Abstract
BackgroundUsing a genome-wide approach, we have previously observed an increase in the frequency of rare copy number variants (CNVs) in familial and early-onset breast cancer cases when compared to controls. Moreover, the biological networks of the CNV disrupted genes differed between the two groups. Here, six of the previously observed CNVs were selected for further investigation. Four of these were singletons and disturbed the following genes: DCLRE1C, CASP3, DAB2IP and ITGA9, encoding proteins that are part of the TP53 and β-estradiol centered network. The two others were recurrent alleles and disrupted CDH19 and CYP2C19 genes. Of these, CDH19 encodes a cadherin functioning as a cell-cell adhesion receptor and CYP2C19 a CYP450 enzyme with a major function in estrogen catabolism.MethodsThe exact breakpoints of the six previously observed CNV deletion alleles were defined by using qPCR, nested PCR and sequencing. The prevalence of these CNVs was investigated in 842 Northern Finnish breast cancer cases, unselected for family history of cancer and age at disease onset, as well as in 497 healthy female controls by using multiplex PCR. Also the association of the relatively common CDH19 and CYP2C19 deletion alleles with different clinical parameters was studied.ResultsNo significant differences in the carrier frequencies between cases and controls were found for any of the studied CNVs. However, the deletion in CYP2C19 showed a significant association with triple-negative breast cancer (p = 0.021).ConclusionOur results indicate that inherited changes in CYP2C19 gene participating in estrogen catabolism have an influence on the molecular subtype of breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-902) contains supplementary material, which is available to authorized users.
Highlights
Using a genome-wide approach, we have previously observed an increase in the frequency of rare copy number variants (CNVs) in familial and early-onset breast cancer cases when compared to controls
The CYP2C19 deletion carrier frequency was only marginally higher in the breast cancer cases (31/842, 3.7%) when compared to the controls (17/497, 3.4%), being relatively high in both groups
Much of the work in this field has been concentrating on single nucleotide polymorphisms (SNPs) whereas the role of CNVs has remained poorly defined, partially because their detection with Sanger or even with sophisticated Next-Generation sequencing is hard or even impossible, and the fast and cost-efficient investigation of CNV alleles requires the characterization of their breakpoints in exact detail
Summary
Using a genome-wide approach, we have previously observed an increase in the frequency of rare copy number variants (CNVs) in familial and early-onset breast cancer cases when compared to controls. CDH19 encodes a cadherin functioning as a cell-cell adhesion receptor and CYP2C19 a CYP450 enzyme with a major function in estrogen catabolism. We observed a consistent increase in the Based on their biological functions and recurrence, two of the previously identified deletion alleles disrupting CYP2C19 and CDH19 genes, respectively, were hypothesized to play a role in breast cancer predisposition in the general population. The CYP2C19 deletion allele was found twice as frequent in familial breast cancer cases (5.8%) as in controls (2.3%), whereas CDH19 was observed once in both familial (1.0%) and control cohorts (0.8%) [4], implicating the need for a larger dataset for the evaluation of their disease relatedness. Besides the breast cancer risk itself, both changes could have an effect on tumor biology
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