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Background: breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility. Patients and methods: we included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. Eligibility criteria: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (Results: 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10 −5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10 −4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM. Conclusions: this is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.

Purpose: Conditions and thresholds applied for evidence weighting of within-codon concordance (PM5) for pathogenicity vary widely between laboratories and expert groups. Because of the sparseness of available clinical classifications, there is little evidence for variation in practice. Methods: We used as a truthset 7541 dichotomous functional classifications of BRCA1 and MSH2, spanning 311 codons of BRCA1 and 918 codons of MSH2, generated from large-scale functional assays that have been shown to correlate excellently with clinical classifications. We assessed PM5 at 5 stringencies with incorporation of 8 in silico tools. For each analysis, we quantified a positive likelihood ratio (pLR, true positive rate/false positive rate), the predictive value of PM5-lookup in ClinVar compared with the functional truthset. Results: pLR was 16.3 (10.6-24.9) for variants for which there was exactly 1 additional colocated deleterious variant on ClinVar, and the variant under examination was equally or more damaging when analyzed using BLOSUM62. pLR was 71.5 (37.8-135.3) for variants for which there were 2 or more colocated deleterious ClinVar variants, and the variant under examination was equally or more damaging than at least 1 colocated variant when analyzed using BLOSUM62. Conclusion: These analyses support the graded use of PM5, with potential to use it at higher evidence weighting where more stringent criteria are met.

In families with multiple affected individuals with early-onset breast/ovarian cancer pathogenic variants in BRCA1 or BRCA2 are identified in approximately 20% of the cases. Extensive efforts have been made to identify additional highly penetrant breast cancer genes or alternative mutational mechanisms affecting BRCA1 and BRCA2 to explain the missing heritability. It has been proposed that part of the missing heritability may be explained by gene silencing due to promoter methylation of cancer associated genes, as described in colorectal cancer (MLH1 and MSH2). Here, for the first time, we report two independent families with multiple individuals affected by breast and ovarian cancer with transgenerational promoter methylation of BRCA1. RNA analysis of BRCA1 in the germline of breast/ovarian families, previously found to be BRCA1/2 mutation negative by Sanger sequencing and copy number analysis, identified two families with allelic loss of expression. To investigate the mechanism of transcriptional silencing, a total of 14 affected and unaffected family members from these two families were tested for BRCA1 promoter methylation by pyrosequencing in blood, buccal, and hair follicle cells. Allele specific methylation was determined by clonal bisulphite sequencing. BRCA1 promoter methylation in all three germ layers was present in 11 of 14 family members. Of the 7 women with promoter methylation five were affected with grade 3 breast/high grade serous ovarian cancer. The four males with BRCA1 promoter methylation had no history of cancer. Methylation levels were ˜50%, consistent with the silencing of one allele detected in RNA in these family members. Clonal bisulphite sequencing of an affected family member of each family confirmed that the alternative allele was specifically methylated. Interestingly, in both families the methylation pattern of the BRCA1 promoter segregated with the same novel heterozygous variant in the 5'UTR of BRCA1. These results indicate a novel mechanism for familial breast/ovarian cancer, caused by epigenetic silencing of one allele by transgenerational hypermethylation of the BRCA1 promoter, secondary to a variant in cis of BRCA1. We propose that methylation analyses are indicated in all families affected by early onset breast/ovarian cancer where standard mutation screening of BRCA1/2 has not identified a causative variant. Citation Format: van Veen EM, Smith MJ, Byers HJ, Wallace AJ, Lalloo FI, Newman WG, Evans DGR. Transgenerational epigenetic silencing of BRCA1 due to a germline variant unmasks a new mechanism for familial breast and ovarian cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD1-05.

Background: Increasingly women at high risk of breast cancer are opting for risk reducing surgery. The aim of this study was to assess the effectiveness of this approach in women at high risk in both carriers and non-carriers of BRCA1/2 . Methods: Data from 10 European centres that offer a genetic counselling and screening service to women at risk were obtained prospectively from 1995. Breast cancer risks were estimated from life tables and a control group of women at risk who did not undergo surgery. Results: The combined centres have data on 550 women who have undergone risk reducing mastectomy with greater than 3334 women years of follow-up. Operations were carried out on women with lifetime risks of 25–80%, with an average expected incidence rate of 1% per year. No breast cancers have occurred in this cohort in the “at risk” unaffected breast, whereas >34 would have been expected. A high rate (2–3.6%) of occult disease was identified in the at risk breast at the time of surgery. Interpretation: We conclude that risk reducing surgery is highly effective.

