Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
Fam Cancer. 2022 Apr;21(2):129-136. doi: 10.1007/s10689-021-00241-5. Epub 2021 Mar 25.
Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC.
302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53.
35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83-66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58-23.95; P < 0.0001); and ATM: OR = 8.01 (95%CI 2.52-29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2.
The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC.
乳腺小叶癌（LBC）约占乳腺癌的 15%。在这里，我们研究了患有 LBC 的女性中一组扩展基因中的致病性种系变异（PGV）的频率。
302 名患有 LBC 的女性和 1567 名无乳腺癌的女性接受了 BRCA1/2 PGV 检测。对 BRCA1/2 PGV 检测阴性的 134 名 LBC 受影响女性进行了扩展筛选，包括：ATM、CDH1、CHEK2、NBN、PALB2、PTEN、RAD50、RAD51D 和 TP53。
在 LBC 组中发现了 35 种 PGV，其中 22 种存在于 BRCA1/2 中。在其他基因中发现了 10 种可操作的 PGV（ATM(4)、CDH1(1)、CHEK2(1)、PALB2(2)和 TP53(2)）。总体而言，三个基因中的 PGV 显著增加了 LBC 的风险。比值比（OR）为：BRCA1：OR=13.17（95%CI 2.83-66.38；P=0.0017），BRCA2：OR=10.33（95%CI 4.58-23.95；P<0.0001）；和 ATM：OR=8.01（95%CI 2.52-29.92；P=0.0053）。我们没有发现 PALB2、CDH1 或 CHEK2 增加 LBC 的风险。
总体 PGV 检出率为 11.59%，BRCA1/2（7.28%）PGV 与其他可操作 PGV（7.46%）的检出率相似，表明在 LBC 中进行扩展面板基因检测具有益处。我们还报告了 ATM 致病性变异与 LBC 之间以前未被识别的关联。
