Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients

Multigene panel testing of breast cancer predisposition genes have been extensively conducted in Europe and America, which is relatively rare in Asia however. In this study, we assessed the frequency of germline mutations in 40 cancer predisposition genes, including BRCA1 and BRCA2, among a large cohort of Chinese patients with high hereditary risk of BC. From 2015 to 2016, consecutive BC patients from 26 centers of China with high hereditary risk were recruited (n = 937). Clinical information was collected and next-generation sequencing (NGS) was performed using blood samples of participants to identify germline mutations. In total, we acquired 223 patients with putative germline mutations, including 159 in BRCA1/2, 61 in 15 other BC susceptibility genes and 3 in both BRCA1/2 and non-BRCA1/2 gene. Major mutant non-BRCA1/2 genes were TP53 (n = 18), PALB2 (n = 11), CHEK2 (n = 6), ATM (n = 6) and BARD1 (n = 5). No factors predicted pathologic mutations in non-BRCA1/2 genes when treated as a whole. TP53 mutations were associated with HER-2 positive BC and younger age at diagnosis; and CHEK2 and PALB2 mutations were enriched in patients with luminal BC. Among high hereditary risk Chinese BC patients, 23.8% contained germline mutations, including 6.8% in non-BRCA1/2 genes. TP53 and PALB2 had a relatively high mutation rate (1.9 and 1.2%). Although no factors predicted for detrimental mutations in non-BRCA1/2 genes, some clinical features were associated with mutations of several particular genes.

Section: Discussionmentioning

confidence: 91%

Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer

Jing

Wei

et al. 2018

“…Among these patients, 9,505 were of Chinese Han ethnicity and had had genomic DNA extracted from blood samples of sufficient quantity and quality for BRCA1/2 mutation analysis. Of these 9,505 patients, 8,278 cases were subjected to next‐generation sequencing (NGS) and/or Sanger sequencing for the entire coding regions and exon/intron boundaries of the BRCA1 and BRCA2 genes. The remaining 1,227 cases were sequenced for recurrent pathogenic variants of BRCA1/2 genes using Sanger sequencing .…”

Section: Methodsmentioning

confidence: 99%

“…The remaining 1,227 cases were sequenced for recurrent pathogenic variants of BRCA1/2 genes using Sanger sequencing . The applied method of mutation screening was described in detail in our previous report . Each pathogenic variant was double‐confirmed by Sanger sequencing.…”

Section: Methodsmentioning

confidence: 99%

BRCA1 c.5470_5477del, a founder mutation in Chinese Han breast cancer patients

Meng

Yao

Yuan

et al. 2020

Self Cite

The spectrum and frequency of BRCA1/2 pathogenic variants may be ethnicity‐specific. Whether high‐frequency founder mutations are present in Chinese women remains largely unknown. In the current study, germline pathogenic variants in the BRCA1/2 genes were determined in 9,505 unselected Chinese Han breast cancer (BC) patients by next‐generation and/ or Sanger sequencing. Four hundred and seventy‐one (5.0%) BC patients carried BRCA1/2 pathogenic variants in this cohort. A total of 25 recurrent pathogenic variants (at least found in four unrelated patients) were identified in this cohort (8 BRCA1 and 17 BRCA2 recurrent pathogenic variants), 161 patients carried one of these recurrent pathogenic variants in this cohort of 9,505 patients. All of these 25 recurrent pathogenic variants were further explored whether they had founder effect through haplotype analysis. The most common pathogenic variant, BRCA1 c.5470_5477del, was found in 30 BC patients from 29 unrelated families. Twenty‐seven of these 29 unrelated patients who carried this BRCA1 c.5470_5477del mutation shared an identical haplotype, indicating that BRCA1 c.5470_5477del was a founder mutation in the Chinese Han population. Furthermore, BRCA1 c.5470_5477del mutation carriers had a significantly worse survival than noncarriers (disease‐free survival, p = 0.049; overall survival, p = 0.029). Taken together, our data suggested that BRCA1 c.5470_5477del is a founder mutation in the Chinese Han population and BRCA1 c.5470_5477del mutation carriers have a poor survival.

“…We had previously recruited a total of 10,378 consecutive breast cancer patients treated at the Breast Center of Peking University Cancer Hospital (Beijing, China) from October 2003 to May 2015, of whom 8,085 received multi‐gene panel sequencing, as described in our previous study . That study showed that 428 (5.3%) patients carried a germline mutation in BRCA1 or BRCA2 . Therefore, 7,657 non‐ BRCA1/2 mutant patients were included in the present study.…”

Section: Methodsmentioning

confidence: 99%

“…The panel covered all RAD50 coding regions and splice sites. Sequencing was performed on a HiSeq 2500 platform (Illumina Inc., San Diego, CA) as described in our previous study . All pathogenic mutations were validated by independent PCR and Sanger sequencing.…”

Section: Pathologymentioning

confidence: 99%

RAD50 germline mutations are associated with poor survival in BRCA1/2–negative breast cancer patients

Fan

Zhang

Ouyang

et al. 2018

Self Cite

RAD50 is a highly conserved DNA double-strand break (DSB) repair gene. However, the associations between RAD50 germline mutations and the survival and risk of breast cancer have not been fully elucidated. Here, we aimed to investigate the clinical impact of RAD50 germline mutations in a large cohort of unselected breast cancer patients. In our study, RAD50 germline mutations were determined using next-generation sequencing in 7657 consecutive unselected breast cancer patients without BRCA1/2 mutations. We also screened for RAD50 recurrent mutations (L719fs, K994fs, and H1269fs) in 5000 healthy controls using Sanger sequencing. We found that 26 out of 7,657 (0.34%) patients had RAD50 pathogenic mutations, and 16 patients carried one of the three recurrent mutations (L719fs, n = 6 cases; K994fs, n = 5 cases; and H1269fs, n = 5 cases); the recurrent mutation rate was 0.21%. The frequency of the three recurrent mutations in the 5,000 healthy controls was 0.18% (9/5,000). These mutations did not confer an increased risk of breast cancer in the studied patients [odds ratios (OR), 1.16; 95% confidence interval (CI), 0.51-2.63; p = 0.72]. Nevertheless, multivariate analysis revealed that RAD50 pathogenic mutations were an independent unfavourable predictor of recurrence-free survival (RFS) [adjusted hazard ratio (HR) 2.66; 95% CI, 1.18-5.98; p = 0.018] and disease-specific survival (DSS; adjusted HR 4.36; 95% CI, 1.58-12.03; p = 0.004) in the entire study cohort. Our study suggested that RAD50 germline mutations are not associated with an increased risk of breast cancer, but patients with RAD50 germline mutations have unfavourable survival compared to patients without these mutations.