背景:生殖系基因检测,以前仅限于家族性和年轻乳腺癌,现在越来越广泛地提供给主流肿瘤诊所的“人口型”乳腺癌患者,包括基因的广泛变异。
方法:对三项基于人群的病例对照研究进行了加权荟萃分析(BRIDGES,CARRIERS和UKBiobank)包括101,397名乳腺癌女性和312,944名无乳腺癌女性,量化37个推定的乳腺癌易感基因(BCSGs)的致病变异(PVs)的频率在未经选择,“人群型”乳腺癌病例及其与乳腺癌及其亚型的关系。
结果:对BRCA1人群型乳腺癌病例中PVs的比值比(ORs)和频率进行Meta分析(OR=8.73(95%CI7.47-10.20),1in101),BRCA2(OR=5.68(5.13-6.30),68分之一)和PALB2(OR=4.30(95%CI3.68-5.03),187中的1)。对于两种CHEK2(OR=2.40(95%CI2.21-2.62),73分之一)和ATM(OR=2.16(95CI1.93-2.41),132个中的1个)亚组分析显示与ER阳性疾病的相关性更强。RAD51C的相关性和PV频率较低(OR=1.53(95CI1.15-2.04),1in913),RAD51D(OR=1.76,(95CI1.15-2.41,1079中的1)和BARD1(OR=2.34(1.85-2.97),672人中有1人);限制三阴性乳腺癌的频率和关联中等较高。“人群型”乳腺癌病例的PV频率非常低,“综合征”BCSGsTP53(1844年有1人),STK11(11,525中的1个),CDH1(2668中的1个),PTEN(1/3755)和NF1(1/1470),相关性指标也适中,从TP53的OR=3.62(95CI1.98-6.61)到STK11的OR=1.60(95CI0.48-5.30)。
结论:这些反映“群体型”乳腺癌的指标将为定义适当的基因集提供信息,因为我们将继续扩展到更多未选择的群体型乳腺癌病例的种系检测。
BACKGROUND: Germline genetic testing, previously restricted to familial and young-onset breast cancer, is now offered increasingly broadly to patients with \'population-type\' breast cancer in mainstream oncology clinics, with wide variation in the genes included.
METHODS: Weighted meta-analysis was carried out for three population-based case-control studies (BRIDGES, CARRIERS and UK Biobank) comprising in total 101 397 women with breast cancer and 312 944 women without breast cancer, to quantify 37 putative breast cancer susceptibility genes (BCSGs) for the frequency of pathogenic variants (PVs) in unselected, \'population-type\' breast cancer cases and their association with breast cancer and its subtypes.
RESULTS: Meta-analysed odds ratios (ORs) and frequencies of PVs in \'population-type\' breast cancer cases were generated for BRCA1 (OR 8.73, 95% confidence interval (CI) 7.47-10.20; 1 in 101), BRCA2 (OR 5.68, 95% CI 5.13-6.30; 1 in 68) and PALB2 (OR 4.30, 95% CI 3.68-5.03; 1 in 187). For both CHEK2 (OR 2.40, 95% CI 2.21-2.62; 1 in 73) and ATM (OR 2.16, 95% CI 1.93-2.41; 1 in 132) subgroup analysis showed a stronger association with oestrogen receptor-positive disease. The magnitude of association and frequency of PVs were low for RAD51C (OR 1.53, 95% CI 1.29-2.04; 1 in 913), RAD51D (OR 1.76, 95% CI 1.29-2.41; 1 in 1079) and BARD1 (OR 2.34, 95% CI 1.85-2.97; 1 in 672); frequencies and associations were higher when the analysis was restricted to triple-negative breast cancers. The PV frequency in \'population-type\' breast cancer cases was very low for \'syndromic\' BCSGs TP53 (1 in 1844), STK11 (1 in 11 525), CDH1 (1 in 2668), PTEN (1 in 3755) and NF1 (1 in 1470), with metrics of association also modest ranging from OR 3.62 (95% CI 1.98-6.61) for TP53 down to OR 1.60 (95% CI 0.48-5.30) for STK11.
CONCLUSIONS: These metrics reflecting \'population-type\' breast cancer will be informative in defining the appropriate gene set as we continue to expand to germline testing to an increasingly unselected group of breast cancer cases.