Evidence That BRCA1- or BRCA2-Associated Cancers Are Not Inevitable

Abstract

Inheriting a BRCA1 or BRCA2 gene mutation can cause a deficiency in repairing complex DNA damage. This step leads to genomic instability and probably contributes to an inherited predisposition to breast and ovarian cancer. Complex DNA damage has been viewed as an integral part of DNA replication before cell division. It causes temporary replication blocks, replication fork collapse, chromosome breaks and sister chromatid exchanges (SCEs). Chemical modification of DNA may also occur spontaneously as a byproduct of normal processes. Pathways containing BRCA1 and BRCA2 gene products are essential to repair spontaneous complex DNA damage or to carry out SCEs if repair is not possible. This scenario creates a theoretical limit that effectively means there are spontaneous BRCA1/2-associated cancers that cannot be prevented or delayed. However, much evidence for high rates of spontaneous DNA mutation is based on measuring SCEs by using bromodeoxyuridine (BrdU). Here we find that the routine use of BrdU has probably led to overestimating spontaneous DNA damage and SCEs because BrdU is itself a mutagen. Evidence based on spontaneous chromosome abnormalities and epidemiologic data indicates strong effects from exogenous mutagens and does not support the inevitability of cancer in all BRCA1/2 mutation carriers. We therefore remove a theoretical argument that has limited efforts to develop chemoprevention strategies to delay or prevent cancers in BRCA1/2 mutation carriers.

Expression of proteins involved in DNA damage response in familial and sporadic breast cancer patients

“…It is well known as an inherited BC susceptibility gene, and is responsible for both normal development and carcinogenesis in the breast. BRCA1 functional‐loss mutations lead to genome instability and predispose to familial BC . Furthermore, disruption of BRCA1 transcriptional activity through epigenetic silencing can be crucial for tumor formation in sporadic BCs …”

“…BRCA1 functional-loss mutations lead to genome instability and predispose to familial BC. 7 Furthermore, disruption of BRCA1 transcriptional activity through epigenetic silencing can be crucial for tumor formation in sporadic BCs. 2 The DDR is complex, and, in addition to BRCA1, poly(-ADP-ribose) polymerase-1 (PARP1), BRCT-repeat inhibitor of hTERT expression (BRIT1) and SWItch 5 (SWI5) proteins appear to have a number of important roles in this process and in the maintenance of genome integrity at various levels.…”

Sister chromatid exchange: A possible approach to characterize familial breast cancer patients

“…It is known that BRCA1 and BRCA2 are required for the maintenance of genomic integrity and that BRCA gene products are necessary for the control of faithful homologous recombination between sister chromatids in response to DNA damage (2). Our statistical analysis demonstrated no significant difference in SCE frequency between 'low-risk and high-risk' patients.…”

“…It is estimated that 5-10% of all breast carcinomas are inherited, whereas the remaining 90-95% are sporadic carcinomas. BRCA1 and BRCA2 genes are responsible for 3-8% of all BCs and for 15-20% of familial cases (1), and because these genes are involved in maintaining genome integrity the complete loss of function of encoded proteins leads to genomic instability (2,3). Increased genetic susceptibility could be associated with genomic instability, which could lead to chromosomal breakage.…”

Breast Cancer: Detection Markers, Prognosis, and Prevention

“…About half of hereditary breast-ovarian cancer syndrome involve unknown genes. [69].GATA-3 directly controls the expression of estrogen receptor(ER) and other genes associated with epithelial differentiation, and the loss of GATA-3 leads to loss of differentiation and poor prognosis due to cancer cell invasion and metastasis [70].…”