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Background: The identification of a BRCA1 or BRCA2 mutation in familial breast cancer kindreds allows genetic testing of at risk relatives. However, considerable controversy exists regarding the cancer risks in women who test positive for the family mutation., Methods: We reviewed 385 unrelated families (223 with BRCA1 and 162 with BRCA2 mutations) ascertained through two regional cancer genetics services. We estimated the penetrance for both breast and ovarian cancer in female mutation carriers (904 proven mutation carriers - 1442 females in total assumed to carry the mutation) and also assessed the effect on penetrance of mutation position and birth cohort., Results: Breast cancer penetrance to 70 and to 80 years was 68% (95%CI 64.7-71.3%) and 79.5% (95%CI 75.5-83.5%) respectively for BRCA1 and 75% (95%CI 71.7-78.3%) and 88% (95%CI 85.3-91.7%) for BRCA2. Ovarian cancer risk to 70 and to 80 years was 60% (95%CI 65-71%) and 65% (95%CI 75-84%) for BRCA1 and 30% (95%CI 25.5-34.5%) and 37% (95%CI 31.5-42.5%) for BRCA2. These risks were borne out by a prospective study of cancer in the families and genetic testing of unaffected relatives. We also found evidence of a strong cohort effect with women born after 1940 having a cumulative risk of 22% for breast cancer by 40 years of age compared to 8% in women born before 1930 (p = 0.0005)., Conclusion: In high-risk families, selected in a genetics service setting, women who test positive for the familial BRCA1/BRCA2 mutation are likely to have cumulative breast cancer risks in keeping with the estimates obtained originally from large families. This is particularly true for women born after 1940.

Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes (polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families (301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 1920-1929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in a user-friendly Web-based program (http://www.srl.cam.ac.uk/genepi/boadicea/boadicea_home.html).

While there are many reports in the literature of mutation testing of BRCA1 and BRCA2 in breast/ovarian cancer families, the question of which type of ovarian cancers are relevant still pertains. We have undertaken whole gene screening including multiple ligation-dependent probe amplification in an affected individual within 442 unrelated non-Jewish families containing at least one reported ovarian cancer diagnosed less than 50 years or at any age with family history of breast or ovarian cancer for mutations in BRCA1 and BRCA2. A total of 166 mutations were identified 110 (25%) in BRCA1 and 56 (13%) in BRCA2. In families without confirmation of ovarian diagnosis, the detection rate drops significantly. In families fulfilling Breast Cancer Linkage Consortium (BCLC) criteria with confirmed ovarian cancer cases, the mutation detection frequency was 80%. If only BCLC families with unconfirmed ovarian cancers were included, the detection rate dropped to 36% when a relevant ovarian cancer diagnosis was not confirmed. In BCLC families containing only one ovarian cancer, BRCA2 accounted for 45% of identified mutations. No mutations were identified in affected individuals with borderline or mucinous tumours. Detection rates dropped below the 10/20% international thresholds in a number of families with unconfirmed ovarian cancers. Borderline/mucinous pathology substantially reduces the likelihood of identifying a BRCA1/2 mutation. Strenuous efforts should be made to confirm ovarian pathology if the lack of confirmation or refuting the diagnosis would decrease a family's likelihood of mutation detection below screening thresholds. In the UK, a higher proportion of families harbour BRCA2 pathogenic mutations than predicted from previous studies.

64 families with a history of male breast cancer aged 60 or less or with a family history of male and female breast cancer were screened for the presence of BRCA1 and BRCA2 mutations. Seventeen pathogenic BRCA2 and four BRCA1 mutations were identified (34%) in samples from an affected family member. All but one of the mutations segregated with disease where samples were available and pedigree structure permitted. Despite high sensitivity of mutation testing only 64% of families fulfilling BCLC criteria had an identifiable pathogenic mutation. It is possible that at least some of these families may have mutations in other genes, although we found no involvement of CHEK2 1100delC.

Women with a family history of breast cancer are commonly offered regular clinical or mammographic surveillance from age 30. Data on the efficacy of such programmes are limited. Clinical, pathological and outcome data were recorded on all breast and ovarian cancers diagnosed within familial breast cancer surveillance programmes at collaborating centers in Norway and the UK up to the end of 2005. These have been analyzed according to the mutation status of the affected women (BRCA1+ve, BRCA2+ve or mutation-negative). Breast cancer was diagnosed in 442 patients subsequently followed for a total of 2095 years. Eighty-nine (20%) had BRCA1 mutations, 35 (8%) BRCA2 mutations and in 318 (72%) no mutation could be detected ("mut neg"). Five-year survival in BRCA1 was 73% compared to 96% in BRCA2 and 92% in mut neg (p = 0.000). Among BRCA1 mutation-carriers, 5-year survival was 67% for cases diagnosed as carcinoma in situ, 84% for node-negative invasive cancers and 58% for those with nodal involvement (p > 0.05). For BRCA2 mutation-carriers the corresponding figures were 100, 100 and 90% (p > 0.05), while for mut neg women they were 100, 97 and 71% (p = 0.03). Regular surveillance in women at increased familial risk of breast cancer is associated with a good outcome if they carry BRCA2 mutations or no detectable mutation. Carriers of BRCA1 mutations fare significantly worse, even when their tumors are diagnosed at an apparently early stage. The differences in outcome associated with different genetic causes of disease were associated with demonstrated differences in tumor biology. The findings demonstrate the outcome for genetically different breast cancers detected within a programme for early diagnosis and treatment, which is relevant to genetic counseling when women at risk have to chose between the options for preventing death from inherited breast cancer., ((c) 2007 Wiley-Liss, Inc.)

