Heritable Breast Cancer Research Articles

Postscript: a status report on hemochromatosis population screening.

testing communities. An opportunity, because with an effective treatment available, the early detection afforded by a genetic screening program will make it possible to reduce the morbidity and mortality associated with the disease. It is a challenge, as well, because the relationship between genotype and clinical phenotype is unclear at present; e.g., not everyone inheriting two mutant copies of the gene responsible for hereditary hemochromato sis (HH) will develop significant disease, and there are concerns about how best to accomplish the screening, what the screening should entail, and social and ethical issues surrounding the screening. With regard to the challenge posed by hemochromato sis screening, there are similarities to issues previously raised with screening for the breast cancer predisposition genes, BRCA1 and BRCA2. For example, not everyone inheriting a BRCA1/BRCA2 mutation will develop breast or any cancer in her or his lifetime. And concerns have been expressed about when and whom to screen, who gets the results, and what might happen with regard to insurability and employability if the results become known to others besides the subject and his/her doctor. However, there are also significant differences between HFE and BRCA1/BRCA2 testing: cancer predisposition, following inheritance of BRCA1/BRCA2 mutations, is a dominant trait, with cancers seen in successive generations; no one really disputes the appropriateness of testing women with a strong family history of early-onset breast and/or ovarian cancer, only whether one extends the screening beyond this, for example, to all Ashkenazi Jewish women. HH, on the other hand, is a recessively inherited disorder, which means that the family history, except for sibs, is likely to be negative for other affecteds, so one cannot limit any testing just to those with a family history of the disease. The mutations in HFE, the gene responsible for HH, are more frequent than are mutations for BRCA1/BRCA2 among caucasians (estimates of carrier frequencies for mutations in HFE and BRCA1/BRCA2 among caucasians are about 1:10 and 1:200, respectively). However, clinically significant disease is less frequent in HH than in heritable breast cancer, a reflection of reduced penetrance in both disorders: for HH, estimates of clinically significant iron overload disease incidence of between 1 in 500 and 1 in 2,000, in different subpopulations have been reported, whereas between 50% and 85% of BRCA1/BRCA2 mutation carriers will develop breast cancer in their lifetimes. In some respects, HH is like another common recessive disease, cystic fibrosis (CF). In HH, homozygosity for one mutation, C282Y, accounts for over 80% of HH among northern Europeans. In CF, one common mutation, D F508, accounts for 75% or more of CF alleles among carriers and affecteds of northern European origin. In CF, the frequency of D F508 is different in different European subpopulations, accounting for only about 50% of all CF mutations in southern Europeans (Italians, Spaniards, Greeks, etc.) and about 30% of total CF in Ashkenazi Jews. In HH, different frequencies for C282Y, the common mutation, have been reported in specific European subpopulations (northern Europeans vs. Italians) and in other parts of the world (see Merryweather- Clarke et al., this issue). With regard to the major questions surrounding HH population screening:

BRCA buccal immunoassay predicts BRCA1 and BRCA2 mutations

Approximately 4% of unaffected, reproductive age women have a significant family history for heritable breast or ovarian cancer. While, BRCA1 and BRCA2 (BRCA) mutation analysis may prove useful in the clinical management of such individuals, such testing is prohibitively expensive. We have developed a rapid, noninvasive. and inexpensive, assay capable of identifying BRCA mutations in buccal cells.Objective: To determine the predictive value of the BRCA buccal immunoassay in the detection BRCA gene mutations.Methods: Buccal cells and peripheral blood were collected from 11 individuals, identified with a greater than 40% risk of carrying a BRCA mutation. To detect protein truncations which are associated with 90% of BRCA mutations, buccal cells were evaluated for BRCA immunoreactivity. Specifically, a qualitative, immunohistochemical comparison using antibodies directed against the amino and carboxy ends of either BRCA proteins, was performed. The presence of diminished immunoreactivity (total or diminished anti-carboxy reactivity relative to anti-amino reactivity) was scored as predictive for mutation. This analysis was compared to the results of BRCA ONA analysis.Results: Of the 11 individuals identified, six were found to have a BRCA1 mutation, two were found to have a BRCA2 mutation, and three were found to carry no mutations at all. The BRCA buccal immunoassay correctly predicted the presence of all eight mutations. Of the three individuals without BRCA mutations, immunoassay correctly predicted no mutation for BRCA1 in all three, while correctly predicting the absence of a BRCA2 mutation in 2 of three individuals.Conclusions: The positive and negative predictive values for this assay were 89% and 100% respectively, suggesting great promise as an inexpensive screen for BRCA mutations.

