School of Cancer and Pharmaceutical Sciences, Guy's Hospital, King's College London, London, SE1 9RT, UK.
Medical and Molecular Genetics, Guy's Hospital, King's College London, London, SE1 9RT, UK.
Breast Cancer Res. 2019 May 6;21(1):58. doi: 10.1186/s13058-019-1143-y.
Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal breast cancer, and approximately 20% of screen-detected tumours are pure DCIS. Most risk factors for breast cancer have similar associations with DCIS and IDC; however, there is limited data on the prevalence of the known high and moderate penetrance breast cancer predisposition genes in DCIS and which women with DCIS should be referred for genetic screening. The aim of this study was to assess the frequency of germline variants in BRCA2, BRCA1, CHEK2, PALB2 and TP53 in DCIS in women aged less than 50 years of age.
After DNA extraction from the peripheral blood, Access Array technology (Fluidigm) was used to amplify all exons of these five known breast cancer predisposition genes using a custom made targeted sequencing panel in 655 cases of pure DCIS presenting in women under the age of 50 years together with 1611 controls.
Case-control analysis revealed an excess of pathogenic variants in BRCA2 (OR = 27.96, 95%CI 6.56-119.26, P = 2.0 × 10) and CHEK2 (OR = 8.04, 95%CI 2.93-22.05, P = 9.0 × 10), with weaker associations with PALB2 (P = 0.003), BRCA1 (P = 0.007) and TP53 (P = 0.02). For oestrogen receptor (ER)-positive DCIS the frequency of pathogenic variants was 9% under the age of 50 (14% with a family history of breast cancer) and 29% under the age of 40 (42% with a family history of breast cancer). For ER-negative DCIS, the frequency was 9% (16% with a family history of breast cancer) and 8% (11% with a family history of breast cancer) under the ages of 50 and 40, respectively.
This study has shown that breast tumourigenesis in women with pathogenic variants in BRCA2, CHEK2, PALB2, BRCA1 and TP53 can involve a DCIS precursor stage and that the focus of genetic testing in DCIS should be on women under the age of 40 with ER-positive DCIS.
导管原位癌（DCIS）是非浸润性导管乳腺癌的强制性前体，约 20%的筛查肿瘤为纯 DCIS。大多数乳腺癌的风险因素与 DCIS 和 IDC 有相似的关联；然而，关于已知高和中度外显率乳腺癌易感性基因在 DCIS 中的患病率以及哪些 DCIS 女性应接受遗传筛查，数据有限。本研究旨在评估 50 岁以下女性纯 DCIS 中 BRCA2、BRCA1、CHEK2、PALB2 和 TP53 种系变异的频率。
从外周血中提取 DNA 后，使用 Access Array 技术（Fluidigm），使用定制的靶向测序面板，对 655 例 50 岁以下女性的纯 DCIS 病例和 1611 例对照进行了这 5 种已知乳腺癌易感性基因的所有外显子扩增。
病例对照分析显示，BRCA2（OR=27.96，95%CI 6.56-119.26，P=2.0×10）和 CHEK2（OR=8.04，95%CI 2.93-22.05，P=9.0×10）中致病性变异的数量过多，而与 PALB2（P=0.003）、BRCA1（P=0.007）和 TP53（P=0.02）的关联较弱。对于雌激素受体（ER）阳性的 DCIS，50 岁以下的致病性变异频率为 9%（有乳腺癌家族史的为 14%），40 岁以下的为 29%（有乳腺癌家族史的为 42%）。对于 ER 阴性的 DCIS，50 岁以下和 40 岁以下的频率分别为 9%（有乳腺癌家族史的为 16%）和 8%（有乳腺癌家族史的为 11%）。
本研究表明，BRCA2、CHEK2、PALB2、BRCA1 和 TP53 种系变异的女性中，乳腺癌的发生可能涉及 DCIS 前体阶段，DCIS 遗传检测的重点应放在 ER 阳性 DCIS 的 40 岁以下女性。