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). © 2008 Cancer Research UK.

Aim: To assess the effectiveness of annual ovarian cancer screening (transvaginal ultrasound and serum CA125 estimation) in reducing mortality from ovarian cancer in women at increased genetic risk. Patients and methods: A cohort of 3532 women at increased risk of ovarian cancer was screened at five European centres between January 1991 and March 2007. Survival from diagnosis of ovarian cancer was calculated using Kaplan–Meier analysis and compared for proven BRCA1/2 carriers with non-carriers and whether the cancer was detected at prevalence or post-prevalent scan. Screening was performed by annual transvaginal ultrasound and serum CA125 measurement. Results: 64 epithelial ovarian malignancies (59 invasive and 5 borderline), developed in the cohort. 26 tumours were detected at prevalent round; there were 27 incident detected cancers and 11 interval. 65% of cancers were stage 3 or 4, however, stage and survival were little different for prevalent versus post-prevalent cancers. Five year and 10 year survival in 49 BRCA1/2 mutation carriers was 58.6% (95% CI 50.9% to 66.3%) and 36% (95% CI 27% to 45%), which was significantly worse than for 15 non-BRCA carriers (91.8%, 95% CI 84% to 99.6%, both 5 and 10 year survival p = 0.015). However, when borderline tumours were excluded, the difference in survival between carriers and non-carriers was no longer significant. Conclusion: Annual surveillance, by transvaginal ultrasound scanning and serum CA125 measurement, in women at increased familial risk of ovarian cancer is ineffective in detecting tumours at a sufficiently early stage to influence substantially survival in BRCA1/2 carriers.

The demand for genetic services by women with a family history of breast cancer has increased exponentially over the last few years. It is important that risks to women are accurately assessed and that processes are in place for appropriate counselling and management. The classification of risk into average, moderate, and high, depending upon the assessed lifetime risk of breast cancer, allows for the management of moderate risk women within cancer units and high risk women within the regional genetic centres. Management of high risk women includes discussion of options including screening, chemoprevention, and preventive surgery. The majority of these options are still unproven in the long term and continuing research is needed for their evaluation. Mutation screening and predictive testing are now a reality for a minority of families, allowing for a more informed basis for decisions regarding management options.

Lynch syndrome (LS) is an autosomal dominant cancer predisposition syndrome with a 60-80% lifetime risk of colorectal cancer. We assessed the uptake of predictive testing and colorectal screening among first-degree relatives (FDRs) in LS families and explored novel methods for informing and engaging at-risk relatives. Uptake of predictive testing was explored using Kaplan-Meier analysis and engagement with colorectal screening was ascertained. A questionnaire was distributed to 216 general practitioners (GPs) of registered LS family members to determine their prior experience and opinion of an enhanced role. Of 591, 329 (55.7%) FDRs had undergone predictive testing. Uptake was significantly lower in males (p = 0.012) and individuals25 years (p0.001). Mutation carriers were more likely to undergo colorectal screening than untested FDRs (97.2% vs 34.9%; P ≤ 0.0001). Of 216, 63 (29.2%) questionnaires were returned. Most GPs (55/63; 87.3%) were not confident to discuss the details of LS with patients and relatives. The main barriers were lack of knowledge and concerns about confidentiality. Compliance with colorectal screening is excellent following a mutation positive predictive test. Uptake of predictive testing could be substantially improved, particularly among males and younger age groups. GPs are unlikely to actively participate in communication with at-risk relatives without considerable support.

