BRCA1 185delAG Mutation Research Articles

84P Frequency of 5382Insc and 185Delag Mutation of Brca1 Gene: An Experience from Eastern India

ABSTRACT Background The search for germline mutations within breast cancer susceptibility genes has been focused on the risk for developing malignancies in specific population. Mutations in the high penetrance breast cancer susceptibility gene BRCA1 account for a significant percentage of hereditary breast cancer cases. As reported earlier, carrier for the 5382insC and 185delAG BRCA1 mutation, lifetime risk of breast cancer for women is increased from 13% -81% in different population. Objectives The aims of the study was to evaluate the contribution of such mutation to the morbidity in eastern Indian breast cancer patients and their clinical manifestation and to study the BRCA1 gene positivity as prognostic factor in breast cancer patients. Methods Out of 92 patients (age range: 23-52) with family history (57 individuals) and without family history (35 individuals) were screened. 25 controls have been systematically investigated. Each mutation was detected separately using duplex PCR, PCR-SSCP. Results Studied mutations were identified in 14 patients (32%); 5382insC in 11 and 185delAG in 3 cases. All mutation carriers are below 45 years and had early onset of disease. They are in a follow up of 2 years at a stable condition. Conclusion 5382insC and 185delAG in BRCA1 gene are the first reported mutation in breast cancer in Eastern Indian origin. The presented data confirm a noticeable contribution of BRCA1 5382insC and 185delAG mutation in BC development in Eastern India that may justify an extended BRCA1 5382insC testing within this population. Further study is required to determine whether routine genetic testing should be offered to this population. The family members of mutation carrier are suggested to evaluate their mutation status to prevent the onset of disease at the earliest. Considering the importance of genetic counseling and recording, the adequate information for the pedigrees of cancer patients put forward the principle approaches in cancer clinics to facilitate early detection for preventing challenges. Disclosure All authors have declared no conflicts of interest.

Genomic and phenotypic analysis of BRCA2mutated breast cancers reveals co-occurring changes linked to progression

BackgroundInherited mutations in the BRCA2 gene greatly increase the risk of developing breast cancer. Consistent with an important role for BRCA2 in error-free DNA repair, complex genomic changes are frequently observed in tumors derived from BRCA2 mutation carriers. Here, we explore the impact of DNA copy-number changes in BRCA2 tumors with respect to phenotype and clinical staging of the disease.MethodsBreast tumors (n = 33) derived from BRCA2 999del5 mutation carriers were examined in terms of copy-number changes with high-resolution aCGH (array comparative genomic hybridization) containing 385 thousand probes (about one for each 7 kbp) and expression of phenotypic markers on TMAs (tissue microarrays). The data were examined with respect to clinical parameters including TNM staging, histologic grade, S phase, and ploidy.ResultsTumors from BRCA2 carriers of luminal and basal/triple-negative phenotypes (TNPs) differ with respect to patterns of DNA copy-number changes. The basal/TNP subtype was characterized by lack of pRb (RB1) coupled with high/intense expression of p16 (CDKN2A) gene products. We found increased proportions of Ki-67-positive cells to be significantly associated with loss of the wild-type (wt) BRCA2 allele in luminal types, whereas BRCA2wt loss was less frequent in BRCA2 tumors displaying basal/TNP phenotypes. Furthermore, we show that deletions at 13q13.1, involving the BRCA2wt allele, represents a part of a larger network of co-occurring genetic changes, including deletions at 6q22.32-q22.33, 11q14.2-q24.1, and gains at 17q24.1. Importantly, copy-number changes at these BRCA2-linked networking regions coincide with those associated with advanced progression, involving the capacity to metastasize to the nodes or more-distant sites at diagnosis.ConclusionsThe results presented here demonstrate divergent paths of tumor evolution in BRCA2 carriers and that deletion of the wild-type BRCA2 allele, together with co-occurring changes at 6 q, 11 q, and 17 q, are important events in progression toward advanced disease.

