Evaluation of a Four-Gene Panel for Hereditary Cancer Risk Assessment (original) (raw)
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Hereditary Risk Assessment for BRCA Breast and/or Ovarian Cancer
Germline BRCA1 and BRCA2 (BRCA1/2) mutations are most frequently associated with hereditary breast/ovarian cancer. The study of genetic discriminators and dysregulated pathways involved in hereditary breast/ovarian syndromes has been key in the development of molecular diagnostic strategies, targeted therapies (such as PARP inhibitors), and prevention approaches. The recent development and implementation of next generation sequencing technologies has improved patient selection processes to offer such prevention and surveillance strategies.
BRCA2: a genetic risk factor for breast cancer
Cancer Letters, 2002
The identification of the breast cancer susceptibility genes BRCA1 and BRCA2 a few years ago has been greeted with great excitement and has raised hopes that they might illuminate the common mechanisms of this disease. Today we have to recognize that these expectations remain unfulfilled. Mutations in BRCA1 and BRCA2 account only for a relatively small proportion of breast cancers, even within the group of familiar clusters, they seem to be virtually non-existing in sporadic breast cancers. A substantial proportion of familiar breast cancer clusters has failed to provide evidence for an association with mutations in either BRCA1 or BRCA2, thus we have to look forward to the identification of additional breast cancer susceptibility genes. What has been most disappointing is that the mutation status of BRCA1/2 can provide only limited information for cancer risk. Initial assessments had indicated a risk of close to 90% for mutation carriers to develop breast cancer until age 75-a value that turned out to be restricted to high-risk families in which the BRCA1 and BRCA2 genes had been genomically mapped. In unselected clusters the risk appears much lower, some estimates suggest less than 40%. Both BRCA1 and BRCA2 large encode proteins that appear to have a plethora of functions, with a conspicuous association to DNA repair and DNA recombination, and probably transcription activation. Defects in DNA repair can result in cancer predisposition syndromes and are recognized as being instrumental in cancer progression. Central questions have remained unanswered: What is the function of damaged BRCA1 and BRCA2 genes in breast cancer risk? What is the basis of large variations of risk conferred to the patients by identical mutations? How can the predictive value of mutation surveys be increased?
Current Oncology, 2012
Background: Nearly 15% of DNA tests for BRCA1/2 results in the identification of an unclassified variant (UV). In DNA diagnostic laboratories in The Netherlands, a 4-group classification system (class I to IV ) is in use (Bell et al.). Aim of this study was to investigate whether the UVs in different classes showed a significant difference in their in silico characteristics and would justify current differences in protocols for counselling with respect to communication to the counselees.
2011
Introduction: Two major high-penetrance breast cancer genes, BRCA1 and BRCA2, are responsible for approximately 20% of hereditary breast cancer (HBC) cases in Finland. Additionally, rare mutations in several other genes that interact with BRCA1 and BRCA2 increase the risk of HBC. Still, a majority of HBC cases remain unexplained which is challenging for genetic counseling. We aimed to analyze additional mutations in HBCassociated genes and to define the sensitivity of our current BRCA1/2 mutation analysis protocol used in genetic counseling. Methods: Eighty-two well-characterized, high-risk hereditary breast and/or ovarian cancer (HBOC) BRCA1/2-founder mutation-negative Finnish individuals, were screened for germline alterations in seven breast cancer susceptibility genes, BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1. BRCA1/2 were analyzed by multiplex ligationdependent probe amplification (MLPA) and direct sequencing. CHEK2 was analyzed by the high resolution melt (HRM) method and PALB2, RAD50, BRIP1 and CDH1 were analyzed by direct sequencing. Carrier frequencies between 82 (HBOC) BRCA1/2-founder mutation-negative Finnish individuals and 384 healthy Finnish population controls were compared by using Fisher's exact test. In silico prediction for novel missense variants effects was carried out by using Pathogenic-Or-Not -Pipeline (PON-P).
Current Oncology, 2014
Objectives: It is estimated that 1–2% of individuals of Ashkenazi Jewish (AJ) ancestry carry one of three pathogenic founder mutations in BRCA1 and BRCA2. Targeted testing for these mutations (BRCA1 187delAG and 5385insC, and BRCA2 6174delT) is therefore recommended for all AJ breast and ovarian cancer patients, regardless of age of diagnosis or family history. Comprehensive analysis of both genes is recommended for a subset of AJ patients in whom founder mutations are not identified, but estimates of the yield from comprehensive analysis in this population vary widely. Methods: We sought to establish the proportion of non-founder mutations in AJ patients undergoing clinical testing in our laboratory from January 2006 through August 2013. Analysis included AJ patients for whom: (1) comprehensive testing was ordered as the initial test, or (2) founder mutation testing was ordered with instructions to “reflex” to comprehensive analysis if negative. The latter group was limited to case...
