Dataset Information

Germline genetic variations in PDZD2 and ITPR2 genes are associated with clear cell renal cell carcinoma in Chinese population.

ABSTRACT: Genome-wide association studies (GWAS) of renal cell carcinoma (RCC) have identified single nucleotide polymorphisms (SNPs) associated with RCC in European and African American population. In this study, we evaluated whether these SNPs are associated with clear cell RCC (ccRCC) in Chinese population. All reported RCC risk-associated SNPs from GWAS were evaluated in 346 ccRCC cases and 1,130 controls. Rs10054504 (at PDZD2, Odds ratio, OR = 0.71, 95%CI:0.59-0.86, P = 0.0006), rs718314 (at ITPR2, OR = 0.56, 95%CI:0.45-0.69, P = 5.26×10-8) and rs1049380 (at ITPR2, by dominant model, OR = 1.58, 95%CI:1.18-2.13, P = 0.0025) were significantly associated with ccRCC risk in Chinese population. To conclude, genetic variations in PDZD2 and ITPR2 are ccRCC-risk associated in Chinese population.

SUBMITTER: Zhang N

PROVIDER: S-EPMC5421839 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Germline genetic variations in PDZD2 and ITPR2 genes are associated with clear cell renal cell carcinoma in Chinese population.

Zhang Ning N Wu Yishuo Y Gong Jian J Li Kaiwen K Lin Xiaolin X Chen Haitao H Yu Yang Y Gou Yuancheng Y Hou Jiangang J Jiang Deke D Na Rong R Wang Xiang X Ding Qiang Q Xu Jianfeng J

Oncotarget 20170401 15

Genome-wide association studies (GWAS) of renal cell carcinoma (RCC) have identified single nucleotide polymorphisms (SNPs) associated with RCC in European and African American population. In this study, we evaluated whether these SNPs are associated with clear cell RCC (ccRCC) in Chinese population. All reported RCC risk-associated SNPs from GWAS were evaluated in 346 ccRCC cases and 1,130 controls. Rs10054504 (at PDZD2, Odds ratio, OR = 0.71, 95%CI:0.59-0.86, P = 0.0006), rs718314 (at ITPR2, O ...[more]

PMID: 26918600

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Project description:Background and objectivePrevious germline studies on renal cell carcinoma (RCC) have usually pooled clear and non-clear cell RCCs and have not adequately accounted for population stratification, which might have led to an inaccurate estimation of genetic risk. Here, we aim to analyze the major germline drivers of RCC risk and clinically relevant but underexplored germline variant types.MethodsWe first characterized germline pathogenic variants (PVs), cryptic splice variants, and copy number variants (CNVs) in 1436 unselected RCC patients. To evaluate the enrichment of PVs in RCC, we conducted a case-control study of 1356 RCC patients ancestry matched with 16 512 cancer-free controls using approaches accounting for population stratification and histological subtypes, followed by characterization of secondary somatic events.Key findings and limitationsClear cell RCC patients (n = 976) exhibited a significant burden of PVs in VHL compared with controls (odds ratio [OR]: 39.1, p = 4.95e-05). Non-clear cell RCC patients (n = 380) carried enrichment of PVs in FH (OR: 77.9, p = 1.55e-08) and MET (OR: 1.98e11, p = 2.07e-05). In a CHEK2-focused analysis with European participants, clear cell RCC (n = 906) harbored nominal enrichment of low-penetrance CHEK2 variants-p.Ile157Thr (OR: 1.84, p = 0.049) and p.Ser428Phe (OR: 5.20, p = 0.045), while non-clear cell RCC (n = 295) exhibited nominal enrichment of CHEK2 loss of function PVs (OR: 3.51, p = 0.033). Patients with germline PVs in FH, MET, and VHL exhibited significantly earlier age of cancer onset than patients without germline PVs (mean: 46.0 vs 60.2 yr, p < 0.0001), and more than half had secondary somatic events affecting the same gene (n = 10/15, 66.7%). Conversely, CHEK2 PV carriers exhibited a similar age of onset to patients without germline PVs (mean: 60.1 vs 60.2 yr, p = 0.99), and only 30.4% carried somatic events in CHEK2 (n = 7/23). Finally, pathogenic germline cryptic splice variants were identified in SDHA and TSC1, and pathogenic germline CNVs were found in 18 patients, including CNVs in FH, SDHA, and VHL.Conclusions and clinical implicationsThis analysis supports the existing link between several RCC risk genes and RCC risk manifesting in earlier age of onset. It calls for caution when assessing the role of CHEK2 due to the burden of founder variants with varying population frequency. It also broadens the definition of the RCC germline landscape of pathogenicity to incorporate previously understudied types of germline variants.Patient summaryIn this study, we carefully compared the frequency of rare inherited mutations with a focus on patients' genetic ancestry. We discovered that subtle variations in genetic background may confound a case-control analysis, especially in evaluating the cancer risk associated with specific genes, such as CHEK2. We also identified previously less explored forms of rare inherited mutations, which could potentially increase the risk of kidney cancer.

Dataset Information

Germline genetic variations in PDZD2 and ITPR2 genes are associated with clear cell renal cell carcinoma in Chinese population.

Publications

Germline genetic variations in PDZD2 and ITPR2 genes are associated with clear cell renal cell carcinoma in Chinese population.

Similar Datasets

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