A deleterious BRCA1 mutation in a young Pakistani woman with metaplastic breast carcinoma

Metaplastic breast carcinoma (MBC) is a relatively rare subtype of breast cancer that encompasses a pathologically heterogeneous group of tumors. Pathogenic germ line mutations in the major breast cancer susceptibility genes BRCA1 and BRCA2 genes have been rarely found or described in MBC. We report the identification of the BRCA1 185delAG mutation in a 22-year-old Pakistani woman with triple-negative MBC that showed biphasic morphological features, including sarcomatous and malignant epithelial components. A comprehensive description of the clinical, histopathological, morphological, and immunohistochemical features of the tumor and the patient's treatment course is presented.

Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.

Associations of high-grade prostate cancer with BRCA1 and BRCA2 founder mutations.

Protein-truncating mutations in BRCA1 and in particular BRCA2 genes have been associated with prostate cancer. However, there is still uncertainty about the magnitude of association particularly with Gleason score, and family history of prostate, breast, and ovary cancers. To further examine associations between three founder mutations located in BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) genes and prostate cancer, we conducted a study of 979 prostate cancer cases and 1,251 controls among Ashkenazi Jewish men. Detailed information was obtained on prostate cancer pathology, age at diagnosis, and family history of all cancers. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression models. Prostate cancer risk was increased (OR, 1.9; 95% CI 0.9-4.1) for BRCA2 mutation carriers but not for BRCA1 mutation carriers. BRCA2 mutation carriers had an OR of 3.2 (95% CI, 1.4-7.3) for Gleason score of 7 to 10, but no association was observed for Gleason score of < 7. Carriers of BRCA1-185delAG mutation also had an OR of 3.5 (95% CI, 1.2-10.3) for Gleason score of > or =7 tumors; however, the association of either BRCA1-185delAG or 5382insC mutation was not statistically significant. Associations between founder mutations and prostate cancer were stronger in men with no first-degree family history of breast and/or ovarian cancers but were unaffected by family history of prostate cancer. These results indicate that the BRCA2 founder mutation confers a 3-fold elevated risk of high-grade prostate cancer. Although BRCA1 mutations were not associated with prostate cancer, the BRCA1-185delAG was associated with high Gleason score tumors. These findings should be carefully considered in genetic counseling and/or evaluating therapeutic options.

Functional variant of the tumor suppressor klotho: a novel risk modifier for breast cancer among BRCA1/2 carriers.

Abstract Abstract #1041 Background: The aging suppressor klotho is a transmembrane protein which is expressed in the kidneys, brain and hormone-responsive tissues and can be shed and act as a circulating hormone. The klotho gene is located on chromosome 13q12, about 700,000 base-pairs upstream to the BRCA2 gene. Klotho is a potent inhibitor of the insulin-like growth factor (IGF)-1 signaling pathway. We have recently found high klotho expression in normal breast tissue and low expression in breast cancer. Over-expression of klotho suppressed growth and inhibited the IGF-1 pathway in breast cancer cells. These data suggest klotho as a tumor suppressor gene in breast cancer. A single nucleotide polymorphism (SNP) in the klotho gene results in an amino acid substitution, F325V, which is associated with altered activity of klotho and reduced lifespan in human. As BRCA mutations may be associated with increased expression of IGF-1 and its receptor in breast cancer, we hypothesized that klotho functional variant may be associated with increased cancer risk among BRCA mutations carriers.&amp;#x2028; Material and Methods: The presence of F325V variant was evaluated using exon-specific polymerase chain reaction followed by restriction enzyme analysis, in a cohort of 784 Israeli women consisting of 236 non-BRCA mutations carriers (healthy: 109, breast cancer: 94, ovarian cancer: 33), 340 BRCA1 185delAG and 5382insC mutation carriers (healthy: 138, breast cancer: 142, ovarian cancer: 60) and 208 BRCA2 6174delT carriers (healthy: 75, breast cancer: 106, ovarian cancer: 27).&amp;#x2028; Results: Similar distribution of the F325V variant was noted in non-carriers and BRCA1 carriers (FF, wild-type 78%; FV, heterozygous 19%; VV, recessive 3%). However, F352V was over-represented among BRCA2 carriers: FF 25%, FV 50% and VV 25%. Analysis of additional SNPs indicated linkage disequilibrium between FV and BRCA2 6174delT mutation. Yet, among BRCA2 carriers, FF was significantly more frequent among healthy individuals compared to cancer patients (18% vs. 6% respectively, p=0.02). Surprisingly, among BRCA1 carriers FV status was associated with significantly younger age at breast cancer presentation compared to FF status (38±1.8 vs. 46±1.6 years respectively, p&amp;lt;0.001). Association between FV status and age at ovarian cancer presentation among BRCA1 carriers could not be assessed due to small sample size. No association was noted between the klotho functional variant and age at presentation among non-carriers of BRCA mutations.&amp;#x2028; Discussion: Taken together, these data suggest klotho F352V functional variant as a novel risk modifier among BRCA mutation carriers but not among non-carriers. As BRCA1/2 mutations can enhance and wild type klotho inhibits the activity of the IGF-1 signaling in cancer, it is possible that the presence of the less active variant of klotho attenuates this balance, thus leading to enhanced activation of the pathway. If validated by additional studies, the presence of the F352V klotho variant may serve as a predictor of cancer risk among BRCA mutation carriers and may also be a novel target for cancer therapy. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1041.

