BRCA1. A new marker in the management of patients with breast cancer?
Explore the source record for details and available documents.
BRCA1 Protein↗
Biomedical subjects
K Offit
Publications and source records attributed to K Offit.
REL proto-oncogene is frequently amplified in extranodal diffuse large cell lymphoma.
Comparative genomic hybridization (CGH) analysis of DNA extracted from a diffuse lymphoma with a large cell component (DLLC) that displayed double minute chromosomes upon conventional karyotypic analysis indicated overt amplification of DNA sequences derived from the 2p13-15 region. Southern blot analysis of this tumor DNA with a cDNA probe for the proto-oncogene REL, previously mapped to 2p14-15, indicated a greater than 35-fold amplification of REL. To determine the incidence of REL amplification and possible clinical or histologic association with DLLC, a panel of 111 tumor DNAs from DLLC specimens was screened for REL amplification by Southern blot analysis. A copy number of > or = 4 was noted in 26 cases (23%). Southern blot analysis of these 26 tumor DNAs with a cDNA probe for TGFA, mapped to 2p13, indicated lack of coamplification except in one case. Another member of the Rel/NF-kappa B family of transcriptional activators, RELA/p65 mapped to 11q13, was amplified in five cases as determined by Southern blot analysis using a cDNA probe. Nineteen of the 26 DLLC (73%) with REL amplification were primary extranodal lymphomas. As a group, the tumors with REL amplification demonstrated an increased frequency of chromosomal aberrations previously associated with tumor progression, suggesting an oncogenic effect of amplified REL in B-lymphoid cells that already contained a transforming genetic lesion. Thus, REL amplification is a frequent event in DLLC, and probably constitutes a progression-associated marker of primary extranodal lymphomas. This study shows the usefulness of the CGH technique in identifying chromosomal regions overrepresented in tumors that can point to amplified genes and may be correlated with clinical features of the disease.
Aneuploidy↗
The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds.
Breast carcinoma is the most common malignancy among women in developed countries. Because family history remains the strongest single predictor of breast cancer risk, attention has focused on the role of highly penetrant, dominantly inherited genes in cancer-prone kindreds (1). BRCA1 was localized to chromosome 17 through analysis of a set of high-risk kindreds (2), and then identified four years later by a positional cloning strategy (3). BRCA2 was mapped to chromosomal 13q at about the same time (4). Just fifteen months later, Wooster et al. (5) reported a partial BRCA2 sequence and six mutations predicted to cause truncation of the BRCA2 protein. While these findings provide strong evidence that the identified gene corresponds to BRCA2, only two thirds of the coding sequence and 8 out of 27 exons were isolated and screened; consequently, several questions remained unanswered regarding the nature of BRCA2 and the frequency of mutations in 13q-linked families. We have now determined the complete coding sequence and exonic structure of BRCA2 (GenBank accession #U43746), and examined its pattern of expression. Here, we provide sequences for a set of PCR primers sufficient to screen the entire coding sequence of BRCA2 using genomic DNA. We also report a mutational analysis of BRCA2 in families selected on the basis of linkage analysis and/or the presence of one or more cases of male breast cancer. Together with the specific mutations described previously, our data provide preliminary insight into the BRCA2 mutation profile.
BRCA2 Protein↗
Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer.
The lifetime risk of breast cancer may approach 80-90% in women who have germline mutations of either of two genes, BRCA1 or BRCA2. A single BRCA1 mutation, 185delAG, has been noted in approximately 20% of Ashkenazi Jewish women with early onset breast cancer and in 0.9% of the Ashkenazi population. We recently detected a 6174delT frameshift mutation in BRCA2 in an hereditary breast cancer kindred of Ashkenazi Jewish ancestry. Here, we investigated the frequency of this mutation in 200 women with early-onset breast cancer. Six of 80 Ashkenazi Jewish women (8%) diagnosed with breast cancer before the age of 42, wer heterozygous for the 6174delT mutation, compared to none of 93 non-Jewish women diagnosed with breast cancer at the same age (P = .005). These cases were ascertained without regard to family history. Two of 27 (7%) additional Jewish families in which the proband was diagnosed with breast cancer at age 42 to 50 and had a family history of breast or ovarian cancer had germline 6174delT mutations. The results of this report suggest that a recurrent mutation of BRCA1 and a recurrent mutation BRCA2 together may account for over a quarter of all early-onset breast cancer in the setting of a personal or family history of ovarian cancer in Ashkenazi Jewish women.
