A comprehensive analysis of Fanconi anemia genes in Chinese patients with high-risk hereditary breast cancer

Abstract

Background Four Fanconi anemia (FA) genes (BRCA1, BRCA2, PALB2 and RAD51C) are defined as breast cancer (BC) susceptibility genes. Other FA genes have been inconsistently associated with BC. Thus, the role of other FA genes in BC should be explored in specific populations. Methods Mutations in 16 FA genes were screened with a 98-gene panel sequencing assay in a cohort of 1481 Chinese patients with high-risk hereditary BC. The association between mutations and clinicopathological characteristics as well as prognosis was analyzed. The risk of BC in carriers of FA gene mutations was assessed in the Genome Aggregation Database and the Westlake Biobank for Chinese cohort. Results A total of 2.57% (38/1481) BC patients were identified who had 12 other FA gene germline mutations. Among them, the most frequently mutated gene was FANCA (8/1481, 0.54%). These 38 patients carried 35 distinct pathogenic/likely pathogenic variants, of which 21 were novel. We found one rare FANCB deleterious variant (c.1327-3dupT) in our cohort. There was a statistically significant difference in lymph node status between FA gene mutation carriers and non-carriers (p = 0.041). We observed a trend that mutation carriers had larger tumor sizes, lower estrogen receptor (ER) and progesterone receptor (PR) positivity rates, and lower 3.5-year invasive disease-free survival (iDFS) and distant recurrence-free survival (DRFS) rates than non-carriers (tumor size > 2 cm: 51.43% vs. 45.63%; ER positivity rates: 51.43% vs. 60.81%; PR positivity rates: 48.57% vs. 55.16%; 3.5-year iDFS rates: 58.8% vs. 66.7%; 3.5-year DRFS rates: 58.8% vs. 68.8%). The frequency of the mutations in FANCD2, FANCM and BRIP1 trended to be higher among BC cases than that in controls (p = 0.055, 0.08 and 0.08, respectively). Conclusion This study comprehensively estimated the prevalence, clinicopathological characteristics, prognosis and risk of BC associated with deleterious variants in FA genes in Chinese high-risk hereditary BC patients. It enriches our understanding of the role of FA genes with BC.

Clinical relevance of double heterozygosity revealed by next-generation sequencing of homologous recombination repair pathway genes in South African breast cancer patients

“…Of these genes, FANCA was the most commonly mutated (0.54%) followed by FANCD2 (0.41%). Upon investigation, various clinicopathological associations (although not statistically significant, possibly hampered by the small sample size) were reported, pertaining to larger tumor sizes, lower ER and PR positivity rates and lower 3.5 year invasive disease-free survival and distant recurrence-free survival rates in mutation carriers when compared to non-carriers [48].…”

“…Recently, Zhu and co-workers [48] screened 1481 Chinese high-risk BC patients for 16 FA genes and reported 38 pathogenic mutation carriers in the 12 unconfirmed BC genes after excluding BRCA1, BRCA2, PALB2, and RAD51C. Of these genes, FANCA was the most commonly mutated (0.54%) followed by FANCD2 (0.41%).…”