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Germline sequence variants in TGM3 and RGS22 confer risk of basal cell carcinoma.

ABSTRACT: To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide association study of 38.5 million single nucleotide polymorphisms (SNPs) and small indels identified through whole-genome sequencing of 2230 Icelanders. We imputed genotypes for 4208 BCC patients and 109 408 controls using Illumina SNP chip typing data, carried out association tests and replicated the findings in independent population samples. We found new BCC susceptibility loci at TGM3 (rs214782[G], P = 5.5 × 10(-17), OR = 1.29) and RGS22 (rs7006527[C], P = 8.7 × 10(-13), OR = 0.77). TGM3 encodes transglutaminase type 3, which plays a key role in production of the cornified envelope during epidermal differentiation.

SUBMITTER: Stacey SN

PROVIDER: S-EPMC4014188 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Germline sequence variants in TGM3 and RGS22 confer risk of basal cell carcinoma.

Stacey Simon N SN Sulem Patrick P Gudbjartsson Daniel F DF Jonasdottir Aslaug A Thorleifsson Gudmar G Gudjonsson Sigurjon A SA Masson Gisli G Gudmundsson Julius J Sigurgeirsson Bardur B Benediktsdottir Kristrun R KR Thorisdottir Kristin K Ragnarsson Rafn R Fuentelsaz Victoria V Corredera Cristina C Grasa Matilde M Planelles Dolores D Sanmartin Onofre O Rudnai Peter P Gurzau Eugene E Koppova Kvetoslava K Hemminki Kari K Nexø Bjørn A BA Tjønneland Anne A Overvad Kim K Johannsdottir Hrefna H Helgadottir Hafdis T HT Thorsteinsdottir Unnur U Kong Augustine A Vogel Ulla U Kumar Rajiv R Nagore Eduardo E Mayordomo José I JI Rafnar Thorunn T Olafsson Jon H JH Stefansson Kari K

Human molecular genetics 20140108 11

To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide association study of 38.5 million single nucleotide polymorphisms (SNPs) and small indels identified through whole-genome sequencing of 2230 Icelanders. We imputed genotypes for 4208 BCC patients and 109 408 controls using Illumina SNP chip typing data, carried out association tests and replicated the findings in independent population samples. We found new BCC susceptibility ...[more]

PMID: 24403052

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Project description:BackgroundDespite guidelines recommending genetic counseling for patients with early-onset renal cell carcinoma (RCC), studies interrogating the spectrum of germline mutations and clinical associations in patients with early-onset RCC are lacking.ObjectiveTo define the germline genetic spectrum and clinical associations for patients with early-onset RCC diagnosed at age ≤46 yr who underwent genetic testing.Design, setting, and participantsWe retrospectively identified patients with early-onset RCC who underwent germline testing at our institution from February 2003 to June 2020.Outcome measurement and statistical analysisThe frequency and spectrum of pathogenic/likely pathogenic (P/LP) variants were determined. Clinical characteristics associated with mutation status were analyzed using two-sample comparison (Fisher's exact or χ2 test).Results and limitationsOf 232 patients with early-onset RCC, 50% had non-clear-cell histology, including unclassified RCC (12.1%), chromophobe RCC (9.7%), FH-deficient RCC (7.0%), papillary RCC (6.6%), and translocation-associated RCC (4.3%). Overall, 43.5% had metastatic disease. Germline P/LP variants were identified in 41 patients (17.7%), of which 21 (9.1%) were in an RCC-associated gene and 20 (8.6%) in a non-RCC-associated gene, including 17 (7.3%) in DNA damage repair genes such as BRCA1/2, ATM, and CHEK2. Factors associated with RCC P/LP variants include bilateral/multifocal renal tumors, non-clear-cell histology, and additional extrarenal primary malignancies. In patients with only a solitary clear-cell RCC, the prevalence of P/LP variants in RCC-associated and non-RCC-associated genes was 0% and 9.9%, respectively.ConclusionsPatients with early-onset RCC had high frequencies of germline P/LP variants in genes associated with both hereditary RCC and other cancer predispositions. Germline RCC panel testing has the highest yield when patients have clinical phenotypes suggestive of underlying RCC gene mutations. Patients with early-onset RCC should undergo comprehensive assessment of personal and family history to guide appropriate genetic testing.Patient summaryIn this study of 232 patients with early-onset kidney cancer who underwent genetic testing, we found a high prevalence of mutations in genes that increase the risk of cancer in both kidneys and other organs for patients and their at-risk family members. Our study suggests that patients with early-onset kidney cancer should undergo comprehensive genetic risk assessment.

Dataset Information

Germline sequence variants in TGM3 and RGS22 confer risk of basal cell carcinoma.

Publications

Germline sequence variants in TGM3 and RGS22 confer risk of basal cell carcinoma.

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