Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
J Med Genet. 2022 Feb;59(2):115-121. doi: 10.1136/jmedgenet-2020-107347. Epub 2021 Mar 23.
While the likelihood of identifying constitutional breast cancer-associated , and pathogenic variants (PVs) increases with earlier diagnosis age, little is known about the correlation with age at diagnosis in other predisposition genes. Here, we assessed the contribution of known breast cancer-associated genes to very early onset disease.
Sequencing of , and c.1100delC was undertaken in women with breast cancer diagnosed ≤30 years. Those testing negative were screened for PVs in a minimum of eight additional breast cancer-associated genes. Rates of PVs were compared with cases ≤30 years from the Prospective study of Outcomes in Sporadic vs Hereditary breast cancer (POSH) study.
Testing 379 women with breast cancer aged ≤30 years identified 75 PVs (19.7%) in , 35 (9.2%) in , 22 (5.8%) in and 2 (0.5%) c.1100delC. Extended screening of 184 PV negative women only identified eight additional actionable PVs. PVs were more common in women aged 26-30 years than in younger women (p=0.0083) although the younger age group had rates more similar to those in the POSH cohort. Out of 26 women with ductal carcinoma (DCIS) alone, most were high-grade and 11/26 (42.3%) had a PV (=6, =2, =2, =1). This PV yield is similar to the 61 (48.8%) PVs identified in 125 women with triple-negative breast cancer. The POSH cohort specifically excluded pure DCIS which may explain lower PV rates in this group (1.7%).
The rates of , and PVs are high in very early onset breast cancer, with limited benefit from testing of additional breast cancer-associated genes.
虽然随着诊断年龄的提前，识别与乳腺癌相关的种系和致病性变异（PVs）的可能性增加，但对于其他易感性基因与诊断年龄的相关性知之甚少。在这里，我们评估了已知的乳腺癌相关基因对极早发性疾病的贡献。
对≤30 岁确诊乳腺癌的女性进行 、 和 c.1100delC 的测序。那些检测结果为阴性的患者，在至少另外 8 个乳腺癌相关基因中进行了 PVs 的筛查。将这些 PVs 的发生率与 Prospective study of Outcomes in Sporadic vs Hereditary breast cancer（POSH）研究中≤30 岁的病例进行比较。
对≤30 岁的 379 名乳腺癌患者进行了检测，发现 75 个 PVs（19.7%）在 、 35 个（9.2%）在 、 22 个（5.8%）在 ，以及 2 个（0.5%）在 c.1100delC。对 184 名 PV 阴性的女性进行了扩展筛查，仅发现了另外 8 个可采取行动的 PVs。26-30 岁年龄组的女性 PVs 更为常见（p=0.0083），尽管年轻组的发生率更接近 POSH 队列。在 26 名仅患有导管原位癌（DCIS）的女性中，大多数为高级别，其中 11/26（42.3%）存在 PV（=6、=2、=2、=1）。这一 PV 发生率与 125 名三阴性乳腺癌患者中发现的 61 个（48.8%）PVs 相似。POSH 队列专门排除了单纯的 DCIS，这可能解释了该组中较低的 PV 发生率（1.7%）。
极早发性乳腺癌中 、 和 种系和致病性变异（PVs）的发生率很高，对其他乳腺癌相关基因的检测获益有限。
