| Summary: | The aim of the study was to elucidate the variation in phenotypic expression
observed within BRCA2 c.8162delG mutation positive families. The study
attempted to identify possible genetic factors that contribute to the residual risk
conferred by the BRCA2 founder mutation. As BC is a polygenetic disorder,
polymorphisms within various low penetrance genes may contribute to the
expression of the disease. The selection of the SNPs were based on the results
of the CIMBA consortium and have been proven to be associated with an
increased BC risk in the general population (Easton et al., 2007) and in BRCA2
mutation carriers specifically (Antoniou et al., 2008). Two SNPs (rs2234693
[PvuII] and rs9340799 [XbaI]) present within ESR1 as well as SNPs present in
TNRC9 (rs3803662), LSP1 (rs3817198), MAP3K1 (rs889312) and FGFR2
(rs2981582) identified by GWAS have been implicated in BC risk. These six
polymorphisms have been selected to evaluate the risk within the Afrikaner
BRCA2 8162delG (c.7934del, p.Arg2645AsnfsX3) mutation carriers specifically.
Genotyping of rs2234693 (PvuII) and rs9340799 (XbaI) was done by PCR-RFLP
analysis whereas Taqman® assays were used for genotyping rs3803662
(TNRC9), rs3817198 (LSP1), rs889312 (MAP3K1) and rs2981582 (FGFR2).
Automated allelic discrimination using the BioRad CFX Manager v1.1.308.1111
software were compared to manual discrimination methods to ensure robust
genotyping. Cohenâs kappa analysis suggested a combination of automated
(Method 1) and manual (Method 3) genotyping was best suited for accurate allelic
discrimination except for LSP1. Due to an putative SNP detected within LSP1, the
validity of the LSP1 results should be treated cautiously as no information on the
frequency of the second putative SNP in white European individuals is available. Of the six polymorphisms analyzed, only rs2234693 (PvuII), indicated a possible
association with BC (P-value = 0.0896), which should be explored within a larger
study group. For FGFR2, the HWE results indicated that the deviation observed in
the BRCA2 mutation carrier group could possibly be associated with BC.
Haplotypes compiled for rs2234693 (PvuII) and rs9340799 (XbaI) as well as the
remaining four SNPs were uninformative as it revealed no differences between the
BC patients and the Cases. These results may have been due to the high allelic
heterogeneity observed within the Afrikaner population, as well as the small test
group used..
Although the results of this study did not deliver significant results, it did provide
insight into allelic distributions of the SNPs in the Afrikaner BRCA2 8162delG
(c.7934del, p.Arg2645AsnfsX3) mutation carriers specifically. Larger scale
genotyping could lead to more significant findings to help elucidate the
polygenetic nature of BC with the Afrikaner.
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