Adult↗
Low incidence of BRCA2 mutations in breast carcinoma and other cancers.
Inherited mutant alleles of familial tumour suppressor genes predispose individuals to particular types of cancer. In addition to an involvement in inherited susceptibility to cancer, these tumour suppressor genes are targets for somatic mutations in sporadic cancers of the same type found in the familial forms. An exception is BRCA1, which contributes to a significant fraction of familial breast and ovarian cancer, but undergoes mutation at very low rates in sporadic breast and ovarian cancers. This finding suggests that other genes may be the principal targets for somatic mutation in breast carcinoma. A second, recently identified familial breast cancer gene, BRCA2 (refs 5-8), accounts for a proportion of breast cancer roughly equal to BRCA1. Like BRCA1, BRCA2 behaves as a dominantly inherited tumour suppressor gene. Individuals who inherit one mutant allele are at increased risk for breast cancer, and the tumours they develop lose the wild-type allele by heterozygous deletion. The BRCA2 coding sequence is huge, composed of 26 exons that span 10,443 bp. Here we investigate the rate of BRCA2 mutation in sporadic breast cancers and in a set of cell lines that represent twelve other tumour types. Surprisingly, mutations in BRCA2 are infrequent in cancers including breast carcinoma. However, a probable germline mutation in a pancreatic tumour cell line suggests a role for BRCA2 in susceptibility to pancreatic cancer.
BRCA2 Protein↗
The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%.
Certain germline mutations in either BRCA1 or BRCA2 confer a lifetime risk of developing breast cancer that may approach 90%. The BRCA1 185delAG mutation was found in 20% and the BRCA2 6174delT mutation in 8% of Ashkenazi Jewish women with early-onset breast cancer. The 185delAG mutation was observed in 0.9% of 858 Ashkenazi Jews unselected for a personal or family history of cancer. Assuming comparable age-specific penetrances, a carrier frequency of 0.3% was estimated for the 6174delT BRCA2 mutation. To test this hypothesis, we performed a population survey of 1,255 Jewish individuals. In two independent groups, a prevalence of approximately 1% (C.I. 0.6-1.5) was observed for the 6174delT mutation. The relative risk of developing breast cancer by age 42 was estimated to be 9.3 (C.I. 2.5-22.5) for 6174delT, compared to 31 (C.I. 11-77) for 185delAG. Analysis of 107 Ashkenazi Jewish women with breast cancer and a family history of breast or ovarian cancer confirmed a four-fold greater prevalence for the BRCA1 185delAG mutation compared to the BRCA2 6174delT mutation. Our findings suggest a difference in cumulative life-time penetrance for the two mutations. Genetic counseling for the one in 50 Ashkenazi Jewish individuals harbouring specific germline mutations in BRCA1 or BRCA2 must be tailored to reflect the different risks associated with the two mutations.
Adult↗
Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families.
Explore the source record for details and available documents.
Age Factors↗
Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study.
Several BRCA1 mutations have now been found to occur in geographically diverse breast and ovarian cancer families. To investigate mutation origin and mutation-specific phenotypes due to BRCA1, we constructed a haplotype of nine polymorphic markers within or immediately flanking the BRCA1 locus in a set of 61 breast/ovarian cancer families selected for having one of six recurrent BRCA1 mutations. Tests of both mutations and family-specific differences in age at diagnosis were not significant. A comparison of the six mutations in the relative proportions of cases of breast and ovarian cancer was suggestive of an effect (P = .069), with 57% of women presumed affected because of the 1294 del 40 BRCA1 mutation having ovarian cancer, compared with 14% of affected women with the splice-site mutation in intron 5 of BRCA1. For the BRCA1 mutations studied here, the individual mutations are estimated to have arisen 9-170 generations ago. In general, a high degree of haplotype conservation across the region was observed, with haplotype differences most often due to mutations in the short-tandem-repeat markers, although some likely instances of recombination also were observed. For several of the instances, there was evidence for multiple, independent, BRCA1 mutational events.
