Further genotype--phenotype correlations in neurofibromatosis 2.

Neurofibromatosis 2 (NF2) is caused by mutations in the NF2 gene predisposing carriers to develop nervous system tumours. Different NF2 mutations result in either loss/reduced protein function or gain of protein function (abnormally behaving mutant allele i.e. truncated protein potentially causing dominant negative effect). We present a comparison between the clinical presentations of patients with mutations that are predicted to produce truncated protein (nonsense/frameshift mutations) to those that results in loss of protein expression (large deletions) to elucidate further genotype-phenotype correlations in NF2. Patients with nonsense/frameshift mutations have a younger age of diagnosis and a higher prevalence/proportion of meningiomas (p = 0.002, p = 0.014), spinal tumours (p = 0.004, p = 0.004) and non-VIII cranial nerve tumours (p = 0.006, p = 0.003). We also found younger age of diagnosis of vestibular schwannomas (p = 0.007), higher mean numbers of cutaneous lesions (p = 0.003) and spinal tumours (p = 0.006) in these patients. With respect to NF2 symptoms, we found younger age of onset of hearing loss (p = 0.010), tinnitus (p = 0.002), paraesthesiae (p = 0.073), wasting and weakness (p = 0.001) and headaches (p = 0.049) in patients with nonsense/frameshift mutations. Our comparison shows, additional, new correlations between mutations in the NF2 gene and the NF2 disease phenotype, and this further confirms that nonsense/frameshift mutations are associated with more severe NF2 symptoms. Therefore patients with this class of NF2 mutation should be followed up closely.

Comparison of proactive and usual approaches to offering predictive testing for BRCA1/2 mutations in unaffected relatives.

There have been few studies addressing uptake of predictive testing for BRCA1/2, only one comparing a proactive with usual family networking approach to dissemination. We report uptake of predictive genetic testing after directly offering BRCA1 presymptomatic genetic testing to 100 individuals in two generations of 5 large BRCA1 families compared with service testing of 196 families since that time. Uptake was significantly higher in the first generation (group 1), who were directly offered testing, and much higher in females. Seventy-four percent of unaffected women in the first generation proceeded to testing, 42% of men. This decreased to 44% of women in the second generation (group 2) and 9% males (p = 0.0003). Uptake in unaffected individuals in the final group (group 3) with no proactive approach was significantly lower than that in the first group. Overall uptake after 10 years was 56% (95% confidence interval, CI, 50-62%) for group 1 and 36% (95% CI 34.3-37.7%) for 1084 group 3 individuals (p = 0.0003). Among women, uptake was 74% (95% CI 67-81%) in group 1 at 10 years compared with 51.5% (95% CI 49-54%) in 552 group 3 women (p = 0.023). In men, uptake was 42% (95% CI 33-52%) in group 1 and 21.1% (95% CI 18.1-23.1%) among 532 men in group 3 (p = 0.0098). Although these results are not from a randomized trial, they show particularly among men a substantially higher uptake of genetic services with a direct approach. Importance should be given to more proactive approaches to ensure that men in BRCA1/2-positive families receive the appropriate information.

Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations.

Lynch syndrome or hereditary non-polyposis colorectal cancer is caused by mutations of DNA mismatch repair (MMR) genes. The extracolonic tumour spectrum includes endometrial, ovarian, gastric, small bowel, pancreatic, hepatobiliary, brain, and urothelial neoplasms. Families were referred on the basis of clinical criteria. Tumour immunohistochemistry and microsatellite testing were performed. Appropriate patients underwent sequencing of relevant exons of the MMR genes. Proven and obligate mutation carriers and first-degree relatives (FDRs) with a Lynch syndrome spectrum cancer were considered mutation carriers, as were a proportion of untested, unaffected FDRs based on the proportion of unaffected relatives testing positive in each age group. Kaplan-Meier analysis of risk to 70 years was calculated. One hundred and eighty-four Lynch syndrome spectrum extracolonic cancers in 839 proven, obligate, or assumed mutation carriers were analysed. Cumulative risk for females of an extracolonic tumour is 47.4% (95% CI 43.9-50.8). The risk to males is 26.5% (95% CI 22.6-30.4). There was no reduction in gynaecological malignancies due to gynaecological screening (examination, transvaginal ultrasound scan, hysteroscopy and endometrial biopsy). Males have a higher risk of gastric cancer than females (p = 0.0003). Gastric cancer risk in those born after 1935 does not justify surveillance. These penetrance estimates have been corrected for ascertainment bias and are appropriate for those referred to a high-risk clinic.

Risk reducing mastectomy: outcomes in 10 European centres.

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.

Screening for familial ovarian cancer: poor survival of BRCA1/2 related cancers.

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.