Lifetime risk of a metachronous colorectal cancer (mCRC) is 0.6-3% following sporadic colorectal cancer (CRC) and 15-26% in Lynch syndrome. The lifetime incidence of CRC in individuals with moderate familial risk is 8-17%. Risk of mCRC is unknown.A retrospective longitudinal study of the Regional Familial CRC Registry was performed. Patients who had at least one CRC were categorized as follows: moderate risk (n = 383), Lynch syndrome (n = 528) and average (population) risk (n = 409). The Kaplan-Meier estimate (1-KM) and the cumulative incidence function were used to calculate the risk of mCRC. The 1-KM gives the risk for individuals remaining at risk (alive) at a given time point and thus is useful for counselling. The cumulative incidence function gives the risk for the whole population.The 1-KM and the cumulative incidence function demonstrated that the risk of mCRC was significantly higher in moderate-risk patients compared with average (population)-risk patients (1-KM, P = 0.008; cumulative incidence function, P = 0.00097). However, the risk of mCRC was higher in patients with Lynch syndrome than in moderate-risk or average (population)-risk patients. The 1-KM in moderate-risk patients was 2.7%, 6.3% and 23.5% at 5, 10 and 20 years, respectively. In average (population)-risk patients, the 1-KM was 1.3%, 3.1% and 7.0% at 5, 10 and 20 years, and the cumulative incidence function was 0.3%, 0.6% and 2.4% at the same time points, respectively.These data indicate that the risk of mCRC is significantly higher in patients with a moderate family history of CRC than in those with an average (population) risk. This justifies proactive lifelong surveillance.

BRCA1 and BRCA2 are major breast cancer susceptibility genes. Nineteen single nucleotide polymorphisms (SNPs) at 18 loci have been associated with breast cancer. We aimed to determine whether these predict breast cancer incidence in women with BRCA1/BRCA2 mutations. BRCA1/2 mutation carriers identified through the Manchester genetics centre between 1996 and 2011 were included. Using published odds ratios (OR) and risk allele frequencies, we calculated an overall breast cancer risk SNP score (OBRS) for each woman. The relationship between OBRS and age at breast cancer onset was investigated using the Cox proportional hazards model, and predictive ability assessed using Harrell's C concordance statistic. In BRCA1 mutation carriers we found no association between OBRS and age at breast cancer onset: OR for the lowest risk quintile compared to the highest was 1.20 (95% CI 0.82-1.75, Harrell's C = 0.54), but in BRCA2 mutation carriers the association was significant (OR for the lowest risk quintile relative to the highest was 0.47 (95% CI 0.33-0.69, Harrell's C = 0.59). The 18 validated breast cancer SNPs differentiate breast cancer risks between women with BRCA2 mutations, but not BRCA1. It may now be appropriate to use these SNPs to help women with BRCA2 mutations make maximally informed decisions about management options.

Triple negative breast cancer (TNBC) is a term that reflects lack of immunostaining for oestrogen, progesterone, and HER2 receptors. It is a relatively uncommon subgroup of breast cancers, accounting for approximately 15% of all types, and overlaps substantially with basal tumours (defined by gene expression pattern) that are the predominant tumour that develops in BRCA1 mutation carriers.1 TNBCs usually have a worse prognosis and no clear options for receptor targeted treatment.2 The recent development of drugs that target the homologous recombination repair deficiency typical of BRCA-null cancer cells has led to an increased referral of women who have developed TNBC to genetic services for (rapid) genetic testing.3 We have tested 63 isolated cases of TNBC

Recent candidate and genome-wide association studies have identified variants altering susceptibility to breast cancer.To establish the relevance of these variants to breast cancer risk in familial breast cancer cases both with and without BRCA1 or BRCA2 (BRCA1/2) mutations.A cohort of unrelated individuals with breast cancer due to the presence of either BRCA1 (121) or BRCA2 mutations (109) and individuals with familial breast cancer not due to BRCA1/2 mutations (722) were genotyped using Taqman SNP Genotyping Assays. Allele frequencies were compared with an ethnically and gender-matched group (436).A synonymous variant (Ser51) in TOX3 (previously TNRC9) was associated with an increased risk of breast cancer (OR=1.82, p0.001) in BRCA2 mutation carriers. The associations for FGFR2 (OR=1.20, p=0.046), TOX3 (OR=1.5, p0.001), MAP3K1 (OR=1.26 p=0.03), CASP8 (OR=0.73 p=0.02) and the chromosome 8-associated SNP (OR=1.31, p=0.004) were replicated in individuals without BRCA1/2 mutations. In addition, homozygote carriers of MAP3K1 variants were shown to have a significantly lower Manchester Score (mean 13.8-17.6, p=0.003), whereas individuals carrying one or two copies of the FGFR2 variant had a higher Manchester Score (mean 17.5-17.9, p=0.01).This study confirms that susceptibility variants in FGFR2, TOX3 and MAP3K1 and on chromosome 8q are all associated with increased risk of cancer in individuals with a family history of breast cancer, whereas CASP8 is protective in this context. The level of risk is dependent on the strength of the family history and the presence of a BRCA1/2 mutation and contributes to the understanding of the use of these variants in clinical risk prediction.