Objective: Screening colonoscopy has been shown to reduce mortality and cancer stage in hereditary nonpolyposis colorectal cancer (HNPCC) individuals. However, the benefit of screening in intermediate risk groups is unknown. The most recent national guidelines have recommended a reduction of screening frequency for the intermediate risk group. Therefore, this study aims to compare the results of colonoscopic screening in HNPCC and intermediate risk groups and assess the effect of the most recent screening protocol recommendations., Method: A total of 244 individuals; 108 from HNPCC families (28 mismatch repair gene carriers) and 136 from intermediate risk families were referred for regular colonoscopic screening by the Regional Genetics Service. Findings from 417 colonoscopies performed between 1992 and 2003 were evaluated., Results: A total of three cancers, 39 adenomas and 41 hyperplastic polyps were found in the HNPCC group compared with one cancer, 22 adenomas and 19 hyperplasic polyps in the intermediate risk group. If the recent screening guidelines for the intermediate group were applied, then 89 (44%) fewer colonoscopies would have been performed. Although no cancers would have been missed, six adenomas (mean size = 5.7 mm, range 2-10 mm) with two graded as severely dysplasic and six hyperplastic polyps would not have been detected., Conclusion: The detection rate and distribution of adenomas were similar in both groups. If the new colonoscopic screening recommendations for the intermediate risk group had been applied, a small number of significant lesions would have been missed.

Background: :The aim of this study was to determine the proportion of patients with familial adenomatous polyposis (FAP) who had mutations in the desmoid region of the adenomatous polyposis coli (APC) gene that phenotypically expresses desmoid disease, and to determine the role for surgery in these patients., Methods: Data from the North West Region FAP database and case notes were analysed retrospectively., Results: Of 363 patients with FAP, 47 from ten families had APC mutations in the desmoid region 3' to codon 1399. Of 22 patients undergoing surgery, 16 developed desmoids, and of these 12 had mesenteric desmoid disease. Complications from mesenteric desmoids were death (two patients), enterectomy (three), local resection (three), fistula (one), cholangitis and local resection (one), bowel obstruction (one) and bowel and ureteric obstruction (one). Preoperative polyp burden ranged from 0 to 100 in eight patients (median age 24.5 (range 16-39) years) and more than 100 in seven (median age 39 (range 31-64) years). One patient had no record of polyp burden., Conclusion: In individuals with 3' APC mutations, abdominal surgery is associated with a 65 per cent risk of developing mesenteric desmoids. An alternative strategy might be to attempt to manage the polyps endoscopically., (Copyright (c) 2007 British Journal of Surgery Society Ltd.)

The hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome is an autosomal dominant disorder caused by mutations of the dual zinc finger transcription factor, GATA3. We investigated 21 HDR probands and 14 patients with isolated hypoparathyroidism for GATA3 abnormalities. Thirteen different heterozygous germline mutations were identified in patients with HDR. These consisted of three nonsense mutations, six frameshifting deletions, two frameshifting insertions, one missense (Leu348Arg) mutation and one acceptor splice site mutation. The splice site mutation was demonstrated to cause a pre-mRNA processing abnormality leading to the use of an alternative acceptor site 8 bp downstream of the normal site, resulting in a frameshift and prematurely terminated protein. Electrophoretic mobility shift assays (EMSAs) revealed three classes of GATA3 mutations: those that lead to a loss of DNA binding which represent over 90% of all mutations, and involved a loss of the carboxy-terminal zinc finger; those that resulted in a reduced DNA-binding affinity; and those (e.g. Leu348Arg) that did not alter DNA binding or the affinity but likely altered the conformational change that occurs during binding in the DNA major groove as predicted by a three-dimensional modeling. These results elucidate further the molecular mechanisms underlying the altered functions of mutants of this zinc finger transcription factor and their role in causing this developmental anomaly. No mutations were identified in patients with isolated hypoparathyroidism, thereby indicating that GATA3 abnormalities are more likely to result in two or more of the phenotypic features of the HDR syndrome and not in one, such as isolated hypoparathyroidism.

Background: The identification of BRCA1 and BRCA2 mutations in familial breast cancer kindreds allows genetic testing of at-risk relatives. Those who test negative are usually reassured and additional breast cancer surveillance is discontinued. However, we postulated that in high-risk families, such as those seen in clinical genetics centres, the risk of breast cancer might be influenced not only by the BRCA1/BRCA2 mutation but also by modifier genes. One manifestation of this would be the presence of phenocopies in BRCA1/BRCA2 kindreds., Methods: 277 families with pathogenic BRCA1/BRCA2 mutations were reviewed and 28 breast cancer phenocopies identified. The relative risk of breast cancer in those testing negative was assessed using incidence rates from our cancer registry based on local population., Results: Phenocopies constituted up to 24% of tests on women with breast cancer after the identification of the mutation in the proband. The standardised incidence ratio for women who tested negative for the BRCA1/BRCA2 family mutation was 5.3 for all relatives, 5.0 for all first-degree relatives (FDRs) and 3.2 (95% confidence interval 2.0 to 4.9) for FDRs in whose family all other cases of breast and ovarian cancer could be explained by the identified mutation. 13 of 107 (12.1%) FDRs with breast cancer and no unexplained family history tested negative., Conclusion: In high-risk families, women who test negative for the familial BRCA1/BRCA2 mutation have an increased risk of breast cancer consistent with genetic modifiers. In light of this, such women should still be considered for continued surveillance.

