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Background  The 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 Findings  We 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/Significance  These 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.

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