Breast cancer cell response to genistein is conditioned by BRCA1 mutations

Soy phytoestrogens, among which genistein, seem to protect from breast cancer development. In order to study the role of the breast tumour suppressor BRCA1 in response to genistein, we used a new breast cancer cell model: the SUM1315MO2 cell line carrying the 185delAG BRCA1 mutation, which we stably transfected with a plasmid encoding wild-type BRCA1. We showed that growth of BRCA1 mutant cells was strongly inhibited by genistein whereas it only had a weak effect in cells expressing wild-type BRCA1 protein. BRCA1 mutant cells hypersensitivity could be linked to higher expression of ERβ gene, which suggests that genistein may be an efficient inhibitor of cancer development in BRCA1 mutant breast cancer cells.

BRCA1 185delAG truncation protein, BRAt, amplifies caspase-mediated apoptosis in ovarian cells

Breast and ovarian cancer patients with germline mutations in BRCA1 respond more favorably to initial chemotherapy. We previously reported that cells from women carrying the BRCA1 185delAG founder mutation undergo an enhanced caspase-3-mediated apoptotic response. Here, we report on the transient and stable transfection of cDNA coding for the putative truncated protein product of the BRCA1 185delAG mutant gene into BRCA1 wild-type human ovarian surface epithelial cells and ovarian cancer cells, resulting in cells with a heterozygous background containing two BRCA1 wild-type alleles and the BRCA1 185delAG transcript. The BRCA1 185delAG truncation (BRAt) protein did not alter epithelial cell morphology or induce tumorigenesis. However, upon treatment with staurosporine, BRAt cells showed increased levels of active caspase-3 and increased cleavage of caspase-3 substrates, PARP and DFF45. Additionally, XIAP and cIAP-1 protein are at reduced levels in untreated BRAt cells as compared to control cells. BRAt also reduced levels of phosphorylated Akt and overexpression of activated Akt in BRAt cells restored caspase-3 activity to that seen in wild-type cells. Further, BRAt expression increased chemosensitivity in platinum-resistant ovarian cancer cells. Taken together, our data demonstrate that truncated proteins arising from BRCA1 185delAG mutation increase Akt-mediated apoptosis, suggesting a possible mechanism by which ovarian cancer patients with this germline BRCA1 mutation may respond better to initial chemotherapy.

BRCA1 (185delAG) Mutation among Egyptian Breast Cancer Female Patients

BRCA1 (185delAG) Mutation among Egyptian Breast Cancer Female Patients

Similar prevalence of founder BRCA1 and BRCA2 mutations among Ashkenazi and non-Ashkenazi men with breast cancer: Evidence from 261 cases in Israel, 1976–1999

To evaluate the potential contribution of mutations in the BRCA1 and BRCA2 genes to male breast cancer (MBC), we expanded a previous study to screen a total of 261 Israeli men diagnosed with breast carcinoma. A total of 21 BRCA2 6174delT and 8 BRCA1 185delAG mutations were found. Similar frequencies of BRCA1 and BRCA2 mutation carriers were found among Ashkenazi (12.8%) and non-Ashkenazi Jews (9.1%). The combined prevalence of BRCA1/ BRCA2 founder mutations among Ashkenazi Jewish men is slightly higher than for women, due to a higher frequency of BRCA2 mutations.