Genetic Heterogeneity and Penetrance Analysis of the BRCA1 and BRCA2 Genes in Breast Cancer Families
The American Journal of Human Genetics, 1998
The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes was found in families with four or five cases of female breast cancer only. These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mu-tation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions. The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 years. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years. The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers !50 years of age.
Genetic heterogeneity in hereditary breast cancer: Role of BRCA1 and BRCA2
The American Journal of Human Genetics, 1996
The common hereditary forms of breast cancer have been largely attributed to the inheritance of mutations in the BRCA1 or BRCA2 genes. However, it is not yet clear what proportion of hereditary breast cancer is explained by BRCA1 and BRCA2 or by some other unidentified susceptibility gene(s). We describe the proportion of hereditary breast cancer explained by BRCA1 or BRCA2 in a sample of North American hereditary breast cancers and assess the evidence for additional susceptibility genes that may confer hereditary breast or ovarian cancer risk. Twenty-three families were identified through two high-risk breast cancer research programs. Genetic analysis was undertaken to establish linkage between the breast or ovarian cancer cases and markers on chromosomes 17q (BRCA1) and 13q (BRCA2). Mutation analysis in the BRCA1 and BRCA2 genes was also undertaken in all families. The pattern of hereditary cancer in 14 (61%) of the 23 families studied was attributed to BRCA1 by a combination of linkage and mutation analyses. No families were attributed to BRCA2. Five families (22%) provided evidence against linkage to both BRCA1 and BRCA2. No BRCA 1 or BRCA2 mutations were detected in these five families. The BRCA1 or BRCA2 status of four families (17%) could not be determined. BRCA1 and BRCA2 probably explain the majority of hereditary breast cancer that exists in the North American population. However, one or more additional genes may yet be found that explain some proportion of hereditary breast cancer.
Cancer prevalence in 129 breast-ovarian cancer families tested for BRCA1 and BRCA2 mutations
South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde, 2010
Breast cancer is the most common malignancy among women in South Africa, with a crude incidence rate of 18.5/100 000 recorded between 1993 and 1995. 1 A small but significant percentage (5 -10%) of breast cancer cases are directly due to an inherited susceptibility. 2 Two tumour suppressor genes involved in early-onset breast and ovarian cancer, BRCA1 and BRCA2, have been mapped and cloned. 3,4 These two genes explain 20 -40% of heritable breast cancer cases in various populations over the world. 5,6 A large linkage and mutation study on 237 families collected by the Breast Cancer Linkage Consortium found that overall BRCA1 accounts for 52% of all families, and BRCA2 for 32%, leaving 16% of the families with a familial breast cancer phenotype unaccounted for. 7 In the study, 81% of the families with both a breast and an ovarian phenotype were BRCA1-positive families while 14% linked to BRCA2. The situation was reversed in families that presented with a male breast cancer phenotype in addition to female breast cancer, where 76% linked to BRCA2 and only a small percentage to BRCA1.
2016
Breast cancer is the most common cancer in Indonesian females with incidence rate approximately 36.2 in 100,000 and in the top ten of mortality cause with mortality incidence is 18.6 in 100,000 among other diseases (Azis et al., 2009; Wahidin et al., 2012). Roughly 5-10% of breast cancer cases related to the Hereditary Breast and/ or Ovarian (HBOC) syndrome. Individuals with HBOC syndrome have significantly higher lifetime risk of breast cancer development compare to general population (life time risk to age 70 for breast cancer is 60-80%). Specific pattern of HBOC syndrome is related to specific mutation in the BRCA1 or BRCA2 gene (Mary et al., 2012; Petrucelli et al., 2013). Compared to BRCA2, BRCA1 has higher prevalence related to HBOC; it is 1 in 300 per 100,000 population, while BRCA2 gene only 1 in 800 (Mary et al., 2012). BRCA1 gene is located in chromosome 17q21. The main function is maintaining chromosome stability through DNA damage repair process and regulation process of...