| Summary: | Introduction
Breast cancer with positive family history is due to the interaction between
genetic and environment factors. An estimated 5-10% of familial breast
cancer is associated with mutations of susceptibility genes. While BRCA
mutation identification is a common practice worldwide, no study has
determined the role of BRCA and other susceptibility genes mutation in
Indonesian population. A few methods exist for the identification of
susceptibility genes. With the identification of Indonesian susceptibility
genes and the new risk assessment model of Indonesian population can
contribute the further further screening and cancer prevention method.
Materials and Methods
408 blood and tissue samples were collected from 1246 cohort in Jakarta,
Yogyakarta and Bali for PCR and DNA sequencing of BRCA1/2 and p53.
Study design is hybrid nested design with the family base genetic
epidemiology approach. Pedigrees were constructed and 26 selected familiy
pedigree were performed for whole-exome sequencing, 3 of which
underwent linkage analysis. Genome-wide association study with with
microarray on 200 samples were performed to identify other susceptibility
genes using SNP markers.
Bayesian-Mendel model was used to calculate the probability of genetic
and non genetic risks. Statistical analysis of R programmend the cox
proportional-hazard regression were used for this hybrid cohort study useda
to determine the cumulative life-time risk.
The new risk calculation model was validated by comparing the ROC curve
amongs the Gail, Claus and BRCAPRO models.
Results
We found 10 mutations in BRCA1 and BRCA2. There were 2 (BRCA2)
nonsense mutation and 8 (1 BRCA1 and 7 BCRA2) missense mutation
p.Ile2627Ser and p.Leu2688Pro, were registerd at BIC as novel mutation.
Other mutation of p.Met1652Ile and p.Ile3412Val were considered as
candidate gene and were identified mostly at BRCA2 exon 11 and 27.
SNPs p53 codon 72 were found with the genotype GC 56%, CG 20%, CC
95% and the polymorphism of the gen MDM2 the SNPs with the genotype
TG 64% and TT 36%.
Linkage analysis suggested the presence of other susceptibility genes on
chromosome 3 and 4. Though further research is needed, this result
confirmed the polygenic inheritance model of familial breast cancer. A few
disease susceptibility markers had also been identified. A new risk
assessment model for Indonesian population incorporating these results
were developed, called SAMANDA.
The GWAS (Genome Wide Association Study) reveals SNPs that
significantly associated with the maximum odd ratios rs2419565,
rs2942428, rs10925947, rs6722296, rs 17030023, rs 12997287 and rs
17115674 respectively grouped according to the family history.
A new model of risk calculation (Samanda) was developed to assess the
genetic and non genetic risks.
Conclusion
Several polygenic mutations of BRCAs, non BRCAs and other subseptible
genes on chromosome 3 and 4 were reported. Polymorphism and SNPs as
disease susceptibility markers were mapped. A new model of risk
assessment was developed to calculate the genetic and non genetic factors.
This model (Samanda) will be updated and publicly opened for further
studies.
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