We wish to reply to the interesting comments concerning our paper on phenocopies in families positive for mutations in BRCA1/2 genes since its electronic publication in October 2006.1 We understand the reservations about changing practice in reassuring individuals who test negative for a family mutation based on one largely retrospective analysis of families, and clearly there is a need to confirm our results in other large series. We were particularly careful to obviate …

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.

The prevalence of BRCA1 and BRCA2 mutations in families with breast and ovarian cancers depends on the type of cancer found, the number of cases, and the ethnic background of the family.1 The proportion of breast cancers attributable to BRCA1 or BRCA2 may also depend on the ethnic origin of families. Several mutations have been identified that are found only in specific countries or ethnic groups, suggesting that they are founder mutations. Individuals with the same founder mutation will also share the same alleles at polymorphic markers within the gene or adjacent to the gene. Some common mutations do not segregate with the same alleles and are therefore recurrent mutations. They occur at ‘hot spots’ for mutation; unstable parts of the gene. In countries with a small founder population, very few mutations may account for the vast majority of breast cancer families. The Ashkenazi Jewish population have three founder mutations, which are found in 2% of the Ashkenazi Jewish population.2 Population studies have shown that the 185delAG mutation predates the separation of the Sephardi and Ashkenazi Jewish populations and is probably 2000 years old.3 Full gene screening for mutations in the northwest of England has identified two recurrent mutations.4 BRCA1 4182delAATC (4184del TCAA or 4184del4) is a frameshift mutation that results in a stop at codon 1364, causing a truncated protein product. This mutation has been reported 75 times in the Breast Cancer Information Core (BIC) website (www.nhgri.nih.gov/Intramural\_research/Lab\_transfer/Bic/).5 In one study, it was identified in breast cancer cases in Britain, France, and the United States.6 The mutation was associated with three different haplotypes, indicating that it is a recurrent rather than a founder mutation. BRCA2 2157delG is also a frameshift mutation resulting in a stop at codon 659, causing a truncated protein product. …

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 age40 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.

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.

Editor—Germline mutations in the BRCA1 and BRCA2 genes cause predisposition to breast and ovarian cancer.1Epidemiological evidence and linkage studies suggested that the likelihood that a woman with breast cancer has a genetic susceptibility to the condition is greater the younger she was at diagnosis and with increasing extent of family history of the disease. Studies of the prevalence of germline mutations in BRCA1 and BRCA2 in women with breast cancer has enabled the frequency of mutations to be determined in women with different ages at diagnosis and extent of family history of breast cancer.2 3 The CASH study into the attributable risk of breast and ovarian cancer estimated that 33% of all breast cancers diagnosed by the age of 29 years, and 22% diagnosed by the age of 30-39 years, are the result of an inherited mutation.4However, the proportion of breast cancer cases diagnosed by 40 years resulting from a BRCA1 mutation was predicted to be 5.3%.5 Previous population based studies of the prevalence of BRCA1 mutations in early onset breast cancer have been in cases unselected for family history, and the majority of mutation carriers detected did have some degree of family history of either breast or ovarian cancer.6-10 The aim of this study was to establish the prevalence of BRCA1 mutations in a large series of British patients with a young age of onset and no known family history of the disease, since such patients are referred relatively frequently for genetic counselling. The presence of BRCA1 mutations in a significant proportion of these patients would have important implications for the planning of a mutation screening strategy in diagnostic services. Patients were ascertained from the Imperial …

In Manchester, approximately 120 women ator = 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.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.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.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.

The risk of breast cancer for unaffected men who test positive for a BRCA2 mutation is based on very few retrospective studies. We have used both retrospective and prospective analysis in 321 families with pathogenic BRCA2 mutations. Three breast cancers occurred in male first-degree relatives after family ascertainment in 4140 years of follow-up suggesting a risk of breast cancer to 80 years of 8.9%. A second analysis excluding index cases identified 16 breast cancers in 905 first-degree male relatives on which Kaplan–Meier analysis was performed after assigning carrier status. This analysis confirmed that breast cancer risk in men was 7.1% (SE 5.2–8.6%) by age 70 years and 8.4% (SE 6.2–10.6%) by age 80 years.