Colorectal cancer in HNPCC: cumulative lifetime incidence, survival and tumour distribution. A report of 121 families with proven mutations.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant condition caused by inactivating mutations of DNA mismatch repair (MMR) genes. An accurate estimation of colorectal cancer risk for mutation carriers is essential for counselling and rationalizing screening programmes. Families were referred on the basis of clinical criteria. Tumour immunohistochemistry and microsatellite testing were performed. Appropriate patients underwent sequencing of all relevant exons of the MMR genes. Proven and obligate mutation carriers and first-degree relatives (FDRs) with an HNPCC spectrum cancer were considered mutation carriers, as were a proportion of untested, unaffected FDRs based on the proportion of unaffected relatives testing positive in each age group. The cumulative lifetime risk was calculated by Kaplan-Meier analysis. Three hundred and forty-one colorectal cancers in 839 proven, obligate, or assumed mutation carriers were analysed. The cumulative risk to age 70 years for all mutation carriers combined was 50.4% (95% CI 47.8-52.9). The cumulative risk in males was 54.3% (95% CI 50.7-57.8), which was significantly higher than in females (log rank p = 0.02) who had a risk of 46.3% (95% CI 42.8-49.9). These penetrance estimates from HNPCC families attending high-risk clinics have been corrected for ascertainment bias and are appropriate risks for those referred to a high-risk clinic. Current colonoscopic screening guidelines are appropriate.

Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics.

OBJECTIVES: Genetic testing for the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 has important implications for the clinical management of people found to carry a mutation. However, genetic testing is expensive and may be associated with adverse psychosocial effects. To provide a cost-efficient and clinically appropriate genetic counselling service, genetic testing should be targeted at those individuals most likely to carry pathogenic mutations. Several algorithms that predict the likelihood of carrying a BRCA1 or a BRCA2 mutation are currently used in clinical practice to identify such individuals. DESIGN: We evaluated the performance of the carrier prediction algorithms BOADICEA, BRCAPRO, IBIS, the Manchester scoring system and Myriad tables, using 1934 families seen in cancer genetics clinics in the UK in whom an index patient had been screened for BRCA1 and/or BRCA2 mutations. The models were evaluated for calibration, discrimination and accuracy of the predictions. RESULTS: Of the five algorithms, only BOADICEA predicted the overall observed number of mutations detected accurately (ie, was well calibrated). BOADICEA also provided the best discrimination, being significantly better (p<0.05) than all models except BRCAPRO (area under the receiver operating characteristic curve statistics: BOADICEA = 0.77, BRCAPRO = 0.76, IBIS = 0.74, Manchester = 0.75, Myriad = 0.72). All models underpredicted the number of BRCA1 and BRCA2 mutations in the low estimated risk category. CONCLUSIONS: Carrier prediction algorithms provide a rational basis for counselling individuals likely to carry BRCA1 or BRCA2 mutations. Their widespread use would improve equity of access and the cost-effectiveness of genetic testing.

Probability of BRCA1/2 mutation varies with ovarian histology: results from screening 442 ovarian cancer families.

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.

The Bradford Burn Study: the epidemiology of burns presenting to an inner city emergency department.

OBJECTIVE: The Bradford Burn Study prospectively reviewed all burn attendances at a single emergency department in the UK over a 1 year period. The study reviewed the epidemiology, demographics and outcomes of all patients entered into the study. DESIGN AND SETTING: A 12 month prospective study of burn injuries attending an inner city emergency department serving a population of 1 million people. RESULTS: 460 patients were enrolled into the study. Average patient age was 22.7 years, male: female ratio was 1:1.4, and children <10 years of age accounted for 36% of the case mix. Asian patients accounted for 41% of all attendances; 85% of the cases in the study were accidental in nature, with scalds accounting for 52% of the injuries. Final outcomes were as follows: 54% of patients were reviewed by the emergency department physicians and only one of these patients ultimately needed skin grafting; 19% had follow-up by their primary care physicians; 12% were reviewed by plastic surgeons, and 5% were admitted; of those patients admitted, 16% needed surgery; only 12 patients (3%) were admitted to specialised burn units. CONCLUSIONS: Emergency departments manage patients with burns well, and referrals to plastic surgery departments are appropriate. The majority of burns can be prevented by addressing educational issues and vulnerable sections of the population.

Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening.

BACKGROUND: Malignancy risks in patients with neurofibromatosis 1 (NF1) are increased, but those occurring outside of the nervous system have not been clearly defined. AIM: To evaluate the risk of breast cancer in women with NF1 in a population-based study. METHODS: The risk of breast cancer in a cohort of 304 women with NF1 aged >or=20 years was assessed and compared with population risks over the period 1975-2005 using a person-years-at-risk analysis. RESULTS: There were 14 cases of breast cancers in the follow-up period, yielding a standardised incidence ratio (SIR) of 3.5 (95% CI 1.9 to 5.9). However, six breast cancers occurred in women in their 40s, and the SIR of breast cancer in women aged <50 years was 4.9 (95% CI 2.4 to 8.8). INTERPRETATION: Women with NF1 aged <50 years have a fivefold risk of breast cancer, are in the moderate risk category and should be considered for mammography from 40 years of age.

Mosaicism in neurofibromatosis type 2: an update of risk based on uni/bilaterality of vestibular schwannoma at presentation and sensitive mutation analysis including multiple ligation-dependent probe amplification.