Evaluation of familial colorectal cancer referral can assist in the planning of future cancer surveillance. The aim of the study is to assess colorectal cancer referral pattern to our regional genetics service. Hospital computer records and/or department referral books were used to identify cases referred to the regional genetic service during a 10-year period (1992-2001 inclusive). All files were reviewed along with associated demographic data, risk assessments, referral details, results from mutation testing and screening recommendations. In terms of result, a total of 1100 family files were reviewed (Familial Adenomatous Polyposis families were in a separate register). The number of referrals showed a 10-fold increase over the 10 years. 171 (15.6%) of families met the Amsterdam criteria II were classified as high-risk, 589 (53.5%) families were classified as moderate-risk and 337 (31.0%) as average or low risk. 22.9% families were referred with inaccurate cancer history. Sixty-one families have been identified with mismatch repair mutations. 56.8% of referred individuals were recommended to have regular colonoscopy ranging from 18 monthly to 5 yearly depending on their risks. In conclusion, there has been a 10-fold increase in individuals with suspected hereditary bowel cancer referred to the North West Regional Genetics Service in the last ten years. Genetic assessment may reduce the number of low-risk individuals and those who were found not to be mutation carriers from having unnecessary colonoscopic screening. Thus genetic risk assessment should precede the initiation of regular endoscopic screening.

We assessed the association between breast cancer (BC) and colorectal cancer (CRC) from referral pattern to the Regional Genetics Service including molecular analysis. Hospital computer records and/or department referral books were used to identify cases referred to the Regional Genetic Service during a 16-year period (1990-2005 inclusive). All files were reviewed along with associated demographic data, risk assessments, referral details and results from mutation testing. Families were assessed for hereditary breast and colorectal cancer (HBCC) criteria, and all families with eligible individuals were tested for the 1100delC mutation in CHEK2. A total of 8,612 families were identified. One hundred and sixteen of 1,631 (7.5%) families with a primary referral for CRC fulfilled the criteria for HBCC, whereas only 68/6981 (1%) BC referrals fulfilled these criteria. Blood samples were obtained from 113 individuals from 83/184 families. Only 1/113 (1%) has screened positive for the CHEK2 mutation, whereas 14 (17%) families segregate BRCA1/2 mutations and at least 7 (8.5%) carry MLH1/MSH2 mutations. HBCC syndrome, if it exists as a separate entity, is not likely to be due to CHEK2 mutations. Many families are explicable by existing high-penetrance genes, and further work is necessary to elucidate whether the remainder is due to chance or as yet undiscovered genes.

Pathological mutations in BRCA1, BRCA2 and TP53 are associated with an increased risk of breast cancer. This study evaluated mutation frequency of these genes in early-onset breast cancer patients, and correlated this with family history and determined relative risks to family members. Patients with breast adenocarcinoma diagnosed 30 years were ascertained between 1980 and 1997. Family history was established and mutation screening of BRCA1, BRCA2 and TP53 genes was performed. Estimates of penetrance and relative risk were undertaken. DNA was obtained from 100/139 women. 17/36 familial cases had a BRCA1, BRCA2 or TP53 mutation. Of 64 non-familial cases, one BRCA2, two BRCA1 and two TP53 mutations were detected. Penetrance estimates (by age 70) for breast cancer were 84% for BRCA1 mutations and 91% for BRCA2 mutations and for ovarian cancer, 60% and 26%, respectively. Relative risks associated with mutations were consistent with previous studies. BRCA1 and BRCA2 mutations in patients with breast cancer 30 years are predicted strongly by family history. The majority of families with ovarian cancer were due to mutations in BRCA1/2 whereas these mutations only accounted for 30-50% of the excess breast cancers.

Introduction: Increasing parity and age at first full-term pregnancy are established risk factors for breast cancer in the general population. However, their effects among BRCA1 and BRCA2 mutation carriers is still under debate. We used retrospective data on BRCA1 and BRCA2 mutation carriers from the UK to assess the effects of parity-related variables on breast cancer risk., Methods: The data set included 457 mutation carriers who developed breast cancer (cases) and 332 healthy mutation carriers (controls), ascertained through families seen in genetic clinics. Hazard ratios were estimated by using a weighted cohort approach., Results: Parous BRCA1 and BRCA2 mutation carriers were at a significantly lower risk of developing breast cancer (hazard ratio 0.54, 95% confidence interval 0.37 to 0.81; p = 0.002). The protective effect was observed only among carriers who were older than 40 years. Increasing age at first live birth was associated with an increased breast cancer risk among BRCA2 mutation carriers (p trend = 0.002) but not BRCA1 carriers. However, the analysis by age at first live birth was based on small numbers., Conclusion: The results suggest that the relative risks of breast cancer associated with parity among BRCA1 and BRCA2 mutation carriers may be similar to those in the general population and that reproductive history may be used to improve risk prediction in carriers.

