Central nervous system (CNS) dural arteriovenous fistulas (DAVF) have been reported in PTEN‐related hamartoma tumor syndrome (PHTS). However, PHTS‐associated DAVF remain an underexplored field of the ...PHTS clinical landscape. Here, we studied cases with a PTEN pathogenic variant identified between 2007 and 2020 in our laboratory (n = 58), and for whom brain imaging was available. Two patients had DAVF (2/58, 3.4%), both presenting at advanced stages: a 34‐year‐old man with a left lateral sinus DAVF at immediate risk of hemorrhage, and a 21‐year‐old woman with acute intracranial hypertension due to a torcular DAVF. Interestingly, not all patients had 3D TOF/MRA, the optimal sequences to detect DAVF. Early diagnosis of DAVF can be lifesaving, and is easier to treat compared to developed, proliferative, or complex lesions. As a result, one should consider brain MRI with 3D TOF/MRA in PHTS patients at genetic diagnosis, with subsequent surveillance on a case‐by‐case basis.
Among a series of patients with PHTS (n = 58), two patients had dural arteriovenous fistulas, both presenting at advanced stages. Early diagnosis facilitates treatment of these rare, life‐threatening lesions and can be lifesaving. Brain MRI with 3D TOF/MRA should be considered in PHTS patients.
Only a few patients with germline AXIN2 variants and colorectal adenomatous polyposis or cancer have been described, raising questions about the actual contribution of this gene to colorectal cancer ...(CRC) susceptibility. To assess the clinical relevance for AXIN2 testing in patients suspected of genetic predisposition to CRC, we collected clinical and molecular data from the French Oncogenetics laboratories analyzing AXIN2 in this context. Between 2004 and June 2020, 10 different pathogenic/likely pathogenic AXIN2 variants were identified in 11 unrelated individuals. Eight variants were from a consecutive series of 3322 patients, which represents a frequency of 0.24%. However, loss‐of‐function AXIN2 variants were strongly associated with genetic predisposition to CRC as compared with controls (odds ratio: 11.89, 95% confidence interval: 5.103–28.93). Most of the variants were predicted to produce an AXIN2 protein devoid of the SMAD3‐binding and DIX domains, but preserving the β‐catenin‐binding domain. Ninety‐one percent of the AXIN2 variant carriers who underwent colonoscopy had adenomatous polyposis. Forty percent of the variant carriers developed colorectal or/and other digestive cancer. Multiple tooth agenesis was present in at least 60% of them. Our report provides further evidence for a role of AXIN2 in CRC susceptibility, arguing for AXIN2 testing in patients with colorectal adenomatous polyposis or cancer.
MUTYH-associated polyposis (MAP) was first described in 2002. It is an autosomal recessive condition associated with germline pathogenic variants of both MUTYH alleles. In 2011, a group of French ...experts reviewed the available data on this syndrome and established recommendations concerning the indications and strategies for molecular analysis of the MUTYH gene in index cases and their relatives, as well as the clinical management of affected individuals under the auspices of the French Institut National du Cancer (INCa). Some of these recommendations have become obsolete as a result of recent progress, especially those concerning the molecular strategy for MUTYH testing, as this gene has recently been included in a consensus panel of 14 colorectal cancer predisposition genes, justifying revision of the previous report. We report here the revised version of this work, which successively considers the phenotype and tumor risks associated with this genotype, differential diagnoses, criteria and strategy for molecular genetic testing and recommendations for the management of affected individuals. We also discuss the phenotype and tumor risks associated with monoallelic pathogenic variants of MUTYH.
Aim
Angiomatosis of soft tissue (AST) is a rare, high‐flow, intramuscular vascular anomaly. In the context of PTEN hamartoma tumour syndrome (PHTS), this AST is referred to as PTEN hamartoma of soft ...tissue. Given that AST is observed in patients with no history of PHTS, we hypothesised that non‐syndromic AST arises as a consequence of a somatic mutation.
