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Previous studies on the counsellees' perception of DNA test results did not clarify whether counsellees were asked about their recollections or interpretations, and focused only on patients' own risks and not on the likelihood that cancer is heritable in the family. We tested differences and correlations of four perception aspects: recollections and interpretations of both cancer risks and heredity likelihood. In a retrospective study, women tested for BRCA1/2 on average, 5 years ago, completed questionnaires about their perception. Participants had received an unclassified variant (n = 76), uninformative (n = 76) or pathogenic mutation (n = 51) result in BRCA1/2. Analyses included t-tests, correlations and structural equation modelling. The counsellees' perception showed to consist of four distinctive phenomena: recollections and interpretations of cancer risks and of heredity likelihood. This distinctiveness was suggested by significant differences between these perception variables. Moderate to strong correlations were found between these variables, suggesting that these differences between variables were consistent. The relationships between these variables were not influenced by actually communicated DNA test results, sociodemographics, medical and pedigree information, or framing of cancer risk questions. The largest differences between recollections and interpretations were found in the unclassified variant group and the smallest in uninformatives. Cancer risks and heredity likelihood correlated least in the pathogenic mutation group. Communication of ambiguous genetic information enlarged the differences. To understand the counsellees' perception of genetic counselling, researchers should study recollections and interpretations of cancer risks and heredity likelihood. Genetic counsellors should explicitly address the counsellees' recollections and interpretations, and be aware of possible inaccuracies., (© 2010 John Wiley & Sons A/S.)

Aims: Ductal carcinoma in situ (DCIS) is an established late precursor of sporadic invasive breast cancer and to a large extent parallels its invasive counterpart with respect to molecular changes and immunophenotype. Invasive breast cancers in germline BRCA1 and BRCA2 mutation carriers have a distinct "basal" and "luminal" immunophenotype, respectively, but the immunophenotype of their precursor lesions has hardly been studied, and this was the aim of this study., Methods: DCIS lesions of 25 proven BRCA1 and 9 proven BRCA2 germline mutation carriers and their 22 and 6, respectively, accompanying invasive lesions were stained by immunohistochemistry for oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER)2/neu, cytokeratin (CK)5/6, CK14, epidermal growth factor receptor (EGFR) and Ki67., Results: DCIS lesions in BRCA1 mutation carriers were mostly of the basal molecular type with low ER/PR/HER2 expression, while they frequently expressed CK5/6, CK14 and EGFR, and were mostly grade 3 and highly proliferative. DCIS lesions in BRCA2 mutation carriers were mostly of luminal molecular type with frequent expression of ER/PR, and infrequent expression of CK5/6, CK14 and EGFR, and they were mostly grade 3 and showed low proliferation. In BRCA1 and BRCA2 mutation carriers there was a high concordance between DCIS lesions and their concomitant invasive counterpart with regard to expression of individual markers as well as "molecular" subtype., Conclusions: Although the number of cases studied was low, DCIS lesions in BRCA1 and BRCA2 mutations carriers are usually of the basal and luminal molecular type, respectively, similar to their accompanying invasive cancers, thereby providing evidence that DCIS is a direct precursor lesion in these hereditary predisposed patients. This also suggests that crucial carcinogenetic events leading to these phenotypes in hereditary predisposed patients occur before the stage of invasion.

Introduction: Breast cancer patients with early disease and a natural humoral response to MUC1 have a favourable prognosis, suggesting a possible role of MUC1 antibodies (ab) in controlling haematogenous tumour dissemination and outgrowth. The aim of the study was to evaluate humoral immune responses to MUC1 in women at hereditary high risk of breast cancer to investigate whether this immune response could play a role in the prevention of disease., Materials and Methods: CA15.3 (U/mL), and IgG and IgM ab to MUC1 (arbitrary units per mL, Arb-U/mL) were measured in serum samples obtained from 422 women at hereditary high risk of breast/ovarian cancer, of whom 127 BRCA1/2 carriers, attending the Familial Cancer Clinic of the VU University Medical Centre, and from 370 age-matched healthy controls. Serum samples obtained from women who developed breast cancer (N=12) or breast cancer recurrence (N=17), and from women who underwent prophylactic mastectomy (N=12) and had no breast lesions were also tested., Results: CA15.3 ranked significantly higher in mutation carriers than in controls (P=0.03). MUC1 IgG ab levels ranked significantly lower in BRCA1/2 mutation carriers than in controls (P=0.003). MUC1 IgG levels were not significantly different (P=0.53) between women who developed primary breast cancer (median 0.72Arb-U/ml, range 0.52-2.44Arb-U/ml) and women who underwent prophylactic mastectomy and had no breast lesions (median 1.04Arb-U/ml, range 0.43-2.88Arb-U/ml)., Conclusion: Serum levels of natural IgG ab to MUC1 are lower in BRCA1/2 mutation carriers than in healthy controls. Furthermore, in contrast to previous results in women with sporadic breast cancer, no elevated MUC1 IgG ab were seen in women at hereditary high risk who developed breast cancer. Prophylactic immunotherapy with MUC1 substrates may be a strategy to reduce the risk of breast cancer in BRCA1/2 mutation carriers, strengthening tumour immune surveillance.

