCA1、BRCA2、TP53）致病错义变异比例显著较高，与蛋白质截短变异比例相似

　　因此，该研究结果确定了对临床最有用的乳腺癌风险预测基因组合，并提供了蛋白质截短变异相关风险推算，可用于指导遗传咨询。

　　对此，加拿大多伦多大学史蒂文·纳罗德教授发表同期评论：哪些基因可遗传乳腺癌？

N Engl J Med. 2021 Jan 20. Online ahead of print.

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium.

BACKGROUND: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.

METHODS: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity.

RESULTS: Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants.

CONCLUSIONS: The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling.

Funded by European Union Horizon 2020 programs and others

DOI: 10.1056/NEJMoa1913948

N Engl J Med. 2021 Jan 20. Online ahead of print.

Which Genes for Hereditary Breast Cancer?

Steven A. Narod.

Women's College Research Institute, Toronto.

DOI: 10.1056/NEJMe2035083