N.N. Petrov Institute of Oncology, Leningradskaya str. 68, Pesochny, Saint Petersburg, Russia, 197758.
Mariinskaya City Hospital, Saint Petersburg, Russia, 191014.
Breast Cancer Res Treat. 2022 Apr;192(2):283-291. doi: 10.1007/s10549-022-06517-3. Epub 2022 Jan 12.
Germline mutations in CHEK2 gene represent the second most frequent cause of hereditary breast cancer (BC) after BRCA1/2 lesions. This study aimed to identify the molecular characteristics of CHEK2-driven BCs.
Loss of heterozygosity (LOH) for the remaining CHEK2 allele was examined in 50 CHEK2-driven BCs using allele-specific PCR assays for the germline mutations and analysis of surrounding single-nucleotide polymorphisms (SNPs). Paired tumor and normal DNA samples from 25 cases were subjected to next-generation sequencing analysis.
CHEK2 LOH was detected in 28/50 (56%) BCs. LOH involved the wild-type allele in 24 BCs, mutant CHEK2 copy was deleted in 3 carcinomas, while in one case the origin of the deleted allele could not be identified. Somatic PIK3CA and TP53 mutations were present in 13/25 (52%) and 4/25 (16%) tumors, respectively. Genomic features of homologous recombination deficiency (HRD), including the HRD score ≥ 42, the predominance of BRCA-related mutational signature 3, and the high proportion of long (≥ 5 bp) indels, were observed only in 1/20 (5%) BC analyzed for chromosomal instability. Tumors with the deleted wild-type CHEK2 allele differed from LOH-negative cases by elevated HRD scores (median 23 vs. 7, p = 0.010) and higher numbers of chromosomal segments affected by copy number aberrations (p = 0.008).
Somatic loss of the wild-type CHEK2 allele is observed in approximately half of CHEK2-driven BCs. Tumors without CHEK2 LOH are chromosomally stable. BCs with LOH demonstrate some signs of chromosomal instability; however, its degree is significantly lower as compared to BRCA1/2-associated cancers.
CHEK2 基因突变是继 BRCA1/2 突变后遗传性乳腺癌（BC）的第二大常见病因。本研究旨在确定 CHEK2 驱动的 BC 的分子特征。
使用针对种系突变的等位基因特异性 PCR 检测和周围单核苷酸多态性（SNP）分析，在 50 例 CHEK2 驱动的 BC 中检测剩余 CHEK2 等位基因的杂合性丢失（LOH）。对 25 例病例的配对肿瘤和正常 DNA 样本进行下一代测序分析。
在 50 例 BC 中检测到 CHEK2 LOH 28/50（56%）。LOH 涉及 24 例 BC 中的野生型等位基因，3 例癌中突变 CHEK2 拷贝缺失，而在 1 例中无法确定缺失等位基因的来源。在 13/25（52%）和 4/25（16%）肿瘤中分别存在体细胞 PIK3CA 和 TP53 突变。仅在分析的 20 例 BC 中，有 1 例（5%）存在同源重组缺陷（HRD）的基因组特征，包括 HRD 评分≥42、BRCA 相关突变特征 3 占主导地位和长（≥5bp）插入缺失比例高。染色体不稳定性分析中，缺失野生型 CHEK2 等位基因的肿瘤与 LOH 阴性病例的 HRD 评分升高（中位数 23 与 7，p=0.010）和受拷贝数异常影响的染色体片段数量增加（p=0.008）有关。
在大约一半的 CHEK2 驱动的 BC 中观察到野生型 CHEK2 等位基因的体细胞丢失。没有 CHEK2 LOH 的肿瘤染色体稳定。具有 LOH 的 BC 表现出一些染色体不稳定的迹象；然而，与 BRCA1/2 相关的癌症相比，其程度显著较低。
