An international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: The Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA)
University of Cambridge, Cambridge, England, United KingdomBreast cancer research: BCR (Impact Factor: 5.49). 02/2007; 9(2):104. DOI: 10.1186/bcr1670
BRCA1 and BRCA2 mutations exhibit variable penetrance that is likely to be accounted for, in part, by other genetic factors among carriers. However, studies aimed at identifying these factors have been limited in size and statistical power, and have yet to identify any convincingly validated modifiers of the BRCA1 and BRCA2 phenotype. To generate sufficient statistical power to identify modifier genes, the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) has been established. CIMBA contains about 30 affiliated groups who together have collected DNA and clinical data from approximately 10,000 BRCA1 and 5,000 BRCA2 mutation carriers. Initial efforts by CIMBA to identify modifiers of breast cancer risk for BRCA1 and BRCA2 mutation carriers have focused on validation of common genetic variants previously associated with risk in smaller studies of carriers or unselected breast cancers. Future studies will involve replication of findings from pathway-based and genome-wide association studies in both unselected and familial breast cancer. The identification of genetic modifiers of breast cancer risk for BRCA1 and BRCA2 mutation carriers will lead to an improved understanding of breast cancer and may prove useful for the determination of individualized risk of cancer amongst carriers.
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- "CIMBA collects data on male and female BRCA1 or BRCA2 pathogenic mutation carriers older than 18 years of age, with the majority recruited through cancer genetics clinics . CIMBA data were submitted by 55 study groups in 24 countries based in Europe, North America and Australia. "
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- "CDH1 mutation by affecting epitheliallike morphology, with polarized cells migrating unidirectionally and BRCA2 SNPs by affecting DNA-protein interaction. Currently, vast efforts are being made to identify modifier genes in BRCA2 mutation carriers (see eg, the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA)) (Chenevix-Trench et al., 2007). For example, the SNP RAD51_c.98GNC has recently been identified as first modifier in BRCA2 mutation carriers, whereas no effect of this SNP was found in BRCA1 mutation carriers and BRCA1/BRCA2 mutation non-carriers (Antoniou et al., 2007). "
ABSTRACT: Germ-line mutation in CDH1 gene is associated with high risk for Hereditary Diffuse Gastric Cancer (HDGC) and Infiltrative Lobular Carcinoma (ILC). Although somatic CDH1 mutations were also detected in ILC with a frequency ranging from 10-56%, CDH1 alterations in more frequent infiltrative ductal carcinoma (IDC) appear to be rare, and no association with germ-line CDH1 mutation and IDC has been established. Here we report the case of a woman diagnosed with IDC at 39years of age, presenting extensive familial history of cancer at multiple sites with early-age onset and with no case of HDGC. Deep sequencing have revealed CDH1 missense mutation c.1849G>A (p.Ala617Thr) in heterozygous and four BRCA2 single nucleotide polymorphism in homozygosis. In this family, the mutation c.1849G>A in the CDH1 gene is not related to HDGC nor ILC. Therefore, here we highlight that multigene analysis is important to detect germ-line mutations and genetic variants in patients with cancers at multiple sites in the family, even if inconclusive genetic counseling can be offered, since hereafter, medical awareness will be held. Copyright © 2015. Published by Elsevier B.V.
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- "Another study by Antoniou et al.9 reanalyzed the association between breast cancer and six susceptibility polymorphisms in gene FGFR2, TNRC9/TOX3, MAP3K1, LSP1, 2q35 using a sample of 12,525 BRCA1, and 7,409 BRCA2 carriers. The six susceptibility polymorphisms were identified in recent large-scale association studies conducted by the Consortium of Investigators of Modifiers of BRCA1/2.10 Three additional SNPs (ie, rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12) were also evaluated in this study. "
ABSTRACT: Cancer risk prediction models are important in identifying individuals at high risk of developing cancer, which could result in targeted screening and interventions to maximize the treatment benefit and minimize the burden of cancer. The cancer-associated genetic variants identified in genome-wide or candidate gene association studies have been shown to collectively enhance cancer risk prediction, improve our understanding of carcinogenesis, and possibly result in the development of targeted treatments for patients. In this article, we review the cancer risk prediction models that have been developed for popular cancers and assess their applicability, strengths, and weaknesses. We also discuss the factors to be considered for future development and improvement of models for cancer risk prediction.