Alleles↗
BCL-6 in diffuse large-cell lymphomas.
Explore the source record for details and available documents.
B-Lymphocytes↗
Frequent somatic hypermutation of the 5' noncoding region of the BCL6 gene in B-cell lymphoma.
The BCL6 gene encodes a zinc-finger transcription factor and is altered by chromosomal arrangements in its 5' noncoding region in approximately 30% of diffuse large-cell lymphoma (DLCL). We report here that, in 22/30 (73%) DLCL and 7/15 (47%) follicular lymphoma (FL), but not in other tumor types, the BCL6 gene is also altered by multiple (1.4 x 10(-3) -1.6 x 10(-2) per bp), often biallelic, mutations clustering in its 5' noncoding region. These mutations are of somatic origin and are found in cases displaying either normal or rearranged BLC6 alleles indicating their independence from chromosomal rearrangements and linkage to immunoglobulin genes. These alterations identify a mechanism of genetic instability in malignant B cells and may have been selected during lymphomagenesis for their role in altering BCL6 expression.
Alleles↗
p53 overexpression as a marker of poor prognosis in mantle cell lymphomas with t(11;14)(q13;q32).
The t(11;14)(q13;q32) translocation, which juxtaposes the BCL1 oncogene with the Ig heavy chain locus, has been associated with an uncommon subtype of non-Hodgkin's lymphoma (NHL) termed mantle cell lymphoma (MCL). To date, no molecular marker that serves as an indicator of tumor progression or clinical prognosis has been described for NHLs with this translocation. We examined a panel of NHLs with t(11;14) for overexpression of p53 and correlated the results with single-strand conformation polymorphism (SSCP) analysis, karyotypic features, and clinical course. NHLs with t(11;14) were identified from 30 patients. The diagnosis was MCL for 23 of 30, small lymphocytic lymphoma for 4 of 30, and diffuse large-cell lymphoma for 3 of 30 cases. The results of immunohistochemistry analysis using a monoclonal anti-p53 antibody on paraffin-embedded specimens were compared with the SSCP data, the tumor karyotypes, and clinical course of each patient. DNA sequencing of exons was performed on cases that showed conformational changes by SSCP analysis. NHLs from 5 of 23 patients with MCL were positive for p53 overexpression. Deletions of chromosome 17p were identified in 2 of 30 cases, both of which were MCLs showing p53 overexpression. Two of the five MCLs with p53 overexpression showed evidence for TP53 mutations. None of the 18 MCLs negative for p53 overexpression showed conformational changes by SSCP. For these 18 patients with MCLs that did not overexpress p53, the median survival was 63 months, compared with 12 months for the 5 patients with MCLs positive for p53 overexpression (P < .001). These results suggest that p53 overexpression in MCL with t(11;14)(q13;q32) may serve as a marker of poor prognosis.
Adult↗
Del (7)(q32) is associated with a subset of small lymphocytic lymphoma with plasmacytoid features.
Deletions of the long arm of chromosome 7, previously documented in myelodysplasias and myeloid leukemias, have also been noted in lymphoid malignancies. Of 558 karyotypically abnormal specimens of non-Hodgkin's lymphoma (NHL) serially ascertained over an 8-year period, del(7q) was identified in 24 cases, 10 of which were of the small lymphocytic (sm lym) subtype. Del(7q) was the third most common karyotypic abnormality among the cohort of 61 sm lym cases in this ascertainment. Mapping of the deletions identified a region of common deletion affecting 7q32, which was the sole karyotypic abnormality in 2 cases. Eight of the ten sm lym cases were characterized by plasmacytoid features in histologic sections of lymphoma tumors or circulating cells in the peripheral blood. The del(7)(q32) was accompanied by 14q32-associated translocations in 11 of the 14 cases with histologies other than sm lym, compared with 2 of the sm lym cases. Extranodal involvement was more frequent in the del(7)(q32) sm lym NHLs, although median survival was typical of other low-grade lymphomas. These results suggest that loss or inactivation of a putative tumor-supressor gene at 7q32 may play a role the progression of lymphomas as well as constitute an early event in the pathogenesis of lymphoplasmacytoid tumors.
