Personalised pathway analysis reveals association between DNA repair pathway dysregulation and chromosomal instability in sporadic breast cancer

Abstract

The Homologous Recombination (HR) pathway is crucial for the repair of DNA double-strand breaks (DSBs) generated during DNA replication. Defects in HR repair have been linked to the initiation and development of a wide variety of human malignancies, and exploited in chemical, radiological and targeted therapies. In this study, we performed a personalised pathway analysis independently for four large sporadic breast cancer cohorts to investigate the status of HR pathway dysregulation in individual sporadic breast tumours, its association with HR repair deficiency and its impact on tumour characteristics. Specifically, we first manually curated a list of HR genes according to our recent review on this pathway (Liu et al., 2014), and then applied a personalised pathway analysis method named Pathifier (Drier et al., 2013) on the expression levels of the curated genes to obtain an HR score quantifying HR pathway dysregulation in individual tumours. Based on the score, we observed a great diversity in HR dysregulation between and within gene expression-based breast cancer subtypes, and by using two published HR-defect signatures, we found HR pathway dysregulation reflects HR repair deficiency. Furthermore, we identified a novel association between HR pathway dysregulation and chromosomal instability (CIN) in sporadic breast cancer. Although CIN has long been considered as a hallmark of most solid tumours, with recent extensive studies highlighting its importance in tumour evolution and drug resistance, the molecular basis of CIN in sporadic cancers remains poorly understood. Our results imply that HR pathway dysregulation might contribute to CIN in sporadic breast cancer.

Ageing as an Important Risk Factor for Cancer

“…Similarly, the number of DNA strand breaks and time required for their repair is significantly influenced by ageing (22,23). Double-strand DNA breaks can even participate to the loss of heterozygosity in the elderly and can be important for cancerogenesis (24,25). The total number of mutations acquired during ageing is extremely high, and robust genomic technologies demonstrated that 3,000-13,000 genes per genome can be affected by 5,000-50,000 mutations (26).…”

Genetic variants of genes in the NER pathway associated with risk of breast cancer: A large‐scale analysis of 14 published GWAS datasets in the DRIVE study

“…A recent large study with pathway‐level analysis using hierarchical modeling across five cancers, including 11 Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) genome‐wide association study (GWAS) datasets of 33,832 BC study subjects of European descent, did not find any specific risk‐associated SNPs in genes involved in NER, but the limited study power did allow the investigators to find an association with the overall genetic variation of the NER pathway . Other prior studies also investigated associations between SNPs in DNA repair pathway genes and BC risk, but these studies had relatively small sample sizes without a focus on the NER pathway, although they have some notable findings, such as XRCC3 and ERCC4 …”

“…16 Other prior studies also investigated associations between SNPs in DNA repair pathway genes and BC risk, but these studies had relatively small sample sizes without a focus on the NER pathway, although they have some notable findings, such as XRCC3 and ERCC4. [17][18][19][20][21][22][23][24] Therefore, we hypothesize that genetic variants in the NER pathway genes are associated with BC risk. To assess the role of functional SNPs of the NER pathway genes in the BC etiology, we performed a much larger meta-analysis of 14 previously published DRIVE GWAS datasets with 53,107 study subjects of European descent.…”

Emerging links among Chromosome Instability (CIN), cancer, and aging

“…That suggested DNA replication stress can cause mitotic chromosome segregation error (CIN) in colon cancer [8]. Additionally, association between homologous recombination pathway (leading to replication stress and MIN) and CIN was identified in sporadic breast cancer, also supporting the notion that DNA metabolism defect leads to CIN [9].…”