Aim: To establish the uptake of contralateral risk reducing mastectomy in women informed of their risks and options at time of diagnosis of their primary unilateral breast cancer., Methods: We have assessed the surgical choices of 70 women diagnosed with breast cancer <50 years as part of a family history surveillance program and fully informed about their contralateral risks and surgical options. We have compared this to women from other surgical clinics who were subsequently found to harbour a pathogenic BRCA1/2 mutation., Results: Sixty-five percent (13/20) of BRCA1/2 mutation carriers and 59% (n=20/34) of those at the highest level of risk pre-diagnosis (33+% lifetime risk) opted for contra-lateral mastectomy in the study sample. In contrast only 10% (n=9/88) women identified as mutation carriers from other clinics opted for such surgery., Conclusions: We would suggest that women with a significant family history and therefore a high contra-lateral breast cancer risk, should have these risks and management options discussed at the time of diagnosis of breast cancer.

Purpose: To investigate the proportion of breast cancers arising in patients with germ line BRCA1 and BRCA2 mutations expressing basal markers and developing predictive tests for identification of high-risk patients., Experimental Design: Histopathologic material from 182 tumors in BRCA1 mutation carriers, 63 BRCA2 carriers, and 109 controls, collected as part of the international Breast Cancer Linkage Consortium were immunohistochemically stained for CK14, CK5/6, CK17, epidermal growth factor receptor (EGFR), and osteonectin., Results: All five basal markers were commoner in BRCA1 tumors than in control tumors (CK14: 61% versus 12%; CK5/6: 58% versus 7%; CK17: 53% versus 10%; osteonectin: 43% versus 19%; EGFR: 67% versus 21%; P < 0.0001 in each case). In a multivariate analysis, CK14, CK5/6, and estrogen receptor (ER) remained significant predictors of BRCA1 carrier status. In contrast, the frequency of basal markers in BRCA2 tumors did not differ significant from controls., Conclusion: The use of cytokeratin staining in combination with ER and morphology provides a more accurate predictor of BRCA1 mutation status than previously available, that may be useful in selecting patients for BRCA1 mutation testing. The high percentage of BRCA1 cases positive for EGFR suggests that specific anti-tyrosine kinase therapy may be of potential benefit in these patients.

Differences in reported uptake of genetic testing for mutations in BRCA1 and BRCA2 can largely be accounted for by different methodologies and by studying research vs nonresearch families. In our joint study of 75 nonresearch families from two UK centres in which at least 3 years had elapsed since the initial proband had been informed of the availability of testing, only 45 and 34% of eligible individuals from Manchester and London, respectively, had come forward for counselling. Final uptake rates using a non-proactive approach were 53 and 29% for women and 11-12% for men, but the figure among those attending clinic was 73 and 62%, respectively. Unlike previous studies, we did not find that uptake had stabilised after a year with 25% of those being tested more than 2 years after the family was informed, and several delaying a considerable time between genetics appointments. We believe that the particularly low uptake even of counselling in men may need to be addressed by improving family communication or providing information sheets for family members to disseminate.

Background: Mass screening for colorectal cancer reduces mortality and, with recent advances in molecular genetics, molecular stool-based tests have produced promising results. This article reviews this innovation and discusses its clinical significance., Methods: Medline searches were used to identify recent key articles relating to stool-based testing. Further articles were obtained by manual scanning of the reference lists of identified papers., Results: Current screening methods are based on endoscopic, radiological and stool-based testing. Recent recognition of the adenoma-carcinoma sequence and pathophysiological studies of colonic epithelium have enabled tumour markers to be used in the screening setting. Non-invasive molecular stool testing has now been shown to have a high sensitivity and specificity., Conclusion: Recent studies on molecular stool-based testing have shown higher sensitivity and specificity than earlier studies, but larger clinical trials are required. Laboratory methods are still undergoing research, with the aim of improving sensitivity to allow large-scale testing., (Copyright 2004 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Purpose: To develop a simple scoring system for the likelihood of identifying a BRCA1 or BRCA2 mutation., Methods: DNA samples from affected subjects from 422 non-Jewish families with a history of breast and/or ovarian cancer were screened for BRCA1 mutations and a subset of 318 was screened for BRCA2 by whole gene screening techniques. Using a combination of results from screening and the family history of mutation negative and positive kindreds, a simple scoring system (Manchester scoring system) was devised to predict pathogenic mutations and particularly to discriminate at the 10% likelihood level. A second separate dataset of 192 samples was subsequently used to test the model's predictive value. This was further validated on a third set of 258 samples and compared against existing models., Results: The scoring system includes a cut-off at 10 points for each gene. This equates to >10% probability of a pathogenic mutation in BRCA1 and BRCA2 individually. The Manchester scoring system had the best trade-off between sensitivity and specificity at 10% prediction for the presence of mutations as shown by its highest C-statistic and was far superior to BRCAPRO., Conclusion: The scoring system is useful in identifying mutations particularly in BRCA2. The algorithm may need modifying to include pathological data when calculating whether to screen for BRCA1 mutations. It is considerably less time-consuming for clinicians than using computer models and if implemented routinely in clinical practice will aid in selecting families most suitable for DNA sampling for diagnostic testing.