BACKGROUND: Neurofibromatosis type 2 (NF2) is almost unique among inherited disorders in the frequency of mosaicism in the first affected generation. However, the implications of this on transmission risks have not been fully elucidated. METHODS: The expanded database of 460 families with NF2 and 704 affected individuals was analysed for mosaicism and transmission risks to offspring. RESULTS: 64 mosaic patients, with a projected mosaicism rate of 33% for sporadic classical NF2 with bilateral vestibular schwannoma at presentation and 60% for those presenting unilaterally, were identified. Offspring risks can be radically reduced on the basis of a sensitive mutation analysis of blood DNA including multiple ligation-dependent probe amplification (MLPA, which detects 15% of all mutations), but even MLPA cannot detect high levels of mosaicism. CONCLUSION: The chances of mosaicism in NF2 and the resultant risks of transmission of the mutation to offspring in a number of different clinical situations have been further delineated. The use of MLPA in this large NF2 series is also reported for the first time.

Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening.

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.

Inherited association of breast and colorectal cancer: limited role of CHEK2 compared with high-penetrance genes.

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.

Screening younger women with a family history of breast cancer--does early detection improve outcome?

Women with a family history are often offered mammographic surveillance at an earlier age and with greater frequency than those in the National Breast Screening Programme. In this study, we compared the survival of 62 breast cancer patients diagnosed in the context of a family history clinic offering 12-18 monthly mammographic screening with that of 1108 patients of the same age range but having no exposure to screening. We subtracted the expected additional observation time due to lead time from the survival of the screen-detected cases. Survival was significantly better in the family history group with relative hazards of 0.19 (95% CI 0.07-0.52, P<0.001) for breast cancer death and 0.19 (95% CI 0.08-0.43, P<0.001) for disease-free survival. After correcting for lead-time, the relative hazards were 0.24 (95% CI 0.09-0.66, P=0.005) for breast cancer death and 0.25 (95% CI 0.11-0.57, P<0.001) for disease-free survival. These results strongly suggest that screening younger women with a family history of breast cancer leads to improved survival. More precise estimates of the benefit will accrue from further follow-up and other such studies.

Burn patterns of Asian ethnic minorities living in West Yorkshire, UK.

Whereas burn morbidity and mortality have been well studied among natives of Southeast Asia, few have studied the epidemiology of burn injury among UK Asian ethnic minority immigrants. A 1 year prospective study of all patients presenting with burns to Bradford Royal Infirmary was carried out. Four hundred and sixty patients were studied, 188 (41%) were Asian ethnic minorities. The average patient age was 17 years for the Asian group and 27 years for the non-Asian patients. Contact burns were responsible for 29% of injuries in Asian patients and 19% in the other group. Thirty-seven percent of contact burns in the Asian ethnic minority group were caused by hot irons. Eleven percent of Asian patients had treated their burn with inappropriate remedies including saiti, butter, and toothpaste. There were no significant differences between Asian and non-Asian patients in terms of large or deep burns, nor in mortality. Morbidity and mortality from burn injury among UK Asian patients and other groups in the UK are similar; however, a disproportionate number of Asian patients sustain smaller burns. Much of this is behaviour related, and it is hoped that through preventative measures a marked reduction in the number of Asian ethnic minority burns can be achieved.

To lead or not to lead? Prospective controlled study of emergency nurses' provision of advanced life support team leadership.

BACKGROUND AND OBJECTIVES: In many emergency departments advanced life support (ALS) trained nurses do not assume a lead role in advanced resuscitation. This study investigated whether emergency nurses with previous ALS training provided good team leadership in a simulated cardiac arrest situation. METHODS: A prospective study was conducted at five emergency departments and one nurses' association meeting. All participants went through the same scenario. Details recorded included baseline blood pressure and pulse rate, time in post, time of ALS training, and subjective stress score (1 = hardly stressed; 10 = extremely stressed). Scoring took into account scenario understanding, rhythm recognition, time to defibrillation, appropriateness of interventions, and theoretical knowledge. RESULTS: Of 57 participants, 20 were ALS trained nurses, 19 were ALS trained emergency senior house officers (SHOs), and 18 were emergency SHOs without formal ALS training. The overall mean score for doctors without ALS training was 69.5%, compared with 72.3% for ALS trained doctors and 73.7% for ALS trained nurses. Nurses found the experience less stressful (subjective stress score 5.78/10) compared with doctors without ALS training (6.5/10). The mean time taken to defibrillate from the appearance of a shockable rhythm on the monitor by the nurses and those SHOs without ALS training was 42 and 40.8 seconds, respectively. CONCLUSION: ALS trained nurses performed as well as ALS trained and non ALS trained emergency SHOs in a simulated cardiac arrest situation and had greater awareness of the potentially reversible causes of cardiac arrest. Thus if a senior or middle grade doctor is not available to lead the resuscitation team, it may be appropriate for experienced nursing staff with ALS training to act as ALS team leaders rather than SHOs.

A new scoring system for the chances of identifying a BRCA1/2 mutation outperforms existing models including BRCAPRO.

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.

Evaluation of breast cancer risk assessment packages in the family history evaluation and screening programme.

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.