Prostate Cancer Progression and Survival in BRCA2 Mutation Carriers

Mutations in the BRCA2 gene are associated with an increased risk of prostate cancer, but it is not known whether they are associated with progression of the disease. We compared prostate cancer-specific survival, disease stage, and tumor grade between prostate cancer patients carrying the Icelandic BRCA2 999del5 founder mutation and noncarriers. Using population-based registries, we identified all 596 prostate cancer patients who were diagnosed in Iceland during 1955 through 2004 among 29603 male relatives of unselected breast cancer probands. BRCA2 mutation status could be determined for 527 patients (88.4%). Stage and grade were abstracted from original records, blindly with respect to mutation status, for a subgroup of 89 patients that included all mutation carriers and, for each carrier, two control patients without the BRCA2 999del5 mutation who were matched to the carrier on years of diagnosis and birth. Hazard ratios (HRs) and 95% confidence intervals (CIs) for prostate cancer-specific survival were estimated using multivariable regression models. All statistical tests were two-sided. The mutation was carried by 30 patients (5.7%). Compared with noncarriers, BRCA2 999del5 mutation carriers had a lower mean age at diagnosis (69.0 years versus 74.0 years; P = .002), more advanced tumor stage (stages 3 or 4, 79.3% versus 38.6%; P < .001), higher tumor grade (grades G3-4, 84.0% versus 52.7%, P = .007), and shorter median survival time (2.1 years, 95% CI = 1.4 to 3.6 years, versus 12.4 years, 95% CI = 9.9 to 19.7 years). Carrying the BRCA2 999del5 mutation was also associated with an increased risk of dying from prostate cancer (adjusting for year of diagnosis and birth, HR = 3.42, 95% CI = 2.12 to 5.51); the association remained after adjustment for stage and grade (HR = 2.35, 95% CI = 1.08 to 5.11). The prognosis of BRCA2 999del5 mutation carriers was not associated with period of diagnosis or with relatedness to breast cancer probands. The Icelandic BRCA2 999del5 founder mutation was strongly associated with rapidly progressing lethal prostate cancer.

Aurora-A amplification associated with BRCA2 mutation in breast tumours

Potential interaction of Aurora-A amplification and BRCA2 mutation was examined in breast tumours from BRCA2 999del5 mutation carriers ( n = 20) and non-carriers ( n = 41). Aurora-A amplification studied by FISH was significantly more common in breast tumours from BRCA2 mutation carriers ( p = 0.0005). Extensive Aurora-A amplification was also detected on metaphase chromosomes in three breast epithelial cell lines with the same BRCA2 mutation. In addition, significant association was found between Aurora-A amplification and TP53 mutations in non- BRCA2 mutation carrier tumours ( p = 0.007). These results suggest that breast tumours with mutations in BRCA2 or TP53 could be promising candidates for Aurora-A targeted treatment.