Background: About 5% of all breast cancer cases are attributable to germline mutations in BRCA1 or BRCA2 genes. BRCA mutations in suspected carriers, however, may be missed, which hampers genetic counselling., Materials and Methods: Different clinicopathological features were compared between 22 breast cancers from carriers of proved BRCA1 mutations and 604 cancers from sporadic controls. In addition, 5 BRCA2-related breast cancers and 66 breast cancers of untested patients at intermediate risk and 19 breast cancers of untested patients at high risk of hereditary disease on the basis of family history were evaluated., Results: A "probably sporadic" class (age >or=54 years and epidermal growth factor receptor (EGFR) negative; 68% of cases) with a 0% chance of BRCA1-related breast cancer containing 79% of the sporadic cases was yielded by using a decision tree with age, Ki67 and EGFR. A 75% chance of BRCA1-related breast cancer was shown by the "probably BRCA1-related" class (age <54 years and Ki67 >or=25%; 8% of cases) with 82% of the BRCA1-related cases but only 1.4% of the sporadic cases. Most cases at intermediate or high risk of hereditary disease on the basis of family history could be classified with high probability as either probably BRCA1 related or probably sporadic., Conclusion: Breast carcinomas can be classified with a high level of certainty as sporadic or related to BRCA1 germline mutations by using a decision tree with age, Ki67 and EGFR. This can be clinically useful in mutation analysis in families with a borderline risk of hereditary disease.

About 5% of all ovarian-cancer cases are caused by a genetic predisposition, in particular as a component of the autosomal dominant hereditary breast-ovarian-cancer syndrome. This syndrome is usually due to germline mutations in the BRCA1- or BRCA2-gene. Ovarian and endometrial cancer also occur in families with hereditary non-polyposis colorectal cancer (HNPCC). This syndrome is caused by germline mutations in DNA mismatch-repair genes. Women at high risk of gynaecological cancer based upon familial clustering of disease or a demonstrated pathogenic germ-line mutation are candidates for surveillance: annual gynaecological examinations, including vaginal echoscopy and serum carcinoma antigen CA125 testing. Prophylactic surgery in the form of adnexectomy leads to a marked, but not complete, reduction of ovarian-cancer risk in high-risk cases. There is insufficient evidence to advise against the use of oral contraceptives or hormonal substitution after adnexectomy for healthy women with a genetic predisposition to breast cancer. Recommendations for surveillance and prevention should only be given after genetic-risk counselling, based on a detailed family study and DNA-based diagnosis.

For families with a small number of cases of breast and/or ovarian cancer, limited data are available to predict the likelihood of genetic predisposition due to mutations in BRCA1 or BRCA2. In 104 families with three or more affected individuals (average 3.8) seeking counselling at family cancer clinics, mutation analysis was performed in the open reading frame of BRCA1 and BRCA2 by the protein truncation test and mutation-specific assays. In 31 of the 104 families tested, mutations were detected (30%). The majority of these mutations (25) occurred in BRCA1. Mutations were detected in 15 out of 25 families (60%) with both breast and ovarian cancer and in 16 out of 79 families (20%) with exclusively cases of breast cancer. Thus, an ovarian cancer case strongly predicted finding a mutation (P < 0.001). Within the group of small breast-cancer-only families, a bilateral breast cancer case or a unilateral breast cancer case diagnosed before age 40 independently predicted finding a BRCA1 or BRCA2 mutation (P = 0.005 and P = 0.02, respectively). Therefore, even small breast/ovarian cancer families with at least one case of ovarian cancer, bilateral breast cancer, or a case of breast cancer diagnosed before age 40, should be referred for mutation screening.

The time course of induction of SOS-like stress responses such as enhanced reactivation (ER) and enhanced mutagenesis (EM) has been investigated in UV-C-irradiated skin fibroblasts from a xeroderma pigmentosum (XP) family, using herpes simplex virus type 1 as a probe. Similar ER studies were performed in a Li-Fraumeni syndrome (LFS) family and in a family with a high incidence of breast, ovarian, and colon cancer. In two XP (complementation group B) patients, with a striking absence of skin tumors even at an age of >40 years, only induction of EM was observed, whereas ER was absent (XPER-). The ER- phenotype was inherited from the father, whereas cells from the mother exhibited normal expression of ER and EM. This suggests that the absence of ER is a hereditary trait that is not correlated with a repair-deficient phenotype. Abnormally high levels of ER were observed in UV-C-exposed skin fibroblasts from rive LFS patients. The inheritance of the ER response was studied in one LFS family. High levels of ER were observed only in cells derived from affected individuals carrying one mutated p53 allele, whereas cells from unaffected family members, carrying two wild-type p53 alleles, exhibited normal ER levels. This result shows that abnormally high levels of ER positively correlate with the occurrence of cancer in affected individuals from a LFS family. Interestingly, abnormally high levels of ER were observed in cells from afflicted as well as from unafflicted members of a family with a high incidence of breast, ovarian, colon, and stomach cancer. This suggests that these latter individuals have inherited a mutated, putative predisposing gene, resulting in abnormal expression of ER, but that cancer had not yet developed. The results indicate that the ER response can possibly be used as a prognostic marker to identify carriers in various hereditary cancer-prone syndromes at an early age.

We searched for criteria that could indicate breast cancer families with a high prior probability of being caused by the breast/ovarian cancer susceptibility locus BRCA1 on chromosome 17. To this end, we performed a linkage study with 59 consecutively collected Dutch breast cancer families, including 16 with at least one case of ovarian cancer. We used an intake cut-off of at least three first-degree relatives with breast and/or ovarian cancer at any age. Significant evidence for linkage was found only among the 13 breast cancer families with a mean age at diagnosis of less than 45 years. An unexpectedly low proportion of the breast-ovarian cancer families were estimated to be linked to BRCA1, which could be due to a founder effect in the Dutch population. Given the expected logistical problems in clinical management now that BRCA1 has been identified, we propose an interim period in which only families with a strong positive family history for early onset breast and/or ovarian cancer will be offered BRCA1 mutation testing.