Background: Germline mutations in three subunits of mitochondrial complex II (SDHB, SDHC and SDHD) may be associated with susceptibility to phaeochromocytoma (PC) and/or head and neck paraganglioma (HNPGL)., Methods: To further define the role of SDH subunit mutations in these disorders, we analysed a series of 22 probands with PC and evidence of genetic susceptibility (seven with familial PC only, one with familial PC and HNPGL, 10 sporadic cases with multiple PC and four cases of isolated paediatric onset PC) for germline SDHB, SDHC and SDHD mutations. In addition, we analysed 34 cases of HNPGL (30 isolated cases with single tumours, three isolated cases with multiple tumours and one familial case with multiple tumours) for somatic and germline mutations in SDHB, SDHC and SDHD., Results: We identified four germline mutations (three SDHB and one SDHD, three novel) in the 22 PC probands. Combining these results with our previous series, we have detected germline SDHB or SDHD mutations in 2/12 (17%) of familial PC only kindreds, 4/5 (80%) of familial PC and HNPGL cases, 1/10 of sporadic multiple PC cases and 2/4 (50%) of paediatric PCs. No somatic mutations were detected in the HNPGL tumours, but four cases with multiple HNPGL had the common P81L germline SDHD mutation. Intriguingly a silent SNP (c.204C > T) in SDHD was significantly more common in HNPGL cases (6/34) than in controls (1/100, P = 0.0011). Combining our results with those from two other large studies in which both SDHB and SDHD have been analysed, SDHB mutations were most commonly associated with phaeochromocytoma susceptibility and SDHD with the development of HNPGL (P = 0.025). However, germline SDHB and SDHD mutations demonstrate considerable phenotypic variability and genotype-phenotype correlations are complex., Conclusion: The significantly lower frequency (P = 0.028) of germline SDH subunit mutations in familial PC only cases compared to those with familial PC and HNPGL suggests that further PC susceptibility gene(s) remain to be identified.

Introduction: Accurate individualised breast cancer risk assessment is essential to provide risk-benefit analysis prior to initiating interventions designed to lower breast cancer risk. Several mathematical models for the estimation of individual breast cancer risk have been proposed. However, no single model integrates family history, hormonal factors, and benign breast disease in a comprehensive fashion. A new model by Tyrer and Cuzick has addressed these deficiencies. Therefore, this study has assessed the goodness of fit and discriminatory value of the Tyrer-Cuzick model against established models namely Gail, Claus, and Ford., Methods: The goodness of fit and discriminatory accuracy of the models was assessed using data from 1933 women attending the Family History Evaluation and Screening Programme, of whom 52 developed cancer. All models were applied to these women over a mean follow up of 5.27 years to estimate risk of breast cancer., Results: The ratios (95% confidence intervals) of expected to observed numbers of breast cancers were 0.48 (0.37 to 0.64) for Gail, 0.56 (0.43 to 0.75) for Claus, 0.49 (0.37 to 0.65) for Ford, and 0.81 (0.62 to 1.08) for Tyrer-Cuzick. The accuracy of the models for individual cases was evaluated using ROC curves. These showed that the area under the curve was 0.735 for Gail, 0.716 for Claus, 0.737 for Ford, and 0.762 for Tyrer-Cuzick., Conclusion: The Tyrer-Cuzick model is the most consistently accurate model for prediction of breast cancer. The Gail, Claus, and Ford models all significantly underestimate risk, although the accuracy of the Claus model may be improved by adjustments for other risk factors.

Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers (P trend.0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.

We aimed to assess frequency and penetrance of BRCA1, BRCA2,and TP53 mutations in women diagnosed with breast cancer aged 30 years or younger, and then correlate this frequency with family history. 17 of 36 familial cases had a BRCA1, BRCA2, or TP53 mutation, compared with three of 63 non-familial cases. The calculated population frequency of TP53 mutations was one in 5000, substantially greater than previous estimates. This finding underlines the importance of accurate elucidation of a family history from young women diagnosed with breast cancer. Establishment of family history could help with development of patient-specific management and tumour surveillance protocols.

Objectives: To describe and compare women's risk perceptions and recall of breast cancer risk information in a cohort of first-time attendees at a family history clinic., Methods: We conducted a 1-year prospective study of 158 women aged 18-45 years with a confirmed lifetime risk of breast cancer of 1 in 6 or greater. Risk perception and recall were assessed using a self-report questionnaire, completed pre-counselling and 3, 6, 9 and 12 months post-counselling, and through interviews conducted at 3 and 12 months., Results: The proportion of women with accurate personal risk perceptions based on 'gambling' odds ('1 chance in x') significantly improved after risk counselling from 12% pre-counselling to 67% 3 months post-counselling (p < 0.001), which was maintained for 1 year. This was the method of reporting perceived risk associated with the best level of risk accuracy and the women's preferred format for describing risk, but the concept of lifetime risk was understood by only 44% of women. Qualitative risk categories ('high', moderate' or 'low') correlated significantly with women's self-reported odds values, but each category comprised a wide range of women's perceived numeric risks. Describing risk as the 'likelihood of breast cancer' resulted in a broad and somewhat inaccurate reporting of risk, compared with numeric ratings made at the same time. There was an increase of up to 4-fold in the proportion of women who failed to recall their risk value over time, and women were unable to accurately put the breast cancer risk in context compared with other health threats., Conclusions: All methods of describing risk have limitations, but the results of the present study provide good support for women's accurate recall of numeric risk values and their preference for use of these 'gambling' odds. This may have been influenced by consistency of the use of this method both in risk communication and in personal summary letters. Descriptive risk formats reflected higher levels of perceived vulnerability to breast cancer, and genetic counsellors need to be aware of these different perceptions., (Copyright 2004 S. Karger AG, Basel)