Adolescent↗
BCL-6 protein is expressed in germinal-center B cells.
Structural alterations of the 5' noncoding region of the BCL-6 gene have been found in 40% of diffuse large cell lymphoma (DLCL) and 5% to 10% of follicular lymphomas (FL), suggesting that deregulated BCL-6 expression may play a role in lymphomagenesis. Nucleotide sequencing of BCL-6 cDNA predicted a protein containing six zinc-finger domains, suggesting that it may function as a transcription factor. Using antisera raised against N- and C-terminal BCL-6 synthetic oligopeptides in immunoprecipitation, immunoblot, and immunocytochemical assays, this study identifies the BCL-6 gene product as a 95-kD nuclear protein. Western blot analysis of human tumor cell lines representative of various hematopoietic lineages/stages of differentiation showed that the BCL-6 protein is predominantly expressed in the B-cell lineage where it was found in mature B cells. Immunohistochemical analysis of normal human lymphoid tissues indicated that BCL-6 expression is topographically restricted to germinal centers including all centroblasts and centrocytes. The BCL-6 protein was also detectable in inter- and intra-follicular CD4+ T cells, but not in other follicular components including mantle-zone B cells, plasma cells, dendritic cells, and macrophages. Immunohistochemical analysis of DLCL and FL biopsy samples showed that the BCL-6 protein is detectable in these tumors independent of the presence of BCL-6 gene rearrangements. These results indicate that the expression of the BCL-6 gene is specifically regulated during B-cell differentiation and suggest a role for BCL-6 in germinal center development or function. Because DLCL derive from germinal-center B cells, deregulated BCL-6 expression may contribute to lymphomagenesis by preventing postgerminal center differentiation.
Amino Acid Sequence↗
Alterations of the BCL-6 gene in diffuse large-cell lymphoma.
Explore the source record for details and available documents.
B-Lymphocytes↗
BCL6 gene rearrangement and other cytogenetic abnormalities in diffuse large cell lymphoma.
Evidence for rearrangement of the BCL6 gene at 3q27 has been documented in 20-30% diffuse lymphomas with a large cell component (DLLC), and was found to be of prognostic significance at the time of diagnosis. To incorporate these observations into current cytogenetic and clinical prognostic models, 76 cases of DLLC with known BCL6 status were analyzed. Cytogenetic indicators of progression, including trisomy 7, trisomy 12, del(6)(q21q25), and structural alterations of 17p were less frequent in BCL6 rearranged DLLC compared to BCL6 germline tumors. Despite a 93% overall survival at median follow-up of 30 months, a trend for continued relapse resulted in a projected freedom from progression for the BCL6 rearranged cohort of 66% at 4 years, compared to 39% for the BCL6 germline cohort. Six cases among the BCL6 rearranged group lacked additional cytogenetic indicators of progression and remained free of disease at follow-up in excess of 7 years, whereas BCL6 rearranged cases with increasing numbers of cytogenetic aberrations showed decreased intervals free from progression of disease. These results suggest that BCL6 rearrangement should be combined with other known clinical and cytogenetic indicators in prognostic analyses of patients with DLLC.
Chromosome Aberrations↗
Familial acute myeloid leukemia and DiGuglielmo syndrome.
A family is described in which two sisters developed acute myeloblastic leukemia (AML FAB M2) and erythroleukemia (FAB M6) at ages 60 and 53, 15 years apart. Their father was diagnosed as having chronic erythremic myelosis (DiGuglielmo syndrome) 24 years earlier at age 56. Cytogenetic analysis of bone marrow blasts in the patient with AML M2 revealed a complex hyperdiploid karyotype with clonal abnormalities -3, -5, del(5)(q13q23), -8, +i(8)(q10), -11, add(11) (q23), add(12)(p13), -13, +3mar. No environmental risk factors could be identified. Hematologic and cytogenetic analysis of all living first degree relatives of the affected persons revealed hematological abnormalities, but normal constitutional karyotypes of peripheral blood lymphocytes and no induction of cytogenetic abnormalities in folate deficient medium.
