Molecular analysis of early onset Indonesian breast cancer

Abstract

Breast cancer is a major health problem in Indonesia, especially among young women. Early onset breast cancer has been known as one of the indicators harboring germline BRCA1/2 mutation. Giving the fact that different BRCA1/2 mutations were found in different ethnic populations and no publications on BRCA1/2 mutation detection in the Indonesian population are available, identifying the Indonesian mutations is important for better risk assessment of Indonesian women who are susceptible to the BRCA1/2 related hereditary cancers. However, the large size of the BRCA1 and BRCA2, and the scattered distribution of mutations complicate the task of mutation detection and make rapid screening for mutations a major technical challenge. In chapter 2, we describe an intelligent pooled DGGE method to screen for BRCA1/2 mutations. This method seems to be the ideal approach for screening naﶥ populations for mutations and was able to detect single base differences using non-toxic and relatively simple and inexpensive procedures. A larger group of early onset breast cancer patients and their family members from three Indonesian cities were screened for BRCA1/2 mutations in chapter 3. A relatively high percentage of early onset Indonesian breast cancer patients were observed to carry a germline mutation in either BRCA1 or BRCA2, which comprises of several novel pathogenic and a variety of novel “unclassified variant” mutations that could be specific for the Indonesian population. Comparison of the three different Indonesian regions for BRCA1/2 mutations pointed to geographic differences. To distinguish between BRCA and non-BRCA carriers among these young women, we investigated in chapter 5 their histopathological and immuno-histochemical characteristics. Within the early onset group (2 genes) were more often poorly differentiated and at advanced stage compared to those with infrequent amplification (0-2 genes). This finding is important because it links gene amplification with well established pathological prognostic and predictive features of breast cancer. In chapter 6, we used the methylation specific MS-MLPA technique to do a comprehensive analysis of promoter methylation status of 22 tumor suppressor genes in invasive breast cancer, which revealed remarkable differences in methylation frequency for various genes. Promoter methylation of multiple genes was correlated to poor differentiation and HER-2/neu amplification. Although earlier studies have shown genetic differences between early and late onset breast cancer patients, such differences were not apparent with regard to promoter methylation of the tumor suppressor genes or amplification of the oncogenes analyzed in our Indonesian breast cancer population