Abnormality of the DNA double-strand-break checkpoint/repair genes, ATM, BRCA1 and TP53, in breast cancer is related to tumour grade

Abstract

The role of the DNA double-strand-break (DSB) checkpoint/repair genes, ATM, BRCA1 and TP53, in sporadic breast cancer requires clarification, since ATM and BRCA1 mutations are rare in sporadic tumours. In an attempt to explain this phenomenon, we postulated that (i) in addition to genetic deletion, abnormal expression of DSB checkpoint/repair proteins might abolish the function of these genes and (ii) there might be a combined effect of individual defective genes during breast cancer pathogenesis. Using a largely homogenous group of 74 specimens of early-onset (p35 years of age) infiltrating ductal carcinomas, we examined associations between pathological grade and genetic deletion and/or abnormal protein expression of ATM, BRCA1 and TP53. The results showed that high-grade tumours displayed a high frequency of loss of heterozygosity (LOH) at, and/or abnormal expression of, ATM, BRCA1 and TP53. Multigenetic analysis showed abnormalities in BRCA1 to be independently associated with high-grade tumours. ATM and TP53 appeared to play an assistant role, abnormalities in these genes significantly increasing the possibility of poor differentiation in tumours with abnormalities in BRCA1. Furthermore, a higher number of abnormalities (LOH or abnormal expression) in these three genes correlated with poor tumour differentiation. Thus, this study suggests that combined changes in several DSB checkpoint/repair genes belonging to a common functional pathway are associated with breast cancer pathogenesis.

Breast Cancer Risk Is Associated with the Genes Encoding the DNA Double-Strand Break Repair Mre11/Rad50/Nbs1 Complex

“…The fact that the familial breast cancer susceptibility genes BRCA1 and BRCA2 are involved in the homologous recombination pathway for DNA DSB repair (48) and our previous finding that the extent of DSB-initiated chromosomal instability in tumors increases significantly, as tumors progress to poorer grades or later stages (21) support the idea that breast cancer pathogenesis is driven by DSB-initiated chromosomal instability, and we hypothesize that the mechanisms regulating DSB repair may play a mutator role. In our recent studies (16,25,26,49), we have identified specific molecular DSB repair mechanisms, functional aberrations of which are related to an increased risk of breast cancer and advanced pathologic/clinical manifestations. The results of the present study provide additional evidence supporting the mutator role of DSB repair mechanisms during breast cancer formation.…”

Genetic Variation in the Premature Aging Gene WRN: A Case-Control Study on Breast Cancer Susceptibility

“…Our case-control study is part of an ongoing cooperative study aimed at understanding the causes of breast cancer in Taiwan, which is characterized by low incidence, early tumor onset, hormone dependency, and novel genomic alterations (15)(16)(17)(18)(19)(20)(21). Because of the low incidence of breast cancer in the Taiwanese population, which suggests an overall lower effect of common risk factors, and because of its homogenous genetic background, this population is considered to have certain advantages for studying the effects of subtle genetic variations (17,20), such as SNPs.…”

Diverse Associations between ESR1 Polymorphism and Breast Cancer Development and Progression

“…This case-control study is part of an ongoing cooperative study aimed at understanding the causes of breast cancer in Taiwan, which is characterized by low incidence, early tumor onset, hormone dependency, and novel genomic alterations (28)(29)(30). We studied 940 female breast cancer women with pathologically confirmed incident primary breast cancer seen at the Tri-Service General Hospital or the Changhua Christian Hospital between March 2002 and August 2005.…”