COsegregation of VARiants in Panel of Genes

Официальное название

Study of Family COsegregation of Nucleotide VARiants in the Panel of Genes to Validate Their Use in Genetic Counseling

Обзор

The aim of the COVAR project is to achieve reliable classification of as many variants of interest as possible from the French OncoGenetics Database (FrOG, https://frog-db.fr/) in order to use them for the genetic counseling. The results obtained through this study will have a major impact on clinical management of the patients and their families conducting in some cases to propose a prophylactic surgery.

Подробное описание

Originally, the COVAR study was designed to investigate Variants of Unknown biological Significance (VUS) in BRCA1 (BReast Cancer 1) and BRCA2 (BReast Cancer 2) genes, which are the two major genes identified in hereditary breast and/or ovarian cancers. Over time, it has evolved alongside advances in genetic diagnostics. First, it incorporated the Partner and Localizer of BRCA2 (PALB2) gene, included in routine testing since 2015, and more recently it has expanded to include all genes analyzed in multigene panels for families suspected of hereditary cancer predisposition syndromes.

To support variant interpretation, national databases have been developed. The Universal Mutation DataBase BRCA1/BRCA2 (UMD-BRCA1/BRCA2), maintained within the French oncogenetics network, collects anonymized genetic data and enables the identification of families sharing the same variants. More recently, the FrOG database (established in 2020) has expanded this approach to 38 genes and over 66,000 families, compiling nearly 20,000 distinct variants, including thousands of VUS and likely pathogenic variants.

As knowledge has progressed, classification systems have evolved. The term VUS now strictly refers to class 3 variants, while class 4 (likely pathogenic) variants are increasingly actionable in clinical care under certain conditions. Additionally, a subset of class 5 variants with intermediate effects ("hypomorphic" variants) has been recognized, highlighting variability in risk depending on the type of genetic alteration. These variants are now included in COVAR to refine risk estimates.

One of the key measurable parameters for classification of variants of interest is their co-segregation with the disease. The average size of French families is relatively small, the information of variant co-segregation limited to one family would not be significant. However, the compilation of co-segregation results obtained from several families will allow to obtain more precise and complete estimations of the pathogenicity of a given variant. The main objective of the COVAR study (COsegregation VARiants) is to organize such co-segregation studies using national database data, in order to determine the pathogenicity of selected variants and improve genetic counseling.

In the selected families the index case will invite the family members (affected and unaffected) to provide a sample of salivary fluid to test the presence of the VUS (class 3). The probability that a VUS is causal will be calculated from the cosegregation data using a Bayesian model. The results will be integrated in the multifactorial model described by D. Goldgar, model integrating different parameters.

For class 4 and hypomorphic class 5 variants, relatives are advised to attend oncogenetic consultations for targeted diagnostic testing without additional sampling. Genetic analyses for class 3 variants are conducted by the identifying laboratory, while classes 4-5 analyses are performed by affiliated GGC laboratories.

Results are sent anonymously to the coordinating center for statistical analysis, and only overall variant classification (not individual results) is communicated back.

If a variant is found pathogenic, the index case is informed, enabling family communication, possible presymptomatic testing (class 3), and potential clinical management impact (classes 4-5).

Вмешательства

• Генная терапия salivary kit
  The saliva samples will be made of selected related (DNA).

Первичные конечные точки

• Perform the co-segregation analysis of the selected VUS (class 3) or likely pathogenic variant (class 4) in the families. [Срок оценки: up to 15 years]

Вторичные конечные точки (3)

• Propose a standardized method to classify as many variants as possible from the national of the Genetics and Cancer Group (GGC) of Unicancer. [Срок оценки: up to 15 years]
• Maximize the number of VUS (class 3) or likely pathogene (class 4) having associated recommendations for clinical management of at-risk relatives that can be used to guide genetic counselling. [Срок оценки: up to 15 years]
• Assess the penetrance of selected variants of interest, particularly hypomorphic pathogenic variant (hypomorphic class 5) shared across multiple families. [Срок оценки: up to 15 years]

Критерии участия

Критерии включения

Index cases:

• A person carrying a variant of interest in a gene analyzed in a diagnostic setting by one of the laboratories within the Genetics and Cancer Group (GGC)-Unicancer network, classified as class 3, 4 or hypomorphic class 5, and selected by the national expert group for the gene concerned.
• Age ≥ 18 years.
• Signed written inform consent "index case"

Related parties:

• Any relative of an index case with cancer
• Any relative without cancer related to an index case, selected by the investigators, according to family structure and degree of related compared to the index case
• For class 4 and hypomorphic class 5 variants; relatives currently undergoing analysis or having already obtained a test result for the variant of interest as part of clinical care.
• Age ≥ 18 years
• Information and signature of the informed consent "selected relatives"

Критерии исключения

• Minors
• Persons deprived of liberty or under guardianship (including curators).
• Absence of signed written inform consent

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Диагностика

Центры проведения

Франция · 58 центров

• Centre Hospitalier de Bastia — Bastia
• Institut Curie - Saint-Cloud site — Saint-Cloud
• CHU Amiens - Hôpital Nord — Amiens
• ICO - Centre Paul Papin — Angers
• Centre Hospitalier d'Angoulème — Angoulême
• Institut Sainte-Catherine — Avignon
• CHU Besançon — Besançon
• Groupe Hospitalier Pellegrin — Bordeaux
• … и ещё 50 центров