Dedicated clinics have been established for the early diagnosis and treatment of women at risk for inherited breast cancer, but the effects of such interventions are currently unproven. This second report on prospectively diagnosed inherited breast cancer from the European collaborating centres supports the previous conclusions and adds information on genetic heterogeneity and the effect of oophorectomy. Of 249 patients, 20% had carcinoma in situ (CIS), 54% had infiltrating cancer without spread (CaN0) and 26% had cancer with spread (CaN+). Five-year survival was 100% for CIS, 94% for CaN0 and 72% for CaN+ (p = 0.007). Thirty-six patients had BRCA1 mutations, and 8 had BRCA2 mutations. Presence of BRCA1 mutation was associated with infiltrating cancer, high grade and lack of oestrogen receptor (p < 0.05 for all 3 characteristics). For BRCA1 mutation carriers, 5-year survival was 63% vs. 91% for noncarriers (p = 0.04). For CaN0 patients, mutation carriers had 75% 5-year disease-free survival vs. 96% for noncarriers (p = 0.01). Twenty-one of the mutation carriers had undergone prophylactic oophorectomy, prior to or within 6 months of diagnosis in 13 cases. All but 1 relapse occurred in the 15 who had kept their ovaries, (p < 0.01); no relapse occurred in those who had removed the ovaries within 6 months (p = 0.04) Contralateral cancer was more frequently observed in mutation noncarriers, but this finding did not reach statistical significance. Our findings support the concept that BRCA1 cancer is biologically different from other inherited breast cancers. While current screening protocols appear satisfactory for the majority of women at risk of familial breast cancer, this may not be the case for BRCA1 mutation carriers. The observed effect of oophorectomy was striking., (Copyright 2002 Wiley-Liss, Inc.)

Endometrial cancer is the ninth most common malignancy in females. Inherited forms of this malignancy exist. Mutations in mismatch repair genes result in hereditary non-polyposis colorectal cancer, which confers a lifetime risk of bowel cancer between 60-80% and an endometrial cancer risk of up to 60%. Current screening involves the use of transvaginal ultrasound and hysteroscopy. Genetic testing for mutations in the mismatch repair genes is available, and if a pathogenic change is found within a family, predictive testing becomes available for unaffected family members. If blood samples from family members are unavailable, tumour blocks may be studied to assess microsatellite instability, a feature of mismatch repair gene mutations. While mutations in the mismatch repair genes are found in inherited endometrial cancer they are rarely seen in sporadic cancers. However, there are a range of somatic gene mutations that are currently being studied in order to provide insight into the pathogenesis of endometrial cancer., (Copyright 2001 Harcourt Publishers Ltd.)

33 families with a history of male breast cancer aged 60 or less or with a family history of male and female breast cancer were screened for the presence of BRCA2 mutations. 12 pathogenic BRCA2 mutations were identified (36%) in samples from an affected family member. All mutations segregated with disease where it was possible to check. Of the 14 families fulfilling BCLC criteria, 9 (64%) had mutations whilst only 3/16 (19%) of male breast cancer patients with less significant female breast cancer family history having a mutation. All 3 families with ovarian cancer and 3 families with multiple male breast cancer cases had BRCA2 mutations. These data are a further guide to how to prioritise samples for BRCA2 mutation analysis.

The purpose of this study was to retrospectively compare the outcomes of treatment in 304 women with familial and sporadic breast cancer to clarify the options for the primary management of familial breast cancer. The majority of women were consecutively ascertained on the basis of either breast cancer diagnosed at age < 40 years or bilateral breast cancer. In addition, known BRCA1 mutation carriers were identified through the genetics services in participating centres. These patients were subdivided into those with a significant family history of breast cancer or known BRCA1 mutation (FH+) and those with no significant family history (FH-). There were no significant differences in age, surgical treatment or adjuvant treatment between the two groups, but there were significantly more women whose nodal status was unknown in the FH+ group. Ipsilateral recurrence occurred in 22.2% of FH+ patients compared with 24.1% of FH- patients (p = 0.774) who underwent breast conserving surgery. There was a striking excess of contralateral breast cancers in the FH+ group (35.9% v 16%, p = 0.0007), with a cumulative risk of contralateral cancer of 36% at 10 years. This was reflected in a non-significant trend toward worse relapse free survival in the FH+ group (p = 0.0563), but no difference was observed in overall survival between the two patient groups (p = 0.142). Similarly, for patients with known BRCA1 mutations, contralateral recurrence occurred more frequently, but other outcomes were not significantly different from the FH- group. Breast conserving treatment is not associated with an increased risk of local recurrence in women with familial breast cancer and the prognosis of these women appears to be similar to that of young women with apparently sporadic breast cancer. However, the risk of contralateral breast cancer is significant in the FH+ group and should be considered in planning primary treatment and follow up.

