SUMMARY: DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 genes recognize and repair double strand DNA breaks via Homologous Recombination Repair (HRR) pathway. Homologous Recombination is a type of genetic recombination, and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway.
BRCA1 and BRCA2 are tumor suppressor genes located on chromosome 17 and chromosome 13 respectively and functional BRCA proteins repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. Mutations in these genes predispose an individual to develop malignant tumors. It is well established that the presence of BRCA1 and BRCA2 mutations can significantly increase the lifetime risk for developing breast and ovarian cancer, as high as 85% and 40% respectively.
BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic). Somatic mutations account for a significant portion of overall BRCA1 and BRCA2 aberrations. Loss of BRCA function due to frequent somatic aberrations likely deregulates HR pathway, and other pathways then come in to play, which are less precise and error prone, resulting in the accumulation of additional mutations and chromosomal instability in the cell, with subsequent malignant transformation. Homologous Recombination Deficiency therefore indicates an important loss of DNA repair function.
Pathogenic Variants (PVs) in BRCA1 and BRCA2 (BRCA1/2) are well known to be associated with increased lifetime risk for breast and ovarian cancer in women, and reliable risk estimates are also available and can be as high as 85% and 40% respectively. However, the association of BRCA1 and BRCA2 Pathogenic Variants with cancers other than female breast and ovarian cancers remain uncertain, and these associations have been based on studies with relatively small sample sizes, resulting in imprecise cancer risk estimates. It is therefore important that precise risk estimates are available, in order to optimize clinical management strategies and guidelines for cancer risk management in female and male BRCA1/2 carriers. The NCCN and other guidelines recommend breast and ovarian cancer screening for BRCA1/2 carriers, prostate cancer screening for BRCA2 carriers. Screening is also recommended for pancreatic cancer in BRCA1/2 carriers, but only in the presence of a positive family history of the disease.
The authors conducted this analysis to provide comprehensive and precise age-specific risk estimates of 22 cancers other than female breast and ovarian cancers associated with Pathogenic Variants in BRCA1 and BRCA2, for effective cancer risk management. The researchers used data from 3,184 BRCA1 families and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), to estimate age-specific Relative Risk (RR) and absolute risks for 22 first primary cancer types, after adjusting for family ascertainment. CIMBA was formed by a collaborative group of researchers working on genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers and provides sufficient sample sizes to allow large scale studies, in order to reliably evaluate the effects of genetic modifiers.
BRCA1 Pathogenic Variants were associated with significantly increased risk of male breast cancer (RR = 4.30; 4.3 times increased risk), pancreatic cancer (RR = 2.36), and stomach cancer (RR = 2.17). Although associations of BRCA1 Pathogenic Variants with colorectal and gallbladder cancers were observed, the results were not robust in the sensitivity analyses performed.
BRCA2 Pathogenic Variants were associated with increased risk of male breast cancer (RR = 44.0), stomach cancer (RR = 3.69), pancreatic cancer (RR = 3.34) and prostate cancer (RR = 2.22). Female carriers had a higher risk of stomach cancer than male carriers (RR = 6.89 versus 2.76; P=0.04).
The absolute/cumulative risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers. In the present study, previously suggested associations of BRCA1 Pathogenic Variants with risks of other genitourinary cancers and increased risk of bone, brain, blood, gallbladder cancers and melanoma for BRCA2 Pathogenic Variants, were not replicated.
It was concluded from this analysis that in addition to female breast and ovarian cancers, BRCA1 and BRCA2 Pathogenic Variants are associated with increased risks of male breast cancer, pancreatic cancer, stomach cancer, and prostate cancer, the later only with BRCA2 Pathogenic Variants , but are not associated with the risks of other previously suggested cancers. These findings provide age-specific cancer risk estimates and will allow for improved cancer risk assessment of male and female BRCA1/2 carriers.
Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants. Li S, Silvestri V, Leslie G, et al. DOI: 10.1200/JCO.21.02112 Journal of Clinical Oncology – published online before print January 25, 2022.
