Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona; Medical Oncology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Hospital Campus, Barcelona, Spain.
Ann Oncol. 2024 Oct;35(10):892-901. doi: 10.1016/j.annonc.2024.07.244. Epub 2024 Jul 8.
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. PATIENTS AND 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.
背景：胚系基因检测，以前仅限于家族性和早发性乳腺癌，现在越来越广泛地应用于主流肿瘤学诊所的“人群型”乳腺癌患者，所包含的基因也有很大差异。
患者和方法：对三项基于人群的病例对照研究（BRIDGES、CARRIERS 和 UK Biobank）进行加权荟萃分析，共纳入 101397 名乳腺癌患者和 312944 名无乳腺癌患者，以量化 37 个潜在乳腺癌易感基因（BCSG）在未经选择的“人群型”乳腺癌病例中的致病性变异（PV）频率及其与乳腺癌及其亚型的关联。
结果：对 BRCA1（OR8.73，95%置信区间（CI）7.47-10.20；1/101）、BRCA2（OR5.68，95%CI5.13-6.30；1/68）和 PALB2（OR4.30，95%CI3.68-5.03；1/187）进行了荟萃分析，得出了 OR 和“人群型”乳腺癌病例中 PV 频率。对于 CHEK2（OR2.40，95%CI2.21-2.62；1/73）和 ATM（OR2.16，95%CI1.93-2.41；1/132）亚组分析，发现与雌激素受体阳性疾病的相关性更强。RAD51C（OR1.53，95%CI1.29-2.04；1/913）、RAD51D（OR1.76，95%CI1.29-2.41；1/1079）和 BARD1（OR2.34，95%CI1.85-2.97；1/672）的关联和 PV 频率较低；当分析仅限于三阴性乳腺癌时，频率和相关性更高。“人群型”乳腺癌病例中“综合征”BCSGs 的 PV 频率非常低，TP53（1/1844）、STK11（1/11525）、CDH1（1/2668）、PTEN（1/3755）和 NF1（1/1470），关联的指标也适中，范围从 TP53 的 OR3.62（95%CI1.98-6.61）到 STK11 的 OR1.60（95%CI0.48-5.30）。
结论：这些反映“人群型”乳腺癌的指标将有助于确定适当的基因集，因为我们将继续扩大胚系检测范围，纳入越来越多未经选择的乳腺癌病例。
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