This paper describes a protocol for women at high risk of breast cancer wishing to undergo preventative mastectomy. The protocol described is a holistic approach to each woman involving the use of a multidisciplinary team. The protocol takes a number of months from initiation to surgery. A time delay is deliberate to allow women to fully address the issues involved with a decision for surgery. Early evidence suggests that this prepares the women emotionally and physically for their surgery., (Copyright 2000 Harcourt Publishers Ltd.)

Background: In Manchester, approximately 120 women at > or = 1:4 lifetime risk of breast cancer have considered preventative surgery since 1992. Women treated within the Manchester protocol receive two genetic counselling sessions, a psychological assessment and a surgical consultation pre-operatively and annual follow-up post-operatively. The vast majority of women have breast reconstruction., Methods: Since 1996, mental health and body image have been assessed in women attending annual follow-up using self-report questionnaires: the 28-item General Health Questionnaire (GHQ) and 10-item Body Image Scale (BIS). Women with high scores are assessed by clinical interview together with a proportion who have no significant problems., Results: Between 1995 and 1999, 76 women completed surgery. Ten were awaiting post-operative review and 60 (91%) attended for follow-up of whom 45 (75%) were interviewed. Questionnaire data were available for 52 (79%) women, mean age 40.8 years (range 27-58). Six women were gene mutation carriers and of these three had had breast cancer. One additional patient was affected but had not been genetically tested. Eight (17%) of 47 women with assessments in the first post-operative year scored in the 'caseness' range on the GHQ: the mean GHQ score was 3.8 (S.D. 6.7), range 0-25. Results were comparable with those for women attending the Family History Clinic for risk assessment. The mean score on the BIS was 5.1 (S.D. 5.5), range 0-25, comparable with scores for women undergoing conservative surgery for breast cancer. Twenty-one percent of women reported no negative change in body image following surgery (i.e. zero questionnaire summary scores) and the majority of changes reported were of minor degree (item scores 0 or 1). The most frequently reported changes were in sexual attractiveness (55%), feeling less physically attractive (53%) and self-consciousness about appearance (53%): a third of women felt less feminine to a minimal degree. These results appeared stable over time. A minority of women had more serious psychological or body image concerns, usually in relation to surgical complications: they received further psychiatric intervention., Conclusions: For the majority of women there is no evidence of significant mental health or body image problems in the first 3 years following Bilateral Prophylactic Mastectomy (BPM), but women who have complications warrant additional psychological help. Careful pre-operative preparation and long-term monitoring are advocated in this new field of cancer prevention.

Increasingly women at high risk of breast cancer are opting for prophylactic surgery to reduce their risks. Data from 10 European centres that offer a risk counselling and screening service to women at risk show different approaches to the option of preventive surgery, although most centres adhere to a protocol including at least two risk counselling sessions and a psychological assessment. Thus far the combined centres have data on 174 women who have undergone prophylactic mastectomy with in excess of 400 women years of follow up. Operations were carried out on women with lifetime risks of 25-80%, with an average annual expected incidence rate of 1% per women. No breast cancers have occurred in this cohort. Long term follow up on an extended group of women will be necessary to truly address the risk of subsequent breast cancer and the psychological sequelae.

Background: Surveillance programmes for women at increased genetic risk of breast cancer are being established worldwide but little is known of their efficacy in early detection of cancers and hence reduction in mortality., Methods: Data were contributed from seven centres participating in the EU Demonstration Programme on Clinical Services for Familial Breast Cancer. All breast tumours (n = 161) detected prospectively, from the time of enrolment of women in a screening programme, were recorded. Analysis took account of age at diagnosis, whether tumours were screen-detected or not, their pathological stage and outcome by Kaplan-Meier survival plots., Results: Mean age at diagnosis was 48.6 years. Overall, 75% of tumours were detected in the course of planned examinations. For women under age 50 at diagnosis, this figure was 68%. Eighteen percent were mammographically negative, (23% in patients under age 50). At first ("prevalence") round and at follow-up screening, 16% and 22% of tumours respectively were carcinoma in situ (CIS) while 27% and 22% respectively had evidence of nodal or distant spread (CaN+). Comparison of screen-detected and other tumours showed that the latter were more frequently mammogram-negative and CaN+. Overall five-year survival was 89% and five-year event-free survival 86%. Five-year event-free survival was 100% for CIS, 88% for invasive cancer without nodal or distant spread and 67% for CaN+., Conclusions: The majority of cancers arising in women at increased genetic risk of breast cancer can be detected by planned screening, even in those under age 50. Surveillance should include regular expert clinical examination and teaching of "breast awareness" as well as mammography. Attention to the logistics of screening programmes may improve still further the proportion of tumours that are screen-detected. The trend towards earlier pathological stage in tumours detected during follow-up rounds and the preliminary findings on survival analysis suggest that this approach will prove to be of long-term benefit for breast cancer families.