Guadeloupe · 1 центр

• CHU de Pointe à Pitre — Pointe-à-Pitre

Martinique · 1 центр

• CHU de Fort de France — Fort-de-France

New Caledonia · 1 центр

• Centre Hospitalier Territorial Gaston Bourret — Noumea

Reunion · 1 центр

• CHU Sud Réunion Saint-Pierre — Saint-Pierre

Публикации

• Caputo SM, Golmard L, Leone M, Damiola F, Guillaud-Bataille M, Revillion F, Rouleau E, Derive N, Buisson A, Basset N, Schwartz M, Vilquin P, Garrec C, Privat M, Gay-Bellile M, Abadie C, Abidallah K, Airaud F, Allary AS, Barouk-Simonet E, Belotti M, Benigni C, Benusiglio PR, Berthemin C, Berthet P, Bertrand O, Bezieau S, Bidart M, Bignon YJ, Birot AM, Blanluet M, Bloucard A, Bombled J, Bonadona V, PMID 34597585
• Caputo SM, Telly D, Briaux A, Sesen J, Ceppi M, Bonnet F, Bourdon V, Coulet F, Castera L, Delnatte C, Hardouin A, Mazoyer S, Schultz I, Sevenet N, Uhrhammer N, Bonnet C, Tilkin-Mariame AF, Houdayer C, Moncoutier V, Andrieu C, French Covar Group Collaborators, Bieche I, Stern MH, Stoppa-Lyonnet D, Lidereau R, Toulas C, Rouleau E. 5' Region Large Genomic Rearrangements in the BRCA1 Gene in French Fa PMID 34202044
• Meulemans L, Mesman RLS, Caputo SM, Krieger S, Guillaud-Bataille M, Caux-Moncoutier V, Leone M, Boutry-Kryza N, Sokolowska J, Revillion F, Delnatte C, Tubeuf H, Soukarieh O, Bonnet-Dorion F, Guibert V, Bronner M, Bourdon V, Lizard S, Vilquin P, Privat M, Drouet A, Grout C, Calleja FMGR, Golmard L, Vrieling H, Stoppa-Lyonnet D, Houdayer C, Frebourg T, Vreeswijk MPG, Martins A, Gaildrat P. Skipping PMID 32046981
• Tubeuf H, Caputo SM, Sullivan T, Rondeaux J, Krieger S, Caux-Moncoutier V, Hauchard J, Castelain G, Fievet A, Meulemans L, Revillion F, Leone M, Boutry-Kryza N, Delnatte C, Guillaud-Bataille M, Cleveland L, Reid S, Southon E, Soukarieh O, Drouet A, Di Giacomo D, Vezain M, Bonnet-Dorion F, Bourdon V, Larbre H, Muller D, Pujol P, Vaz F, Audebert-Bellanger S, Colas C, Venat-Bouvet L, Solano AR, Stopp PMID 32641407
• Parsons MT, Tudini E, Li H, Hahnen E, Wappenschmidt B, Feliubadalo L, Aalfs CM, Agata S, Aittomaki K, Alducci E, Alonso-Cerezo MC, Arnold N, Auber B, Austin R, Azzollini J, Balmana J, Barbieri E, Bartram CR, Blanco A, Blumcke B, Bonache S, Bonanni B, Borg A, Bortesi B, Brunet J, Bruzzone C, Bucksch K, Cagnoli G, Caldes T, Caliebe A, Caligo MA, Calvello M, Capone GL, Caputo SM, Carnevali I, Carrasc PMID 31131967
• Caputo SM, Leone M, Damiola F, Ehlen A, Carreira A, Gaidrat P, Martins A, Brandao RD, Peixoto A, Vega A, Houdayer C, Delnatte C, Bronner M, Muller D, Castera L, Guillaud-Bataille M, Sokilde I, Uhrhammer N, Demontety S, Tubeuf H, Castelain G; French COVAR group collaborators; Jensen UB, Petitalot A, Krieger S, Lefol C, Moncoutier V, Boutry-Kryza N, Nielsen HR, Sinilnikova O, Stoppa-Lyonnet D, Spurd PMID 29707112
• Moghadasi S, Meeks HD, Vreeswijk MP, Janssen LA, Borg A, Ehrencrona H, Paulsson-Karlsson Y, Wappenschmidt B, Engel C, Gehrig A, Arnold N, Hansen TVO, Thomassen M, Jensen UB, Kruse TA, Ejlertsen B, Gerdes AM, Pedersen IS, Caputo SM, Couch F, Hallberg EJ, van den Ouweland AM, Collee MJ, Teugels E, Adank MA, van der Luijt RB, Mensenkamp AR, Oosterwijk JC, Blok MJ, Janin N, Claes KB, Tucker K, Viassol PMID 28490613
• Spurdle AB, Whiley PJ, Thompson B, Feng B, Healey S, Brown MA, Pettigrew C; kConFab; Van Asperen CJ, Ausems MG, Kattentidt-Mouravieva AA, van den Ouweland AM; Dutch Belgium UV Consortium; Lindblom A, Pigg MH, Schmutzler RK, Engel C, Meindl A; German Consortium of Hereditary Breast and Ovarian Cancer; Caputo S, Sinilnikova OM, Lidereau R; French COVAR group collaborators; Couch FJ, Guidugli L, Hans PMID 22889855

Идентификаторы

NCT: NCT01689584 · IC 2011-11

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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