The BARD1 Cys557Ser Variant and Breast Cancer Risk in Iceland

BackgroundMost, if not all, of the cellular functions of the BRCA1 protein are mediated through heterodimeric complexes composed of BRCA1 and a related protein, BARD1. Some breast-cancer-associated BRCA1 missense mutations disrupt the function of the BRCA1/BARD1 complex. It is therefore pertinent to determine whether variants of BARD1 confer susceptibility to breast cancer. Recently, a missense BARD1 variant, Cys557Ser, was reported to be at increased frequencies in breast cancer families. We investigated the role of the BARD1 Cys557Ser variant in a population-based cohort of 1,090 Icelandic patients with invasive breast cancer and 703 controls. We then used a computerized genealogy of the Icelandic population to study the relationships between the Cys557Ser variant and familial clustering of breast cancer.Methods and FindingsThe Cys557Ser allele was present at a frequency of 0.028 in patients with invasive breast cancer and 0.016 in controls (odds ratio [OR] = 1.82, 95% confidence interval [CI] 1.11–3.01, p = 0.014). The alleleic frequency was 0.037 in a high-predisposition group of cases defined by having a family history of breast cancer, early onset of breast cancer, or multiple primary breast cancers (OR = 2.41, 95% CI 1.22–4.75, p = 0.015). Carriers of the common Icelandic BRCA2 999del5 mutation were found to have their risk of breast cancer further increased if they also carried the BARD1 variant: the frequency of the BARD1 variant allele was 0.047 (OR = 3.11, 95% CI 1.16–8.40, p = 0.046) in 999del5 carriers with breast cancer. This suggests that the lifetime probability of a BARD1 Cys557Ser/BRCA2 999del5 double carrier developing breast cancer could approach certainty. Cys557Ser carriers, with or without the BRCA2 mutation, had an increased risk of subsequent primary breast tumors after the first breast cancer diagnosis compared to non-carriers. Lobular and medullary breast carcinomas were overrepresented amongst Cys557Ser carriers. We found that an excess of ancestors of contemporary carriers lived in a single county in the southeast of Iceland and that all carriers shared a SNP haplotype, which is suggestive of a founder event. Cys557Ser was found on the same SNP haplotype background in the HapMap Project CEPH sample of Utah residents. ConclusionsOur findings suggest that BARD1 Cys557Ser is an ancient variant that confers risk of single and multiple primary breast cancers, and this risk extends to carriers of the BRCA2 999del5 mutation.

Population-Based Study of Changing Breast Cancer Risk in Icelandic BRCA2 Mutation Carriers, 1920–2000

Mutations in the BRCA genes increase the risk of breast cancer. Valid estimates of the magnitude of the lifetime risk of breast cancer in BRCA gene mutation carriers are needed for genetic counseling. Recent results suggest that penetrance has increased in recent birth cohorts. We examined the cumulative breast cancer incidence and mortality before age 70 over a diagnosis period of 80 years in Icelandic women who carried the BRCA2 founder mutation 999del5. Information on all breast cancers diagnosed in Iceland since 1911 was obtained from the Icelandic Cancer Registry. Mutation status was determined by molecular analysis of tissue samples for 847 breast cancer probands who were diagnosed from 1921 through 1985 and selected without knowledge of family history of breast cancer. We estimated the cumulative incidence and mortality from breast cancer before age 70 years in BRCA2 mutation carriers from the observed risks in first-degree relatives who were classified according to mutation status of probands and followed-up through 2002. Poisson modeling of these risks was also carried out. All statistical tests were two-sided. Of the 847 probands, 88 carried the BRCA2 999del5 mutation and 759 did not. According to Poisson modeling, the cumulative incidence of breast cancer before age 70 years in mutation carriers increased from 18.6% (95% CI = 11.0% to 29.5%) in calendar year 1920 to 71.9% (95% CI = 45.9% to 100%) in 2002 (P < .001); in relatives of probands who did not carry the BRCA2 mutation and in the general Icelandic population incidence increased over the same period from 2.6% to 10.7% and from 1.8% to 7.5%, respectively (all increases of approximately fourfold). During the same period, the cumulative risk of death from breast cancer before age 70 years for BRCA2 mutation carriers increased from 12.1% (95% CI = 5.3% to 23.9%) to 26.9% (95% CI = 10.9% to 55.5%) (P = .08). However, because the probands were breast cancer patients and not a random sample from the population, some bias in the estimation of time trends in penetrance cannot be ruled out. The results indicate that the penetrance of the Icelandic BRCA2 founder mutation increased nearly fourfold in 80 years, whereas the risk of death from breast cancer before age 70 years increased only approximately twofold. Changes in penetrance with time should be considered when penetrance is estimated.

