COsegregation of VARiants in the BRCA1/2 Genes (COVAR)

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2012 by Institut Curie
Sponsor:
Information provided by (Responsible Party):
Institut Curie
ClinicalTrials.gov Identifier:
NCT01689584
First received: May 14, 2012
Last updated: September 20, 2012
Last verified: April 2012
  Purpose

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.


Condition Intervention
Genes, BRCA1
Genes, BRCA2
Ovarian Neoplasms
Breast Neoplasms
Genetic: salivary kit

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: Study of Family COsegregation of VARiants in the BRCA1/2 Genes to Validate Their Use in Genetic

Resource links provided by NLM:


Further study details as provided by Institut Curie:

Primary Outcome Measures:
  • 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 [ Time Frame: up to 15 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • • 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). [ Time Frame: up to 15 years ] [ Designated as safety issue: No ]
  • • 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. [ Time Frame: up to 15 years ] [ Designated as safety issue: No ]
  • Assess the penetrance of several class 3 and 4 VUS probably associated with moderate cancer risk, using collected phenotype/genotype data on extended pedigrees. [ Time Frame: up to 15 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 2000
Study Start Date: April 2012
Estimated Study Completion Date: December 2027
Estimated Primary Completion Date: December 2022 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: Covar Genetic: salivary kit
The saliva samples will be made ​​of selected related (DNA).

Detailed Description:

The BRCA1 and BRCA2 genes are the two major high-risk breast and/or ovarian cancer susceptibility genes. Monoallelic germline mutations that disrupt their normal gene function significantly increase the risk of developing cancer in carriers. The identification of a causal mutation in a proband allows proposing pre-symptomatic testing for the causal mutation to all at-risk relatives. Currently, a causal mutation, used for genetic counseling, is presented in approximatively 13% of families tested. Variants of unknown biological significance (VUS) are detected in more than 20% of proband tested. For the families of these probands, genetic testing could not be proposed to relatives and the genetic counseling is guided by family history and epidemiological knowledges exclusively.

The French UMD-BRCA1/2 database, 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. One of the key measurable parameters for classification of VUS as causal mutations is their co-segregation with the disease. As 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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Index cases:

  • A person carrying a BRCA1 or BRCA2 variant class 3 or 4, this at least three different families in the national database UMD-BRCA1/2, national database of genetic group and cancer (GGC Unicancer) which identifies changes in BRCA1 and BRCA2 genes of all French laboratories.
  • Age ≥ 18 years.
  • Signed written inform consent "index case"

Related parties:

  • Everything related to an index case, diagnosed with breast cancer or ovarian cancer.
  • Any related case of a free index, selected by the investigators, according to family structure and the degree of related compared to the index case
  • Age ≥ 18 years
  • Signed written inform consent "Related selected"

Exclusion Criteria:

  • Minors
  • Persons deprived of liberty or under guardianship (including curators).
  • Absence of signed written inform consent
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01689584

Contacts
Contact: Patricia TRESCA, UGEC Leader 33156245630 patricia.tresca@curie.net
Contact: Isabelle TURBIEZ, Project Manager 33147111659 isabelle.turbiez@curie.net

Locations
France
Institut Curie - Hopital Rene Huguenin Recruiting
Saint-Cloud, Haut de Seine, France, 92210
Contact: Sandrine CAPUTO, PhD    33147112309    sandrine.caputo@curie.net   
Contact: Rosette LIDEREAU, PhD    33147112309    rosette.lidereau@curie.net   
Principal Investigator: Catherine NOGUES, MD         
Institut Curie Recruiting
Paris, Ile de France, France, 75005
Contact: Dominique STOPPA-LYONNET, PU-PH    33144324694    dominique.stoppa-lyonnet@curie.net   
Principal Investigator: Dominique Stoppa-Lyonnet, PU-PH         
Sponsors and Collaborators
Institut Curie
Investigators
Principal Investigator: Dominique STOPPA-LYONNET, PU-PH Institut Curie
Study Director: Sandrine CAPUTO, PhD Institut Curie - Hopital Rene Huguenin
Study Director: Rosette LIDEREAU, PhD Institut Curie - Hopital Rene Huguenin
  More Information

Additional Information:
No publications provided

Responsible Party: Institut Curie
ClinicalTrials.gov Identifier: NCT01689584     History of Changes
Other Study ID Numbers: IC 2011-11
Study First Received: May 14, 2012
Last Updated: September 20, 2012
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by Institut Curie:
BRCA1
BRCA2
VUS
co-segregation
genetic counseling

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms
Ovarian Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Endocrine Gland Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders

ClinicalTrials.gov processed this record on August 28, 2014