Approximately 5% of all breast cancers are due to one of the high-risk breast cancer genes BRCA1 and BRCA2, or possibly to a third or fourth moderate- to high-risk gene(s). A further proportion of cases arise in the presence of a less striking family history, with later average age at onset and lower penetrance: familial breast cancer. Bilaterality is a recognized feature of hereditary breast cancer. Cancers often present at an early age, with the contralateral risk high within 10 years. Proof that bilateral malignancies are separate primaries can be difficult histologically, however, especially within 3 years. The recent finding of specific pathological features related to BRCA1 and, to a lesser extent, BRCA2 mutations means that, in addition to bilaterality and family history, a pathological element can be entered into the risk calculation for the presence of BRCA1/BRCA2 mutations. This will facilitate the targeting of mutation testing to families in which a positive result is most likely, and may subsequently influence the clinical management of these families.

Several BRCA2 mutations are found to occur in geographically diverse breast and ovarian cancer families. To investigate both mutation origin and mutation-specific phenotypes due to BRCA2, we constructed a haplotype of 10 polymorphic short tandem-repeat (STR) markers flanking the BRCA2 locus, in a set of 111 breast or breast/ovarian cancer families selected for having one of nine recurrent BRCA2 mutations. Six of the individual mutations are estimated to have arisen 400-2,000 years ago. In particular, the 6174delT mutation, found in approximately 1% of individuals of Ashkenazi Jewish ancestry, was estimated to have arisen 29 generations ago (1-LOD support interval 22-38). This is substantially more recent than the estimated age of the BRCA1 185delAG mutation (46 generations), derived from our analogous study of BRCA1 mutations. In general, there was no evidence of multiple origins of identical BRCA2 mutations. Our study data were consistent with the previous report of a higher incidence of ovarian cancer in families with mutations in a 3.3-kb region of exon 11 (the ovarian cancer cluster region [OCCR]) (P=.10); but that higher incidence was not statistically significant. There was significant evidence that age at diagnosis of breast cancer varied by mutation (P<.001), although only 8% of the variance in age at diagnosis could be explained by the specific mutation, and there was no evidence of family-specific effects. When the age at diagnosis of the breast cancer cases was examined by OCCR, cases associated with mutations in the OCCR had a significantly older mean age at diagnosis than was seen in those outside this region (48 years vs. 42 years; P=.0005).

The aim of this study was to describe the experience of screening women under the age of 50 years with a family history of breast cancer. 1259 women attended the Family History Clinic in Manchester for their first and subsequent consultations between 30 September 1992 and 30 April 1997. All women were under the age of 50 years at the initial consultation and had a lifetime risk of breast cancer of 1 in 6 or greater. Seven prevalent, seven incident and two interval cancers were detected. The number of invasive cancers expected to occur if this high risk population had not been screened was 8.45 (in 2722 person years at risk). 12 invasive cancers were detected, giving a ratio of 1.42 (95% confidence interval 0.73-2.48). The overall cancer detection rates in this young, at risk population were similar to those in older women in the National Health Service Breast Screening Programme. The number of cancers detected in the study was greater than expected in this population. As the numbers were small, a national trial needs to be undertaken to confirm these results and to determine the long term effects of screening.

Objectives: In view of the recent reports of recurrent mutations in BRCA1 and BRCA2 in the Ashkenazi Jewish population, we have undertaken to assess the frequency of these mutations in this population attending for genetic counselling and risk assessment of familial breast cancer., Design: Mutation screening for the 185delAG and the 5382insC mutations in BRCA1 and the 6174delT mutation in BRCA2 was performed on DNA samples from either subjects affected by breast or ovarian cancer or obligate gene carriers. The likelihood of the cancers being hereditary in each family was calculated., Subjects: Blood samples were obtained from 26 affected subjects or obligate gene carriers from 23 Ashkenazi Jewish families, all with a history of either early onset breast or ovarian cancers, or multiple cases of breast or ovarian cancer., Results: Twelve mutations have been identified in the 23 families (52%) of which eight (67%) were the 185delAG mutation, three (25%) were the 6174delT mutation, and one (8%) was the 5382insC mutation. While the majority of these mutations were identified in families with a greater than 50% probability of being hereditary under the CASH segregation model, three mutations were identified in families with a 35% or less probability., Conclusions: Genetic screening of the recurrent mutations in Ashkenazi Jewish families will lead to the availability of predictive testing in a reasonably large proportion, even if the family history of breast/ovarian cancer is not particularly strong. In our view it is possible to reassure high risk unaffected members of these families, if the screening is negative for these mutations, even if a sample from an affected member of the family is unavailable for previous screening.

A polyposis register has been established in the Northern Region of England. A total of 48 families with 71 living affected subjects has been identified during the first three years of operation, a prevalence of 2.29 x 10(-5). Indirect ophthalmoscopy identifies the majority of gene carriers by showing multiple areas of congenital hypertrophy of the retinal pigment epithelium (CHRPE). The absence of this sign in families limits its value where a relative with CHRPE has not been identified. Combining eye examination with data on age of onset and linked DNA markers is highly effective in carrier exclusion; 38% of 528 first, second, and third degree relatives had their carrier risk reduced to less than 1 in 1000. Even with such assurance many subjects will request continued bowel screening at a reduced frequency. Little interest has been shown in prenatal diagnosis. The principal value of a genetic register with domiciliary nurse visiting is the reduction in early mortality among unrecognised gene carriers.