Dataset Information

Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide.

ABSTRACT: Background:The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a hereditary tumor syndrome caused by germline pathogenic variants in BAP1 encoding a tumor suppressor associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and cutaneous BAP1-inactivated melanocytic tumors. However, the full spectrum of tumors associated with the syndrome is yet to be determined. Improved understanding of the BAP1-TPDS is crucial for appropriate clinical management of BAP1 germline variant carriers and their families, including genetic counseling and surveillance for new tumors. Methods:We collated germline variant status, tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS. Tumor spectrum and ages of onset were compared between missense and null variants. All statistical tests were two-sided. Results:The 181 families carried 140 unique BAP1 germline variants. The collated data confirmed the core tumor spectrum associated with the BAP1-TPDS and showed that some families carrying missense variants can exhibit this phenotype. A variety of noncore BAP1-TPDS -associated tumors were found in families of variant carriers. Median ages of onset of core tumor types were lower in null than missense variant carriers for all tumors combined (P?

SUBMITTER: Walpole S

PROVIDER: S-EPMC6292796 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide.

Walpole Sebastian S Pritchard Antonia L AL Cebulla Colleen M CM Pilarski Robert R Stautberg Meredith M Davidorf Frederick H FH de la Fouchardière Arnaud A Cabaret Odile O Golmard Lisa L Stoppa-Lyonnet Dominique D Garfield Erin E Njauw Ching-Ni CN Cheung Mitchell M Turunen Joni A JA Repo Pauliina P Järvinen Reetta-Stiina RS van Doorn Remco R Jager Martine J MJ Luyten Gregorius P M GPM Marinkovic Marina M Chau Cindy C Potrony Miriam M Höiom Veronica V Helgadottir Hildur H Pastorino Lorenza L Bruno William W Andreotti Virginia V Dalmasso Bruna B Ciccarese Giulia G Queirolo Paola P Mastracci Luca L Wadt Karin K Kiilgaard Jens Folke JF Speicher Michael R MR van Poppelen Natasha N Kilic Emine E Al-Jamal Rana'a T RT Dianzani Irma I Betti Marta M Bergmann Carsten C Santagata Sandro S Dahiya Sonika S Taibjee Saleem S Burke Jo J Poplawski Nicola N O'Shea Sally J SJ Newton-Bishop Julia J Adlard Julian J Adams David J DJ Lane Anne-Marie AM Kim Ivana I Klebe Sonja S Racher Hilary H Harbour J William JW Nickerson Michael L ML Murali Rajmohan R Palmer Jane M JM Howlie Madeleine M Symmons Judith J Hamilton Hayley H Warrier Sunil S Glasson William W Johansson Peter P Robles-Espinoza Carla Daniela CD Ossio Raul R de Klein Annelies A Puig Susana S Ghiorzo Paola P Nielsen Maartje M Kivelä Tero T TT Tsao Hensin H Testa Joseph R JR Gerami Pedram P Stern Marc-Henri MH Paillerets Brigitte Bressac-de BB Abdel-Rahman Mohamed H MH Hayward Nicholas K NK

Journal of the National Cancer Institute 20181201 12

<h4>Background</h4>The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a hereditary tumor syndrome caused by germline pathogenic variants in BAP1 encoding a tumor suppressor associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and cutaneous BAP1-inactivated melanocytic tumors. However, the full spectrum of tumors associated with the syndrome is yet to be determined. Improved understanding of the BAP1-TPDS is crucial for appropriat ...[more]

PMID: 30517737

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Project description:INTRODUCTION:Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with variants in E-cadherin (CDH1), diffuse gastric cancer and lobular breast cancer. There is considerable heterogeneity in its clinical manifestations. This study aimed to determine associations between CDH1 germline variant status and clinical phenotypes of HDGC. METHODS:One hundred and fifty-two HDGC families, including six previously unreported families, were identified. CDH1 gene-specific guidelines released by the Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel were applied for pathogenicity classification of truncating, missense and splice site CDH1 germline variants. We evaluated ORs between location of truncating variants of CDH1 and incidence of colorectal cancer, breast cancer and cancer at young age (gastric cancer at <40?or breast cancer <50 years of age). RESULTS:Frequency of truncating germline CDH1 variants varied across functional domains of the E-cadherin receptor gene and was highest in linker (0.05785 counts/base pair; p=0.0111) and PRE regions (0.10000; p=0.0059). Families with truncating CDH1 germline variants located in the PRE-PRO region were six times more likely to have family members affected by colorectal cancer (OR 6.20, 95% CI 1.79 to 21.48; p=0.004) compared with germline variants in other regions. Variants in the intracellular E-cadherin region were protective for cancer at young age (OR 0.2, 95% CI 0.06 to 0.64; p=0.0071) and in the linker regions for breast cancer (OR 0.35, 95% CI 0.12 to 0.99; p=0.0493). Different CDH1 genotypes were associated with different intracellular signalling activation levels including different p-ERK, p-mTOR and ?-catenin levels in early submucosal T1a lesions of HDGC families with different CDH1 variants. CONCLUSION:Type and location of CDH1 germline variants may help to identify families at increased risk for concomitant cancers that might benefit from individualised surveillance and intervention strategies.

Project description:Leber congenital amaurosis (LCA) is the earliest and most severe retinal degeneration (RD), and the most common cause of incurable blindness diagnosed in children. It is occasionally the presenting symptom of multisystemic ciliopathies which diagnosis will require a specific care of patients. Nineteen LCA genes are currently identified and three of them account for both non-syndromic and syndromic forms of the disease. RD3 (LCA12) was implicated as a LCA gene based on the identification of homozygous truncating mutations in two LCA families despite the screening of large cohorts of patients. Here we provide a comprehensive survey of RD3 mutations and of their clinical expression through the screening of a cohort of 852 patients originating worldwide affected with LCA or early-onset and severe RD. We identified three RD3 mutations in seven unrelated consanguineous LCA families - i.e., a 2 bp deletion and two nonsense mutations - predicted to cause complete loss of function. Five families originating from the Southern Shores of the Mediterranean segregated a similar mutation (c.112C>T, p.R38*) suggesting that this change may have resulted from an ancient founder effect. Considering the low frequency of RD3 carriers, the recurrence risk for LCA in non-consanguineous unions is negligible for both heterozygote and homozygote RD3 individuals. The LCA12 phenotype in our patients is highly similar to those of patients with mutant photoreceptor-specific guanylate cyclase (GUCY2D/LCA1). This observation is consistent with the report of the role of RD3 in trafficking of GUCYs and gives further support to a common mechanism of photoreceptor degeneration in LCA12 and LCA1, i.e., inability to increase cytoplasmic cGMP concentration in outer segments and thus to recover the dark-state. Similar to LCA1, LCA12 patients have no extraocular symptoms despite complete inactivation of both RD3 alleles, supporting the view that extraocular investigations in LCA infants with RD3 mutations should be avoided.

Dataset Information

Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide.

Publications

Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide.

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