Methods and results
Thirteen patients with histologically confirmed AST were retrospectively studied. Details of the patients’ personal and family medical histories and symptoms were retrieved from their medical records. The histological analyses were reviewed and a tissue sample was used for genetic testing. Somatic mutations in the PIK3CA gene (p.Glu542Lys; p.Glu545Lys; p.His1047Arg) were identified in the tissue samples from seven patients, all of whom had unremarkable medical histories and had presented with a single lesion located in the lower limb. Five pathogenic variations in the PTEN gene (mutations: p.Lys263Arg; c.1026+2T>A; p.Ala126Thr; p.Leu108Arg; deletion, log ratio −0.55) were identified in the lesions of four patients; two of the latter had multifocal lesions. All four patients displayed macrocephaly, three boys presented with penile freckles, but none had a family history of PHTS. There were no histological differences between the PIK3CA and PTEN groups.
Conclusions
AST can be related to either PTEN or PIK3CA mutations and may be multifocal in PHTS. AST appears to be a manifestation of PHTS that occurs in early childhood. The patient's medical history and clinical presentation should prompt the physician to perform specific genetic testing.
ABSTRACT
As next‐generation sequencing increases access to human genetic variation, the challenge of determining clinical significance of variants becomes ever more acute. Germline variants in the ...BRCA1 and BRCA2 genes can confer substantial lifetime risk of breast and ovarian cancer. Assessment of variant pathogenicity is a vital part of clinical genetic testing for these genes. A database of clinical observations of BRCA variants is a critical resource in that process. This article describes BRCA Share™, a database created by a unique international alliance of academic centers and commercial testing laboratories. By integrating the content of the Universal Mutation Database generated by the French Unicancer Genetic Group with the testing results of two large commercial laboratories, Quest Diagnostics and Laboratory Corporation of America (LabCorp), BRCA Share™ has assembled one of the largest publicly accessible collections of BRCA variants currently available. Although access is available to academic researchers without charge, commercial participants in the project are required to pay a support fee and contribute their data. The fees fund the ongoing curation effort, as well as planned experiments to functionally characterize variants of uncertain significance. BRCA Share™ databases can therefore be considered as models of successful data sharing between private companies and the academic world.
BRCA ShareTM is an international alliance of academic centers and commercial testing laboratories. By integrating content of the Universal Mutation Database generated by the French Unicancer Genetic Group with the testing results of Quest Diagnostics and Laboratory Corporation of America (LabCorp), BRCA ShareTM has assembled one of the largest publicly accessible collections of BRCA variants with over 6,200 variants currently available.
In addition, to funding high quality curation, BRCA ShareTM seeks to support functional studies, targeting variants of uncertain significance.
The rate of genetic diagnosis of French patients with familial pancreatic ductal adenocarcinoma (PDAC) is not known. We report germline genetic testing data from 133 index cases meeting criteria for ...familial pancreatic cancer (FPC) as well as 87 ‘FPC‐like’ index cases who did not fulfilled strict FPC definition but were evocative for a PDAC predisposition. The overall rate of genetic diagnosis (in BRCA1, BRCA2, CDKN2A, and ATM genes) was 8.3% in FPC patients and 4.6% in FPC‐like patients, consistent with the literature in other populations. Genetic variants were also identified in FANCA and BAP1 genes, as well as in the CDKN2A p12 transcript. This pancreas‐specific transcript is a known key player in driving pancreatic oncogenesis. This might be the first described case of a PDAC genetic predisposition due to a variant in this specific transcript.
Pulmonary arterial hypertension (PAH) is a rare, severe disease resulting from progressive obliteration of small-caliber pulmonary arteries by proliferating vascular cells. PAH can occur without ...recognized etiology (idiopathic PAH), be associated with a systemic disease or occur as a heritable form, with BMPR2 mutated in approximately 80% of familial and 15% of idiopathic PAH cases. We conducted a genome-wide association study (GWAS) based on 2 independent case-control studies for idiopathic and familial PAH (without BMPR2 mutations), including a total of 625 cases and 1,525 healthy individuals. We detected a significant association at the CBLN2 locus mapping to 18q22.3, with the risk allele conferring an odds ratio for PAH of 1.97 (1.59-2.45; P = 7.47 × 10(-10)). CBLN2 is expressed in the lung, and its expression is higher in explanted lungs from individuals with PAH and in endothelial cells cultured from explanted PAH lungs.
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