Analysis of Germline Variants in CDH1, IGFBP3, MMP1, MMP3, STK15 and VEGF in Familial and Sporadic Renal Cell Carcinoma

Christopher Ricketts,Eamonn R Maher,Maurice P Zeegers,Jan Lubinski,Philip Awadalla

doi:10.1371/journal.pone.0006037

Christopher Ricketts, Eamonn R Maher + Show 3 more

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https://doi.org/10.1371/journal.pone.0006037

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Abstract

BackgroundThe investigation of rare familial forms of kidney cancer has provided important insights into the biology of sporadic renal cell carcinoma (RCC). In particular, the identification of the von Hippel Lindau (VHL) familial cancer syndrome gene (VHL) provided the basis for the discovery that VHL is somatically inactivated in most sporadic clear cell RCC. Many cases of familial RCC do not have mutations in known RCC susceptibility genes and there is evidence that genetic modifiers may influence the risk of RCC in VHL disease patients. Hence we hypothesised that low-penetrance functional genetic variants in pathways related to the VHL protein (pVHL) function might (a) modify the phenotypic expression of VHL disease and/or (b) predispose to sporadic RCC.Methodology/Principal FindingsWe tested this hypothesis for functional polymorphisms in CDH1 (rs16260), IGFBP3 (rs2854744), MMP1 (rs1799750), MMP3 (rs679620), STK15 (rs2273535) and VEGF (rs1570360). We observed that variants of MMP1 and MMP3 were significant modifiers of RCC risk (and risks of retinal angioma and cerebellar haemangioblastoma) in VHL disease patients. In addition, higher frequencies of the MMP1 rs1799750 2G allele (p = 0.017, OR 1.49, 95%CI 1.06–2.08) and the MMP1/MMP3 rs1799750/rs679620 2G/G haplotype (OR 1.45, 95%CI 1.01–2.10) were detected in sporadic RCC patients than in controls (n = 295).Conclusions/SignificanceThese findings (a) represent the first example of genetic modifiers of RCC risk in VHL disease, (b) replicate a previous report of an association between MMP1/MMP3 variants and sporadic RCC and (c) further implicate MMP1/MMP3-related pathways in the pathogenesis of familial and sporadic RCC.

Highlights

Familial renal cell carcinoma (RCC) accounts for 2–3% of all patients with RCC, but the investigation of rare familial forms of kidney cancer has provided important insights into the pathogenesis of non-familial RCC
To determine if the observed modifier effects of Matrix metalloproteinase 1 (MMP1) and MMP3 variants extended to other features of von Hippel Lindau (VHL) disease, we repeated the Cox proportional hazard model analysis for age at diagnosis of retinal and cerebellar haemangioblastomas
Our findings suggest that functional SNPs in MMP1/MMP3 can influence susceptibility to RCC in familial (VHL disease) and sporadic patients and that MMP1 rs1799750 and MMP3 rs679620 genotypes can influence the risk of retinal angioma and cerebellar haemangioblastoma in VHL disease

Summary

Introduction

Familial renal cell carcinoma (RCC) accounts for 2–3% of all patients with RCC, but the investigation of rare familial forms of kidney cancer has provided important insights into the pathogenesis of non-familial RCC. We hypothesised that functional genetic variants in pathways related to pVHL function might modify the phenotypic expression of VHL disease and/or predispose to sporadic RCC. We tested this hypothesis for polymorphisms in CDH1, IGFBP3, MMP1, MMP3, STK15 and VEGF. Many cases of familial RCC do not have mutations in known RCC susceptibility genes and there is evidence that genetic modifiers may influence the risk of RCC in VHL disease patients. We hypothesised that low-penetrance functional genetic variants in pathways related to the VHL protein (pVHL) function might (a) modify the phenotypic expression of VHL disease and/or (b) predispose to sporadic RCC

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