Aged↗
Rearrangement of the bcl-6 gene as a prognostic marker in diffuse large-cell lymphoma.
BACKGROUND: About 40 percent of non-Hodgkin's lymphomas are diffuse lymphomas with a large-cell component (DLLC). Current therapy can induce a long-term remission in half the patients with DLLC, but more intensive treatment has the potential to improve outcome, particularly in patients at high risk for treatment failure. Clinical and cytogenetic markers can identify subgroups at high or low risk. Rearrangement of a novel candidate proto-oncogene, bcl-6, is a possible prognostic indicator in DLLC. METHODS: We performed Southern blot hybridization to detect bcl-6 and bcl-2 gene rearrangement in samples of lymphoma from 102 patients with B-cell DLLC. The results were correlated with the patients' histologic features, age, disease stage, tumor sites and bulk of disease, serum lactate dehydrogenase level, and treatment outcome. RESULTS: Rearranged bcl-6 was found in 23 cases, and rearranged bcl-2 in 21 cases. Nineteen of the patients with rearranged bcl-6 had extranodal DLLC, two had primary splenic lymphomas, and only one had bone marrow involvement. Thirty-six months after diagnosis, the proportion with freedom from progression of disease was projected to be 82 percent (95 percent confidence interval, 66 to 98 percent) among the patients with rearranged bcl-6, as compared with 56 percent (95 percent confidence interval, 43 to 70 percent) for the patients with germ-line bcl-6 and bcl-2 and 31 percent (95 percent confidence interval, 8 to 53 percent) for the patients with rearranged bcl-2. The status of the bcl-6 gene was an independent prognostic marker of survival and freedom from disease progression in a multivariate model and added predictive value to established prognostic signs. CONCLUSIONS: Rearrangement of the bcl-6 gene correlated with a favorable clinical outcome in DLLC and may thus serve as a prognostic marker in patients with this form of malignant lymphoma.
Aged↗
Clinical and morphologic features of B-cell small lymphocytic lymphoma with del(6)(q21q23).
Deletions of the long arm of chromosome 6 have been described in acute and chronic lymphocytic leukemia (ALL and CLL) and prolymphocytic leukemia (PLL), and have been associated with t(14;18)(q32;q21) in non-Hodgkin's lymphoma (NHL). Of 55 cases of small lymphocytic (sm lym) NHL, deletions of 6(q21q23) were the most common recurring cytogenetic abnormality. Among 14 sm lym NHL with del(6)(q21q23), this abnormality occurred as a solitary change in 3 cases. Each of these 3 cases, and 5 additional cases with del(6q) and other abnormalities, showed atypical larger forms with the morphologic appearance of prolymphocytes or paraimmunoblasts in the peripheral blood. In comparison, of the 11 cases without del(6q) and circulating abnormal cells, prolymphocytoid forms were observed in 4 cases (P < .001). Of the 31 sm lym without del(6q), trisomies of chromosomes 3, 12, or 18, or t(11;14)(q13;q32) occurred in greater than 10% of cases. Proliferation centers or infiltration by larger forms were observed in similar proportions of tissue sections derived from sm lym NHL with or without del(6q). The presence of the larger forms in the peripheral blood did not have an adverse prognostic impact on the survival of the del(6q) cohort, who experienced a median survival in excess of 6 years. All 14 cases of del(6q) sm lym NHL were characterized by a mature B-cell phenotype. Expression of CD11c, a feature of a CLL/PLL variant previously described, was not detected in 9 cases analyzed. In 5 cases of del(6q) sm lym NHL, no circulating abnormal lymphocytes were noted. Twelve cases presented with, or developed, clinical splenomegaly. These results suggest that deletion of a gene or genes at 6q21-23 is associated with the pathogenesis of a subset of B-cell sm lym NHL that may display larger prolymphocytoid cells in the peripheral blood, but that follows a clinical course typical of other well-differentiated lymphocytic neoplasms.
Antigens, CD↗