Prevalence of BRCA Mutations and Founder Effect in High-Risk Hispanic Families

Approximately 12% of the U.S. population is Hispanic, with the majority residing in urban centers such as Los Angeles. The prevalence of BRCA mutations among high-risk Hispanic families is unknown. One hundred and ten unrelated probands of Hispanic origin, with a personal or family history of breast and/or ovarian cancer, presented for genetic cancer risk assessment, were enrolled in an Institutional Review Board-approved registry and underwent BRCA testing. Haplotype analyses were done if BRCA mutations were observed in two or more unrelated probands. Mean age at diagnosis was 37 years (range = 23-59) for the 89 (81%) probands with invasive breast cancer. Overall, 34 (30.9%) had deleterious mutations (25 in BRCA1, 9 in BRCA2), 25 (22.7%) had one or more unclassified variants, and 51 (46.4%) had negative results. The mean pretest mutation probability using the Couch model, Myriad model, and BRCAPro was 19.6% (range = 4-77%). The combined average mutation probability was 32.8% for carriers, 15.5% for noncarriers, and 12.9% for variant carriers (P < 0.0001). The most common deleterious mutation was 185delAG (4 of 34, 11.8%). The Hispanic 185delAG carrier families share the same haplotype from D17s1320 through BRCA1, as do two reference Ashkenazi Jewish families. Haplotype analyses of additional recurrent BRCA1 mutations [IVS5+1G>A (n=2),S955X (n = 3), R1443X (n = 3), and 2552delC (n = 2)] also suggest founder effects, with four of six mutations seen almost exclusively in families with Latin American/Caribbean or Spanish ancestry. This is the largest study to date of high-risk Hispanic families in the United States. Six recurrent mutations accounted for 47% (16 of 34) of the deleterious mutations in this cohort. The BRCA1185delAG mutation was prevalent (3.6%) in this clinic-based cohort of predominantly Mexican descent, and shared the Ashkenazi Jewish founder haplotype.

BRCA1 185delAG mutation inhibits Akt-dependent, IAP-mediated caspase 3 inactivation in human ovarian surface epithelial cells

BRCA1 mutations have long been associated with altered apoptosis. We have recently reported that caspase 3 activation is increased in human ovarian surface epithelial (OSE) cells expressing a germline N-terminal BRCA1 185delAG mutation. Here, we report increased caspase 3 activity in 185delAG OSE cells associated with decreased expression of cIAP-1 and X-linked inhibitor of apoptosis (XIAP), and decreased ubiquitination of caspase 3. Overexpression of XIAP restored active caspase 3 ubiquitination and lowered levels of caspase 3 activity. Further, the BRCA1 185delAG mutation was associated with reduced levels of phosphorylated Akt1. Transfection with activated Akt1 led to increased cIAP-1 and XIAP levels similar to that seen in BRCA1 185delAG cell lines. Taken together, these data suggest a direct link between the BRCA1 185delAG mutation and alterations in the caspase-mediated apoptotic pathway.

Use of oral contraceptives and risk of breast cancer in BRCA1/2 mutation carriers

Objective: To determine the frequency of BRCA1 mutations 185delAG and 5382insC and BRCA2 mutation 6174delT in Jewish women with ovarian cancer and in matched controls in a population-based study.Methods: Forty-eight Jewish women with epithelial ovarian cancer (32 invasive and 16 borderline) and 33 Jewish control subjects were obtained from a population-based, case-control study of ovarian cancer in eastern Massachusetts and New Hampshire. Mutational analysis on exons 2 and 20 of BRCA1 and exon 11 of BRCA2 was conducted on blood samples from patients and controls.Results: Fourteen (44%) of 32 Jewish patients with invasive epithelial ovarian cancer carried either a 185delAG mutation of BRCA1 (n = 8) or a 6174delT mutation on BRCA2 (n = 6). Neither of these mutations was identified in 16 women with borderline ovarian tumors or in 33 controls. No 5382insC mutation of BRCA1 was identified in any of the patients or control subjects in the series. Family history did not predict mutation status.Conclusion: BRCA1 185delAG and BRCA2 6174delT mutations are frequent in Jewish women with invasive epithelial ovarian cancer, irrespective of family history. Genetic counseling might be warranted in women with invasive epithelial ovarian cancer based on Jewish ethnicity alone.

