High chromosome instability identified by low-pass whole-genome sequencing assay is associated with TP53 copy loss and worse prognosis in BRCA1 germline mutation breast cancer

Abstract

Background Though BRCA1 mutation is the most susceptible factor of breast cancer, its prognostic value is disputable. Here in this study, we use a novel method which based on whole-genome analysis to evaluate the chromosome instability (CIN) value and identified the potential relationship between CIN and prognosis of breast cancer patients with germline-BRCA1 mutation. Materials and methods Sanger sequencing or a 98-gene panel sequencing assay was used to screen for BRCA1 germline small mutations in 1151 breast cancer patients with high-risk factors. MLPA assay was employed to screen BRCA1 large genomic rearrangements in familial breast cancer patients with BRCA1 negative for small mutations. Thirty-two samples with unique BRCA1 germline mutation patterns were further subjected to CIN evaluation by LPWGS (low-pass whole-genome sequencing) technology. Results Firstly, 113 patients with germline BRCA1 mutations were screened from the cohort. Further CIN analysis by the LPWGS assay indicated that CIN was independent from the mutation location or type of BRCA1. Patients with high CIN status had shorter disease-free survival rates (DFS) (HR = 6.54, 95% CI 1.30–32.98, P = 0.034). The TP53 copy loss was also characterized by LPWGS assay. The rates of TP53 copy loss in CIN high and CIN low groups were 85.71% (12/14) and 16.67% (3/18), respectively. Conclusion CIN-high is a prognostic factor correlated with shorter DFS and was independent with the germline BRCA1 mutation pattern. Higher CIN values were significantly correlated with TP53 copy loss in breast cancer patients with germline BRCA1 mutation. Our results revealed a reliable molecular parameter for distinguishing patients with poor prognosis from the BRCA1-mutated breast cancer patients.

HR-positive/HER2-negative breast cancer arising in patients with or without BRCA2 mutation: different biological phenotype and similar prognosis

“…We analysed the genetic variants in BRCA2 using a 98-gene panel sequencing assay. 30 We focused on the overall exons and the 10-bp regions upstream and downstream of each exon in these genes. Based on ClinVar ( http://www.ncbi.nlm.nih.gov/clinvar/ ), gnomAD ( http://www.gnomad-sg.org/ ) and RefGene ( https://annovar.openbioinformatics.org/en/latest/user-guide/download/ ) annotated by ANNOVA (24 October 2019, https://annovar.openbioinformatics.org/en/latest/ ), we classified all variants into different grades: pathogenic, likely pathogenic, variant of uncertain significance, likely benign and benign based on the American College of Medical Genetics guidelines.…”

The progress in our understanding of CIN in breast cancer research

“…Next-generation sequencing (NGS) provides a new approach for evaluating CIN. For instance, low-pass whole gene sequencing (LPWGS) ( 27 ) has been applied in the field of prenatal diagnosis. Wells et al.…”

Conditional in vivo deletion of LYN kinase has little effect on a BRCA1 loss-of-function-associated mammary tumour model

“…Women who inherit one functional and one mutated copy are at an approximately 70% lifetime risk of developing breast cancer and 40% lifetime risk of ovarian cancer ( Kuchenbaecker et al, 2017 ). Tumour formation is associated with loss-of-heterozygosity events that delete the functional copy ( Mahdavi et al, 2019 ) and is accelerated by concomitant inactivation of the TP53 (or p53) tumour suppressor protein ( Kim et al, 2016 ; Liu et al, 2007 ; Zhu et al, 2022 ). However, carriers of BRCA1 mutations may also show functional haploinsufficiency, which increases the risk of overt neoplasia ( Lim et al, 2009 ).…”