Dataset Information

Combined germline pathogenic variants in FLCN and TP53 are associated with early onset renal cell carcinoma and brain tumors.

ABSTRACT:

Background

We present a family consisting of a father and his two children with an exceptional phenotype of childhood renal cell carcinoma and brain tumors. Extensive genetic testing revealed two inherited tumor predisposition syndromes in all three family members: Birt-Hogg-Dubé syndrome and Li-Fraumeni syndrome. The corresponding genes (FLCN and TP53) are both located on the short arm of chromosome 17.

Methods

We describe the phenotype and performed single nucleotide polymorphism (SNP)-based loss of heterozygosity (LOH) analysis of the tumors.

Results

All examined tumors showed somatic loss of the wild-type alleles of both FLCN and TP53.

Conclusions

We hypothesize that a synergistic effect of both mutations caused the unusual phenotype of childhood renal cell carcinoma in this family. This family emphasizes the importance of further genetic testing if a tumor develops at an unexpected young age in an inherited cancer predisposition syndrome.

SUBMITTER: van de Beek I

PROVIDER: S-EPMC9938753 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

Combined germline pathogenic variants in FLCN and TP53 are associated with early onset renal cell carcinoma and brain tumors.

van de Beek Irma I Glykofridis Iris E IE Wagner Anja A den Toom Dorine T DT Bongers Ernie M H F EMHF van Leenders Geert J L H GJLH Johannesma Paul C PC Meijers-Heijboer Hanne E J HEJ Wolthuis Rob M F RMF van Steensel Maurice A M MAM Dubbink Hendrikus J HJ Houweling Arjan C AC

Molecular genetics & genomic medicine 20221116 2

<h4>Background</h4>We present a family consisting of a father and his two children with an exceptional phenotype of childhood renal cell carcinoma and brain tumors. Extensive genetic testing revealed two inherited tumor predisposition syndromes in all three family members: Birt-Hogg-Dubé syndrome and Li-Fraumeni syndrome. The corresponding genes (FLCN and TP53) are both located on the short arm of chromosome 17.<h4>Methods</h4>We describe the phenotype and performed single nucleotide polymorphis ...[more]

PMID: 36382415

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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.

Project description:In breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somatic TP53 or PIK3CA mutation status in breast tumors. A genome-wide association study was conducted in 2,850 women of European ancestry with breast cancer using TP53 and PIK3CA mutation status (positive or negative) as well as specific functional categories [e.g., TP53 gain-of-function (GOF) and loss-of-function, PIK3CA activating] as phenotypes. Germline variants showing evidence of association were selected for validation analyses and tested in multiple independent datasets. Discovery association analyses found five variants associated with TP53 mutation status with P values <1 × 10-6 and 33 variants with P values <1 × 10-5. Forty-four variants were associated with PIK3CA mutation status with P values <1 × 10-5. In validation analyses, only variants at the ESR1 locus were associated with TP53 mutation status after multiple comparisons corrections. Combined analyses in European and Malaysian populations found ESR1 locus variants rs9383938 and rs9479090 associated with the presence of TP53 mutations overall (P values 2 × 10-11 and 4.6 × 10-10, respectively). rs9383938 also showed association with TP53 GOF mutations (P value 6.1 × 10-7). rs9479090 showed suggestive evidence (P value 0.02) for association with TP53 mutation status in African ancestry populations. No other variants were significantly associated with TP53 or PIK3CA mutation status. Larger studies are needed to confirm these findings and determine if additional variants contribute to ancestry-specific differences in mutation frequency.SignificanceEmerging data show ancestry-specific differences in TP53 and PIK3CA mutation frequency in breast tumors suggesting that germline variants may influence somatic mutational processes. This study identified variants near ESR1 associated with TP53 mutation status and identified additional loci with suggestive association which may provide biological insight into observed differences.

Dataset Information

Combined germline pathogenic variants in FLCN and TP53 are associated with early onset renal cell carcinoma and brain tumors.

Background

Methods

Results

Conclusions

Publications

Combined germline pathogenic variants in FLCN and TP53 are associated with early onset renal cell carcinoma and brain tumors.

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