Germline mutations in DNA repair and cell cycle checkpoint genes: consequential somatic gene alterations and genome instability

Germline alterations in the BRCA1, BRCA2 and CHK2 genes were analysed in a series of breast cancer cases from the Icelandic population of 285,000 and risk was estimated. By screening 1172 cancer patients for the detected T59K sequence variant in the CHK2 gene, it was detected in a total of four breast cancer patients, two colon cancer patients, one stomach cancer patient and one ovary cancer patient, but not in 452 healthy individuals. The results suggest a tumor suppressor function for CHK2 in a small proportion of breast tumors and that the T59K CHK2 sequence variant is a low-penetrance allele with respect to tumor growth. A rare mutation was detected in the BRCA1 gene and a frequent mutation in the BRCA2 gene. The BRCA2 999del5 is classified as a founder mutation and the Icelandic population-based analysis gives an excellent opportunity to define the risk of this sequence variant for breast cancer and other cancer types. The BRCA2 999del5 mutation is present in 7% of unrelated breast cancer patients in Iceland, the prevalence increases with lower age of diagnosis and the estimated breast cancer risk in mutation carriers at the age of 70 years is 40%. A detailed analysis was done on the somatic events in tumors of 46 BRCA2 999del5 carriers with respect to genomic instability and gene alteration. Chromosome alterations were elevated and of specific architecture compared with sporadic cases, in line with the DNA/chromosome repair function of Brca2. An alternative mechanism of TP53 involvement seems to be specific to the pathogenesis of BRCA2 999del5 tumors. Furthermore, alterations at the FHIT gene located at the FRA3B locus with subsequent reduced expression seem to be of specific relevance in the BRCA2 tumors.

Hereditary breast and ovarian cancer in Asia: genetic epidemiology of BRCA1 and BRCA2.

Ethnic differences in cancer incidence and mortality result from differences in genetic and epidemiologic risk factors. Mutations in BRCA1 and BRCA2 account for a small proportion of all breast cancer cases, but for a much higher proportion of cases with a strong family history of breast or ovarian cancer. Germline mutations in BRCA1 and BRCA2 have been identified in individuals of many races and ethnic groups and the frequency of mutations varies between these groups. Some of the differences in cancer risk between populations may be the result of founder mutations in these genes. The cost and time required for mutation analysis are reduced considerably when founder mutations are identified for a specific ethnic group. The BRCA2 999del5 mutation in Iceland and three BRCA mutations in Ashkenazi Jews are well characterized. However, considerably less is known about the contribution of mutations in the BRCA1 and BRCA2 genes outside of European groups. Studies conducted on the Asian populations described here have expanded our current knowledge of genetic susceptibility and its contribution to breast and ovarian cancer rates in Asian populations.

Mutation analysis of the CHK2 gene in breast carcinoma and other cancers.

Mutations in the CHK2 gene at chromosome 22q12.1 have been reported in families with Li-Fraumeni syndrome. Chk2 is an effector kinase that is activated in response to DNA damage and is involved in cell-cycle pathways and p53 pathways. We screened 139 breast tumors for loss of heterozygosity at chromosome 22q, using seven microsatellite markers, and screened 119 breast tumors with single-strand conformation polymorphism and DNA sequencing for mutations in the CHK2 gene. Seventy-four of 139 sporadic breast tumors (53%) show loss of heterozygosity with at least one marker. These samples and 45 tumors from individuals carrying the BRCA2 999del5 mutation were screened for mutations in the CHK2 gene. In addition to putative polymorphic regions in short mononucleotide repeats in a non-coding exon and intron 2, a germ line variant (T59K) in the first coding exon was detected. On screening 1172 cancer patients for the T59K sequence variant, it was detected in a total of four breast-cancer patients, two colon-cancer patients, one stomach-cancer patient and one ovary-cancer patient, but not in 452 healthy individuals. A tumor-specific 5' splice site mutation at site +3 in intron 8 (TTgt [a --> c]atg) was also detected. We conclude that somatic CHK2 mutations are rare in breast cancer, but our results suggest a tumor suppressor function for CHK2 in a small proportion of breast tumors. Furthermore, our results suggest that the T59K CHK2 sequence variant is a low-penetrance allele with respect to tumor growth.