Editor,—We wish to report a patient with a ring abnormality of chromosome 13 who developed keratoconus. As far as we are aware such an association has not previously been reported. This case may provide some further insight into the presumed genetic basis of keratoconus. ### CASE REPORT A 19 year old woman was referred by her optometrist because of impaired distance vision present for several months which could not be satisfactorily corrected with spectacles. There was no history of familial ocular problems. The patient did not suffer from atopy. Unaided visions were: right 6/9 part, left 6/24. The optimal spectacle correction and visual acuities were: right +1.00/−1.00 × 90 = 6/7.5, left +1.50/−3.00 × …

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.

We were most interested to read the report of Gronwald and colleagues suggesting that there was non-random transmission of the mutant BRCA1 gene to female offspring in a Polish cohort.1 We have undertaken a similar analysis in an English cohort but found no evidence for non-random transmission. Gronwald et al reported that 61.5% of unaffected female offspring carried the mutant allele and this ratio did not decrease with age (as might be expected from the exclusion of affected females at advancing age). We have analysed the ratio of positive predictive tests in first degree relatives of proven mutation carriers from 284 BRCA1 and BRCA2 families from central and north western England. Like Gronwald et al 1, we excluded women who were affected with cancer or whose daughter was affected as they were potential obligate carriers. We did not include branches of the family where the mutation status of the parent was unknown even if it was a mother with breast or ovarian cancer in a family with a known mutation. This excluded the possibility of including the testing of daughters of potential phenocopies. We did not reach the level of 89% uptake of predictive testing achieved with the daughters of 91 female mutation carriers in …

Affected individuals from 431 families gave blood for mutational analysis in BRCA1 and BRCA2 mainly to develop genetic tests for their family. Individuals were eligible if there was at least a 50% chance of a gene predisposing to breast cancer (not necessarily BRCA1/2 ) in their family. Assessment was made using the Cancer and Steroid Hormone (CASH) dataset and the Claus curves.1,2 A minimal requirement was two close relatives with breast cancer before the age of 50 years, but combinations of male and female breast cancer, and breast and ovarian cancer were particularly identified. An exception to this were two research projects where population based cases of breast cancer before the age of 31 years3 and sporadic breast cancer before the age of 36 years4 were screened for both genes. Male breast cancer (MBC) families presenting to the clinic with at least one MBC before the age of 60 years or at any age if female breast cancer had occurred were screened for BRCA2 .5 Initial screening for mutations involved a whole gene assessment using single strand conformational polymorphism (SSCP) analysis and protein truncation testing (PTT) of exon 11 in each gene. All mutations were confirmed, in both orientations, by direct fluorescent sequencing of the appropriate exon. We excluded one exon 13 duplication and two exonic deletions detected on screening 95 BRCA1 negative breast/ovarian families. A further two exon 13 duplications in five subsequent BRCA1 negative breast/ovary families originating from east of the Pennines were also excluded. Of the non large-scale rearrangement mutations, 26/78 (33%) were detected outside the commonly screened regions of BRCA1 (exons 2, 11, 20) in the UK (table 1). Similarly 15/50 (30%) BRCA2 mutations were detected outside exons 10 and 11. View this table: Table 1 Mutations in BRCA1/2 outside the commonly screened exons in the UK …

Editor—An important aim of genetic risk counselling is to confirm a level of cancer risk and offer risk management strategies.1 By giving counsellees accurate information about their risk, in place of ignorance, uncertainty, or a false assumption of the inevitability of breast cancer, it is hoped that some of the associated worry about personal risk may be alleviated. Earlier work by the authors showed that women frequently overestimate their risk of breast cancer,2 creating the possibility of reassuring women by providing a more realistic risk value. Subsequent research showed that risk counselling significantly improved risk accuracy over a one year follow up period, both for women who overestimated and underestimated risk.3 This improvement was more likely if women were sent a personal letter containing the risk information after their visit.3However, there was concern that accurate risk information may induce or increase anxiety in women referred for genetic counselling, especially in those who initially underestimated their risk. This was not borne out by a study of first time attendees at the Family History Clinic, who were followed for a one year period after genetic risk counselling. Women were found to adopt a more accurate perception of their risk without an increase in scores on general measures of anxiety at any time point post-counselling.4 There was a suggestion from questionnaire data that women with an accurate appraisal of risk after genetic counselling had the best levels of mental health and psychiatric diagnoses derived by interview were not caused by risk counselling. However, some women with psychiatric morbidity reported that the early loss of a mother was very difficult to resolve,4 a problem also reported in adolescent daughters of breast cancer patients.5 The relationship between early loss and cancer worry in high risk …