A minimally invasive assay detects BRCA 1 germline mutations

Previously, we described an antibody based assay which detects BRCA 1 gene alterations in surgical specimens from individuals with ovarian cancer. We also reported that this assay can detect BRCA 1 expression in human buccal cells and demonstrated BRCA 1 transcription in these cells using RT-PCR.To determine whether this antibody based assay can detect protein truncations resulting from germline BRCA 1 gene mutations in buccal cells, a study was conducted in which immunohistochemical reactivity was compared with BRCA I genetic analysis.Buccal cells of three individuals at high risk for developing heritable breast or ovarian cancer were collected. Mutation analysis was performed using PCR and SSCP followed by gene sequencing of unique polymorphisms. Immunohistochemical analysis of cytospin deposited buccal cells was performed using antibodies directed at the amino and carboxy ends of the BRCA 1 protein.In two of three specimens, germline mutations were detected. This was consistent with the immunohistochemical results which showed reduced reactivity with the carboxy binding antibody, suggesting the presence for a protein truncation. In the third specimen, no BRCA 1 polymorphisms were detected and immunohistochemical reactivity for the amino and carboxy termini were similar to the controls.We conclude that this immunohistochemical assay using buccal cells may serve as a minimally invasive, clinical tool to detect germline BRCA 1 gene mutations.

Identification by representational difference analysis of a homozygous deletion in pancreatic carcinoma that lies within the BRCA2 region.

Homozygous deletions have been central to the discovery of several tumor-suppressor genes, but their finding has often been either serendipitous or the result of a directed search. A recently described technique [Lisitsyn, N., Lisitsyn, N. & Wigler, M. (1993) Science 259, 946-951] held out the potential to efficiently discover such events in an unbiased manner. Here we present the application of the representational difference analysis (RDA) to the study of cancer. We cloned two DNA fragments that identified a homozygous deletion in a human pancreatic adenocarcinoma, mapping to a 1-centimorgan region at chromosome 13q12.3 flanked by the markers D13S171 and D13S260. Interestingly, this lies within the 6-centimorgan region recently identified as the BRCA2 locus of heritable breast cancer susceptibility. This suggests that the same gene may be involved in multiple tumor types and that its function is that of a tumor suppressor rather than that of a dominant oncogene.

DNA-Testing for Heritable Breast Cancer Risks: Lessons from Traditional Genetic Counseling

Abstract This article provides a brief overview of recent work in breast cancer genetics and addresses three areas of relevant behavioral medicine research: (a) understanding individuals' motivations to undergo genetic testing, (b) evaluating the impact of genetic testing on psychosocial outcomes, and (c) identifying moderators of the impact of genetic risk information. Recent studies show that levels of interest in genetic testing for breast cancer are high; however, most women who come forward lack understanding about inherited breast cancer risks and the benefits and limitations of genetic testing. Among those who participate in genetic testing for breast cancer, sociodemographic factors, psychological factors, and social/contextual factors may moderate their responses to genetic information. Before genetic testing for breast cancer is widely available, it is critical that prospective controlled trials be conducted to identify determinants of testing behavior, to elucidate the decision-making process, and to evaluate the behavioral and medical outcomes.

Recent advances in the genetics of heritable breast cancer.

Recent advances in the genetics of heritable breast cancer.

Mutations in p53 do not account for heritable breast cancer: a study in five affected families

Mutations in p53 do not account for heritable breast cancer: a study in five affected families

Heritability of breast cancer and its role in pre-menopausal cases.

The causes for the pre-menopausal incidence peak in breast cancer are still controversial. Other cancers also show an early incidence peak. Since the mammary tissue only starts to develop in puberty, the pre-menopausal incidence peak for breast cancer is comparable to the 'juvenile' peak in other cancers (retina, kidney). The four-mutation model for oncogenesis can explain pre-menopausal breast cancer. The model suggests that malignant transformation of a cell is due to four specific oncogenic mutations. These specific mutations accumulate during the proliferation of somatic cells. According to the model, one inherited oncogenic mutation can cause hereditary cancer. In this case only three additional specific mutations have to be accumulated during somatic cell proliferation. Epidemiological data and mathematical calculations indicate that in this case tumors occur early in life. Thus, the four-mutation model for oncogenesis predicts that the impact of heritability in pre-menopausal breast cancer is more significant than is generally believed. At this point, molecular biological studies are needed, to identify the involved specific mutations. Other implications of the model are an increased incidence of second primary tumors and an increased sensitivity for mutagenic factors in these patients.