Clinical trial NCT01689584: COsegregation of VARiants in Panel of Genes
Official title: Study of Family COsegregation of Nucleotide VARiants in the Panel of Genes to Validate Their Use in Genetic Counseling
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Gene Mutation-Related Cancer
Genetic Predisposition
Keywords: BRCA1
BRCA2
VUS
co-segregation
genetic counseling
PALB2
panel of genes
Lead sponsor: Institut Curie
Sponsor class: OTHER
First posted: 2012-09-21
Enrollment: 3500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

Brief summary: The aim of the COVAR project is to classify reliably a maximum of VUS of the French database 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.

Detailed description: Originally, the COVAR study was designed to explore 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. Since then the study has evolved, in parallel with the evolution of diagnosis, first introducing the PALB2 (Partner and localizer of BRCA2) gene explored in diagnosis since 2015 and now opening the study to all the genes of the panels performed in diagnosis in families with a genetic predisposition syndrome to cancers.

The French UMD (Universal Mutation Database)-BRCA1/2, accredited by the French National Cancer Institute, collects anonymous results of genetic tests performed by authorized French laboratories since 1995, giving a real-time vision of families carrying the same VUS. In september 2011, the French UMD-BRCA1/2 database comprised 706 different variants in 1,300 BRCA1 families and 1,089 different variants in 2,101 BRCA2 families. In April 2021, this database contained 1,651 different VSU for BRCA1, 3,015 different VUS for BRCA2, 471 different VUS for PALB2, 68 for RAD51C and 66 for RAD51D.

Since 2017, new genes have been explored in the diagnostic setting as they have been reported as predisposing factors for cancers. This list is constantly evolving (Moretta et al., 2018; Dhooge et al., 2020). Data collection for these genes is ongoing and a new database (FrOG) gathering all VUS and mutations identified in the French oncogenetic network has been set up. We have set up a consortium agreement at the end of 2020. This database gathers to date 12 genes and 11,912 different variants in more than 40,000 French families.

One of the key measurable parameters for classification of VUS as causal mutations 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 probability of causality of a given variant.

The objective of the COVAR study (COsegregation VARiants) is to organize co-segregation studies of the VUS of the database UMD-BRCA1/2, in order to determine the causal or non-causal nature of these variants. To organize the variants by their clinical relevance, a grid with 5 classes has been used: 1=neutral, 2=likely neutral, 3=VUS, 4=likely causal, 5=causal. The VUS of classes 3 and 4 will be candidates to co-segregation studies because they cannot be used for the 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. 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 as amino acid conservation, structural impact of the variant, co-occurrence with a pathogenic mutation, family history and tumor characteristics.

Eligibility criteria: Inclusion Criteria:

Index cases:

* A person carrying a gene variant class 3 or 4, present and selected in the families of national database of genetic group and cancer (GGC Unicancer) which identifies the variations of all genes from the panel of genes of all French laboratories.
* 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, retained by investigators, based on family structure and degree of related compared to the index case
* Age ≥ 18 years
* Information and signature of the informed consent "selected relatives"

Exclusion Criteria:

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

Primary outcomes:
measure: Perform the co-segregation analysis of the selected VUS in the families in order to classify the maximum of variants in terms of their probability to be pathogenic
timeFrame: up to 15 years
Secondary outcomes:
measure: • Propose a standardized method to classify VUS that can be integrated into the already existing classification established in the UMD-BRCA1/2 database, with the main focus on variants of class 4 (probably causal) and class 3 (unknown significance).
timeFrame: up to 15 years
measure: • Maximize the number of VUS (both pathogenic and neutral) having associated recommendations for clinical management of at-risk relatives that can be used to guide genetic counselling.
timeFrame: up to 15 years
measure: Assess the penetrance of several class 3 and 4 VUS probably associated with moderate cancer risk, using collected phenotype/genotype data on extended pedigrees.
timeFrame: up to 15 years
Other outcomes:
Locations:
city: Saint-Cloud
country: France
facility: Institut Curie - Hopital Rene Huguenin
state: Haut De Seine
city: Paris
country: France
facility: Institut Curie
state: Ile De France
city: Amiens
country: France
facility: CHU Amiens - Hôpital Nord
city: Angers
country: France
facility: ICO - Centre Paul Papin
city: Angoulême
country: France
facility: Centre Hospitalier d'Angoulème
city: Avignon
country: France
facility: Institut Sainte-Catherine
city: Besancon
country: France
facility: CHU Besançon
city: Bordeaux
country: France
facility: Groupe Hospitalier Pellegrin
city: Bordeaux
country: France
facility: Institut Bergonié
city: Bourges
country: France
facility: Centre Hospitalier Jacques Coeur
city: Brest
country: France
facility: CHU Morvan de Brest
city: Caen
country: France
facility: Centre François Baclesse
city: Chambery
country: France
facility: Centre Hospitalier Hôtel Dieu
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Colmar
country: France
facility: Hôpital Civil de Colmar
city: Dijon
country: France
facility: CHU de Dijon
city: Grenoble
country: France
facility: CHU de Grenoble
city: La Rochelle
country: France
facility: Groupe Hospitalier La Rochelle-Ré-Aunis
city: Le Havre
country: France
facility: Hôpital Flaubert
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lille
country: France
facility: Chru Lille
city: Limoges
country: France
facility: CHU Dupuytren
city: Lyon
country: France
facility: Hospices Civils de Lyon
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Marseille
country: France
facility: CHU La Timone
city: Montpellier
country: France
facility: CHU Arnaud de Villeneuve
city: Nantes
country: France
facility: Centre Catherine de Sienne
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Niort
country: France
facility: Centre Hospitalier Georges Renon
city: Nîmes
country: France
facility: CHRU Caremeau
city: Orléans
country: France
facility: Hôpital de la Source
city: Paris
country: France
facility: Hôpital Saint-Antoine
city: Paris
country: France
facility: Groupe Hospitalier Pitié-Salpêtrière
city: Paris
country: France
facility: Hôpital Tenon
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Paris
country: France
facility: HEGP
city: Poitiers
country: France
facility: CHU La Milétrie
city: Reims
country: France
facility: CHU de Reims
city: Reims
country: France
facility: ICC Courlancy
city: Reims
country: France
facility: Institut Jean Godinot
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Rouen
country: France
facility: CHU de Rouen
city: Saint-Herblain
country: France
facility: ICO - Centre René Gauducheau
city: Saint-Étienne
country: France
facility: CHU Saint Etienne
city: Strasbourg
country: France
facility: Institut de Cancérologie Strasbourg Europe ICANS
city: Strasbourg
country: France
facility: Hopital de Hautepierre - Hôpital Universitaire
city: Toulouse
country: France
facility: Institut Claudius Regaud - IUCT - Oncopole
city: Tours
country: France
facility: CHU Bretonneau
city: Troyes
country: France
facility: CH Simone VEIL
city: Valence
country: France
facility: Centre Hospitalier de Valence
city: Vandoeuvre les Nancy
country: France
facility: Centre Alexis Vautrin
city: Vandoeuvre les Nancy
country: France
facility: CHU Nancy - Hôpital Brabois
city: Villejuif
country: France
facility: Gustave Roussy
city: Pointe à Pitre
country: Guadeloupe
facility: CHU de Pointe à Pitre
city: Fort de France
country: Martinique
facility: CHU de Fort de France
city: Saint-Pierre
country: Réunion
facility: CHU Sud Réunion Saint-Pierre
Study officials:
affiliation: Institut Curie
name: Dominique STOPPA-LYONNET, PU-PH
role: STUDY_CHAIR
affiliation: Institut Curie
name: Sandrine CAPUTO, PhD
role: STUDY_DIRECTOR
References: