Clinical Genetics Centres Research Articles

Effect of Oophorectomy on Survival After Breast Cancer in BRCA1 and BRCA2 Mutation Carriers.

Women who carry a germline mutation in either the BRCA1 or BRCA2 gene face a lifetime risk of breast cancer of up to 70%, and once they receive a diagnosis of breast cancer, they face high risks of both second primary breast and ovarian cancers. Preventive bilateral salpingo-oophorectomy is recommended to women with a BRCA mutation at age 35 years or thereafter to prevent breast and ovarian cancer, but it is unclear whether oophorectomy has an impact on survival in women with BRCA-associated breast cancer. To estimate the impact of oophorectomy on survival in women with breast cancer with a BRCA1 or BRCA2 mutation. Retrospective analysis of patients selected by pedigree review of families who received counseling at 1 of 12 participating clinical genetics centers. Patients were 676 women with stage I or II breast cancer and a BRCA1 or BRCA2 mutation who were observed for up to 20 years after receiving a diagnosis between 1975 and 2008. Survival experience was compared for women who did and who did not undergo oophorectomy. In all analyses, the primary end point was death due to breast cancer. Of the 676 women, 345 underwent oophorectomy after the diagnosis of breast cancer and 331 retained both ovaries. The 20-year survival for the entire patient cohort was 77.4%. The adjusted hazard ratio for death attributed to breast cancer in women who underwent oophorectomy was 0.38 (95% CI, 0.19-0.77; P = .007) for BRCA1 carriers and 0.57 (95% CI, 0.23-1.43; P = .23) for BRCA2 carriers. The hazard ratio for breast cancer-specific mortality was 0.76 (95% CI, 0.32-1.78; P = .53) for women with estrogen receptor-positive breast cancer and 0.07 (95% CI, 0.01-0.51; P = .009) for women with estrogen receptor-negative breast cancer. Oophorectomy is associated with a decrease in mortality in women with breast cancer and a BRCA1 mutation. Women with estrogen receptor-negative breast cancer and a BRCA1 mutation should undergo oophorectomy shortly after diagnosis.

Next-generation sequencing-based genome diagnostics across clinical genetics centers: implementation choices and their effects.

Implementation of next-generation DNA sequencing (NGS) technology into routine diagnostic genome care requires strategic choices. Instead of theoretical discussions on the consequences of such choices, we compared NGS-based diagnostic practices in eight clinical genetic centers in the Netherlands, based on genetic testing of nine pre-selected patients with cardiomyopathy. We highlight critical implementation choices, including the specific contributions of laboratory and medical specialists, bioinformaticians and researchers to diagnostic genome care, and how these affect interpretation and reporting of variants. Reported pathogenic mutations were consistent for all but one patient. Of the two centers that were inconsistent in their diagnosis, one reported to have found ‘no causal variant', thereby underdiagnosing this patient. The other provided an alternative diagnosis, identifying another variant as causal than the other centers. Ethical and legal analysis showed that informed consent procedures in all centers were generally adequate for diagnostic NGS applications that target a limited set of genes, but not for exome- and genome-based diagnosis. We propose changes to further improve and align these procedures, taking into account the blurring boundary between diagnostics and research, and specific counseling options for exome- and genome-based diagnostics. We conclude that alternative diagnoses may infer a certain level of ‘greediness' to come to a positive diagnosis in interpreting sequencing results. Moreover, there is an increasing interdependence of clinic, diagnostics and research departments for comprehensive diagnostic genome care. Therefore, we invite clinical geneticists, physicians, researchers, bioinformatics experts and patients to reconsider their role and position in future diagnostic genome care.

Error rates in forensic DNA analysis: Definition, numbers, impact and communication

Forensic DNA casework is currently regarded as one of the most important types of forensic evidence, and important decisions in intelligence and justice are based on it. However, errors occasionally occur and may have very serious consequences. In other domains, error rates have been defined and published. The forensic domain is lagging behind concerning this transparency for various reasons. In this paper we provide definitions and observed frequencies for different types of errors at the Human Biological Traces Department of the Netherlands Forensic Institute (NFI) over the years 2008-2012. Furthermore, we assess their actual and potential impact and describe how the NFI deals with the communication of these numbers to the legal justice system. We conclude that the observed relative frequency of quality failures is comparable to studies from clinical laboratories and genetic testing centres. Furthermore, this frequency is constant over the five-year study period. The most common causes of failures related to the laboratory process were contamination and human error. Most human errors could be corrected, whereas gross contamination in crime samples often resulted in irreversible consequences. Hence this type of contamination is identified as the most significant source of error. Of the known contamination incidents, most were detected by the NFI quality control system before the report was issued to the authorities, and thus did not lead to flawed decisions like false convictions. However in a very limited number of cases crucial errors were detected after the report was issued, sometimes with severe consequences. Many of these errors were made in the post-analytical phase. The error rates reported in this paper are useful for quality improvement and benchmarking, and contribute to an open research culture that promotes public trust. However, they are irrelevant in the context of a particular case. Here case-specific probabilities of undetected errors are needed. These should be reported, separately from the match probability, when requested by the court or when there are internal or external indications for error. It should also be made clear that there are various other issues to consider, like DNA transfer. Forensic statistical models, in particular Bayesian networks, may be useful to take the various uncertainties into account and demonstrate their effects on the evidential value of the forensic DNA results.

Ritka genetikai betegségek klinikai és genetikai diagnosztikájában szerzett tapasztalataink a kelet-magyarországi régióban (2007–2013)

80% of rare diseases have a genetic origin, and 50% manifest themselves as congenital anomalies. Their adequate health care includes early recognition of genetic anomalies and prevention of recurrence. The aims of the authors were to provide correct diagnoses to patients with multiple congenital anomalies with or without mental retardation attending to the outpatient clinic of the Clinical Genetics Center at the University of Debrecen in the time interval between August 1, 2007 and March 31, 2013, establish the possibility of prenatal diagnosis, assess the distribution of different genetic mechanisms in the background of rare genetic diseases, compare them with international data, and develop an algorithm for the diagnostic approach of rare genetic diseases applicable in Hungary. Clinical data and genetic results of patients were evaluated, and patients were categorized into one of the ten proposed etiological groups, based on which the distribution of genetic causes was defined. Clinical diagnosis was achieved in 64.3% of patients, confirmed genetic diagnosis in 37.8%, while 35.7% of patients remained undiagnosed. Several dysmorphic syndromes and metabolic disorders were first diagnosed in Hungary, two of which unique in the literature. In the centre of the authors the diagnostic effectiveness of chromosome aberrations exceeds the international standards, that of known microdeletions and dysmorphic syndromes meets international data, and the genetic diagnosis of mendelian disorders and submicroscopic copy number changes remain below international figures.

After the Introduction into the National Newborn Screening Program: Who Is Receiving Genetic Counseling for Hemoglobinopathies in The Netherlands?

Objective: Universal newborn screening for hemoglobinopathies started in The Netherlands in 2007. Herewith severe conditions, such as sickle cell disease, β-thalassemia major and hemoglobin H disease are putatively identified. Additionally, at least 1,800 carriers of hemoglobin variants associated with severe conditions in homozygote or compound heterozygote forms are identified yearly. Thus far, approximately 60 patients and 800 healthy sickle cell (HbS) carriers are reported each year among 180,000 newborns. Results are sent to the general practitioner with the recommendation to inform and diagnose both parents of the healthy carriers to exclude genetic risk, while patients and their parents are referred directly to a pediatrician. This study was performed to determine how often parents of identified carriers and affected newborns are seen in genetic centers for counseling. Methods: In this retrospective study, we collected anonymized data from 7 of the 8 Dutch clinical genetic centers from January 1, 2007, until December 31, 2010. Results: After an initial general increase in total counseling intakes, a decline was noticed in the third year, while the requests for prenatal diagnoses remained relatively stable. In 2007 and 2013, genetic counselors were asked for self-reported knowledge. They found hemoglobinopathy counseling complex, but by 2013, they indicated they had acquired sufficient knowledge on most hemoglobinopathy aspects. Conclusion: We could not observe a significant increase in genetic counseling for hemoglobinopathy after its introduction into newborn screening. Although 120 HbS carriers and 60 patients are expected to be born from couples at risk annually, only 33 at risk couples out of 540 families of diagnosed newborns received optimal care and information at a genetics center in 4 years.

Identifying Outcomes of Clinical Genetic Services: Qualitative Evidence and Methodological Considerations

Extensive research into the tangible and intangible implications of Clinical Genetic Services (CGSs) has confirmed the relevance of a multidimensional outcome of benefit conceptually linked to perceived control. This paper aims to report qualitative findings from one small study aiming to add to the evidence pool confirming the relevance of such an outcome to participants from one UK clinical genetics center. Data were collected using focus groups and individual interviews with 22 service users from the following conditions: Hereditary Breast and Ovarian Cancer (HBOC), von Hippel Lindau disorder (VHL), Duchenne and Becker muscular dystrophy (DBMD), cystic fibrosis (CF) and tuberous sclerosis (TS). Transcripts were analyzed using thematic analysis and four dimensions of benefit were identified relating to cognitive, behavioral, social and emotional consequences. These dimensions related to an overarching conceptual outcome described as Perceived Familial Control. Findings are discussed to illustrate the inter-generational and intra-generational familial dimensions of CGSs and reinforce the significance of a familial focus to any genetics-specific outcome measure. The prospect and methodological considerations of a familial composite outcome measure for measuring overall benefit of CGSs is discussed based on current and past findings.

Cancer risk and genotype–phenotype correlations in PTEN hamartoma tumor syndrome

Patients with germline PTEN mutations are at high risk of developing benign and malignant tumours. We aimed to evaluate the cumulative risk of several types of cancer and of dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease, LDD). In addition, genotype-phenotype correlations in PTEN hamartoma tumour syndrome (PHTS) were assessed. Data on patients with PTEN mutations were collected from clinical genetic centres in Western Europe, Australia, and the USA. The cumulative risk of developing cancers of the breast, thyroid, endometrium, skin, kidneys, colorectum, and lungs, and also LDD was calculated by Kaplan-Meier methods. Associations between mutations and cancer were assessed by Chi square means. A total of 180 germline PTEN mutation carriers, 81 males (45%), from nine countries were included. The cumulative risk of developing any cancer and/or LDD at age 60 was 56% for males and 87% for females (p = 0.001). Females had significant higher risks of developing breast cancer, thyroid cancer, and LDD than males. The only genotype-phenotype correlation identified was a lower frequency of thyroid cancer in patients with missense mutations (p = 0.014). In conclusion, PHTS patients, particularly females, have a substantial risk of developing one or more tumours from a broad tumour spectrum. Major genotype-phenotype associations could not be identified.

Prevalence of beckwith–wiedemann syndrome in North West of Italy

Although Beckwith-Wiedemann syndrome (BWS, OMIM #130650) is the most common genetic overgrowth disorder, data on its epidemiology are scanty and the estimates of its occurrence show wide variability. The aim of this study is to assess its prevalence in Piedmont Region (Italy). We included in the study all patients diagnosed with BWS born in Piedmont from 1997 to 2009 through a search in the Italian Registry for Rare Diseases. This source was further validated with data from the network of Regional Clinical Genetics services and surveys in extra-regional Clinical Genetics centres, laboratories and the Italian BWS patients association. All cases were further ascertained through physical exam, medical history and specific molecular tests. The search identified 46 clear-cut cases of BWS born across the 13-year period, providing a prevalence of 1:10 340 live births (95% confidence interval 1:7,752-13,698 live births). Among the 41 patients who underwent molecular tests, 70.7% were positive, showing hypomethylation of the IC2 imprinting center (29.3%), paternal chromosome 11 uniparental disomy (pUPD11, 24.4%), IC1 hypermethylation (14.6%), CDKN1c mutation (2.4%), whereas 29.3% had negative molecular tests. The study provides an approximate BWS prevalence of 1:10,000 live birth, the highest reported to date.

Existing data sources for clinical epidemiology: Danish registries for studies of medical genetic diseases

Denmark has an extensive collection of national and regional medical registries. There are many advantages to registry-based research when investigating genetic diseases which, due to their rarity, can be difficult to identify. In this study, we aimed to provide an updated overview of Danish registries for medical genetic conditions and describe how data linkage across registries can be used to collect data on genetic diseases at the individual level and at the family level. We present a list of medical genetic registries in Denmark at the national level, data sources from the departments of clinical genetics and other specialized centers, and project-specific data sources. We also summarize key general registries, such as the Danish National Registry of Patients, the Danish Medical Birth Registry, and the Civil Registration System, which are renowned for their comprehensive and high quality data, and are useful supplemental data sources for genetic epidemiology research. We describe the potential for data linkage across multiple registries, which allows for access to medical histories with follow-up time spanning birth to death. Finally, we provide a brief introduction to the Danish epidemiological research setting and legalities related to data access. The Danish collection of medical registries is a valuable resource for genetic epidemiology research.

Meeting the challenge of interpreting high‐resolution single nucleotide polymorphism array data in prenatal diagnosis: does increased diagnostic power outweigh the dilemma of rare variants?

Several studies have already shown the superiority of chromosomal microarray analysis (CMA) compared with conventional karyotyping for prenatal investigation of fetal ultrasound abnormality. This study used very high-resolution single nucleotide polymorphism (SNP) arrays to determine the impact on detection rates of all clinical categories of copy number variations (CNVs), and address the issue of interpreting and communicating findings of uncertain or unknown clinical significance, which are to be expected at higher frequency when using very high-resolution CMA. Prospective validation study. Tertiary clinical genetics centre. Women referred for further investigation of fetal ultrasound anomaly. We prospectively tested 104 prenatal samples using both conventional karyotyping and high-resolution arrays. The detection rates for each clinical category of CNV. Unequivocal pathogenic CNVs were found in six cases, including one with uniparental disomy (paternal UPD 14). A further four cases had a 'likely pathogenic' finding. Overall, CMA improved the detection of 'pathogenic' and 'likely pathogenic' abnormalities from 2.9% (3/104) to 9.6% (10/104). CNVs of 'unknown' clinical significance that presented interpretational difficulties beyond results from parental investigations were detected in 6.7% (7/104) of samples. Increased detection sensitivity appears to be the main benefit of high-resolution CMA. Despite this, in this cohort there was no significant benefit in terms of improving detection of small pathogenic CNVs. A potential disadvantage is the high detection rate of CNVs of 'unknown' clinical significance. These findings emphasise the importance of establishing an evidence-based policy for the interpretation and reporting of CNVs, and the need to provide appropriate pre- and post-test counselling.

A 10-year step forward in hereditary cancer in Spain

Genetic counselling in cancer is a multistep medical process that includes cancer risk assessment, evaluation of patient’s needs and concerns, education, genetic testing in selected cases, medical management, and psychosocial support. Potential benefits, limitations and risks of gene tests are important considerations in the decision-making process. The most detrimental factor in the development of genetic counselling in hereditary cancer in Spain in the late 90’s was the lack of certified formation and training in this field. To solve this gap, a tremendous effort has been done from the Spanish Society of Medical Oncology (SEOM) by promoting training courses, publishing books, guidelines, and consensus documents, fostering multidisciplinary meetings to address controversial issues, and participating in research projects. In June 2000, the first Spanish working group in hereditary cancer was created. A key priority was making genetic counselling in cancer accessible to anyone in Spain, uniting for this purpose the expertise of different motivated health professionals, such as oncologists, geneticists, nurses, psychologists, and others. Ten years have already passed since the establishment of the Hereditary Cancer Section of SEOM and results are nicely evident: members of this section have pioneered the creation of hereditary cancer genetic counseling units (HCGCUs), which have allowed genetic counseling in familial cancer accessible to individuals at risk in our country. Nevertheless, we still have a long way to be equated with European countries like The Netherlands, where genetic counselling has been available since early 80’s in several clinical genetics centers spread along the country, each one attending a region with a population of 1–2 million individuals, and all undergoing strict quality controls both at the laboratory and in the clinics [1]. As stated by the WHO, governments have an extra duty to avoid an access gap to genetic testing with proven clinical validity and cost-efficiency. According to that, most European member states have signed and ratified the European Convention on Human Rights and Biomedicine, which has been updated in November 2008 concerning Genetic Testing for Health Purposes [2]. Despite the fact that the Spanish legislation established, in articles 56 and 57 of Law 14/2007 on Biomedical Research, that genetic counseling should be performed by qualified personnel in accredited centers meeting the quality requirements set by the competent authority [3]; only a few regions have developed and implemented legal regulations on the structure and organization of HCGCUs [4]. The recommendations published by the Hereditary Cancer Section of SEOM in this number of Clinical Translational Oncology come to fill this gap by establishing the minimum necessary requirements in relation to the structure, resources, organization, and functions of HCGCUs in order to promote uniformity and quality access to genetic counselling in cancer all over Spain. But time moves on, and we are facing new challenges regarding the future of genetic counselling in hereditary cancer in our country: First of all, the inclusion of formal education and skills training in genetic counselling during the MIR (Medico Interno Residente) period in Oncology, and the need to reinforce the ongoing training tools of B. Grana (&) Medical Oncology Department, Arquitecto Marcide Hospital (SERGAS), Ferrol, Spain e-mail: begona.grana.suarez@sergas.es

PWE-073 Colonoscopy for a family history of colorectal cancer: are we screening “the worried well”?

IntroductionThe British Society of Gastroenterology (BSG) updated guidelines for colonoscopic screening of people with family history (FH) of colorectal cancer (CRC) in 2010. In the UK, most patients anxious about...

Evaluation of Association Methods for Analysing Modifiers of Disease Risk in Carriers of High‐Risk Mutations

There is considerable evidence indicating that disease risk in carriers of high-risk mutations (e.g. BRCA1 and BRCA2) varies by other genetic factors. Such mutations tend to be rare in the population and studies of genetic modifiers of risk have focused on sampling mutation carriers through clinical genetics centres. Genetic testing targets affected individuals from high-risk families, making ascertainment of mutation carriers non-random with respect to disease phenotype. Standard analytical methods can lead to biased estimates of associations. Methods proposed to address this problem include a weighted-cohort (WC) and retrospective likelihood (RL) approach. Their performance has not been evaluated systematically. We evaluate these methods by simulation and extend the RL to analysing associations of two diseases simultaneously (competing risks RL-CRRL). The standard cohort approach (Cox regression) yielded the most biased risk ratio (RR) estimates (relative bias-RB: -25% to -17%) and had the lowest power. The WC and RL approaches provided similar RR estimates, were least biased (RB: -2.6% to 2.5%), and had the lowest mean-squared errors. The RL method generally had more power than WC. When analysing associations with two diseases, ignoring a potential association with one disease leads to inflated type I errors for inferences with respect to the second disease and biased RR estimates. The CRRL generally gave unbiased RR estimates for both disease risks and had correct nominal type I errors. These methods are illustrated by analyses of genetic modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers.

Prioritization of future genetics education for general practitioners: a Delphi study

PurposeGeneral practitioners (GPs) are increasingly expected to deliver genetics services in daily patient care. Education in primary care genetics is considered suboptimal and in urgent need of revision and innovation. The aim of this study was to prioritize topics for genetics education for general practice. MethodsA Delphi consensus procedure consisting of three rounds was conducted. A purposively selected heterogeneous panel (n = 18) of experts, comprising six practicing GPs who were also engaged in research, five GP trainers, four clinical genetics professionals, and three representatives of patient organizations, participated. Educational needs regarding genetics in general practice in terms of knowledge, skills, and attitudes were rated and ranked in a top-10 list. ResultsThe entire panel completed all three rounds. Kendall's coefficient of concordance indicated significant agreement regarding the top 10 genetic education needs (P < 0.001). “Recognizing signals that are potentially indicative of a hereditary component of a disease” was rated highest, followed by “Evaluating indications for referral to a clinical genetics centre” and “Knowledge of the possibilities and limitations of genetic tests.” ConclusionsThe priorities resulting from this study can inform the development of educational modules, including input for case-based education, to improve GP performance in genetic patient care.

Knowledge and perceived risks in couples undergoing genetic testing after recurrent miscarriage or for poor semen quality

Couples with recurrent miscarriage (RM) and men with poor semen quality may undergo genetic testing as part of the diagnostic work-up. This study explored their knowledge and perception of genetic testing, evaluated psychological wellbeing and identified associated variables. A prospective questionnaire study was conducted in seven clinical genetics centres and referring gynaecological departments in couples with RM or poor semen quality. Questionnaires were completed before disclosure of genetic test results. Main outcome measures were knowledge, perceived risk, anxiety and depression. Of 439 participants, 256 were not aware genetic testing was part of the diagnostic work-up. One-third (36% RM, 33% poor semen quality) indicated they had not received information about the genetic test from their doctor. Perceived risk of receiving an abnormal genetic test result was higher than objective risk. Anxiety was highly correlated with perceived risk. Women with RM were more anxious than women in the poor semen quality group or men ( P < 0.01). These couples undergoing genetic testing have a suboptimal understanding of the nature of testing, overestimate the risks of receiving an abnormal result and some show high levels of anxiety. The results of this study can be used to improve patient counselling before genetic testing. Couples with recurrent miscarriage (RM) and couples with men with poor semen quality, may undergo genetic testing as part of the diagnostic work-up to establish the cause. We explored the knowledge and perception of genetic testing in these couples and evaluated their psychological wellbeing. We provided questionnaires in seven clinical genetics centres and referring gynaecological departments to couples with RM or poor semen quality. The questionnaires were completed before receiving the result of the genetic test. We asked couples about knowledge, perceived risk, anxiety and depression. Of 439 participants, 256 said they were not aware genetic testing was part of the diagnostic work-up. One-third (36% RM, 33% poor semen quality) indicated they had not received information about the genetic test from their doctor. Almost all participants overestimated their risk of receiving an abnormal genetic test result. The overestimation was highest in participants who were more anxious. Women with RM were more anxious than women in the poor semen quality group or men ( P < 0.01). These couples undergoing genetic testing have a suboptimal understanding of the nature of testing, overestimate the risks of receiving an abnormal result and some indicate high levels of anxiety. The results of this study can be used to improve patient counselling before genetic testing.

Genetic Testing for BRCA Mutations Can Save Lives

JAMA Association of Risk-Reducing Surgery in BRCA1 or BRCA2 Mutation Carriers With Cancer Risk and Mortality Susan M. Domchek, MD; Tara M. Friebel, MPH; Christian F. Singer, MD, MPH; D. Gareth Evans, MD; Henry T. Lynch, MD; Claudine Isaacs, MD; Judy E. Garber, MD, MPH; Susan L. Neuhausen, PhD; Ellen Matloff, MS; Rosalind Eeles, PhD; Gabriella Pichert, MD; Laura Van t’veer, PhD; Nadine Tung, MD; Jeffrey N. Weitzel, MD; Fergus J. Couch, PhD; Wendy S. Rubinstein, MD, PhD; Patricia A. Ganz, MD; Mary B. Daly, MD, PhD; Olufunmilayo I. Olopade, MD; Gail Tomlinson, MD, PhD; Joellen Schildkraut, PhD; Joanne L. Blum, MD, PhD; Timothy R. Rebbeck, PhD Context: Mastectomy and salpingo-oophorectomy are widely used by carriers of BRCA1 or BRCA2 mutations to reduce their risks of breast and ovarian cancer. Objective: To estimate risk and mortality reduction stratified by mutation and prior cancer status. Design, Setting, and Participants: Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. The study was conducted at 22 clinical and research genetics centers in Europe and North America to assess the relationship of risk-reducing mastectomy or salpingo-oophorectomy with cancer outcomes. The women were followed up until the end of 2009. Main Outcomes Measures: Breast and ovarian cancer risk, cancer-specific mortality, and overall mortality. Results: No breast cancers were diagnosed in the 247 women with risk-reducing mastectomy compared with 98 women of 1372 diagnosed with breast cancer who did not have risk-reducing mastectomy. Compared with women who did not undergo risk-reducing salpingo-oophorectomy, women who underwent salpingo-oophorectomy had a lower risk of ovarian cancer, including those with prior breast cancer (6% vs 1%, respectively; hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.04-0.59) and those without prior breast cancer (6% vs 2%; HR, 0.28 [95% CI, 0.12-0.69]), and a lower risk of first diagnosis of breast cancer in BRCA1 mutation carriers (20% vs 14%; HR, 0.63 [95% CI, 0.41-0.96]) and BRCA2 mutation carriers (23% vs 7%; HR, 0.36 [95% CI, 0.16-0.82]). Compared with women who did not undergo risk-reducing salpingo-oophorectomy, undergoing salpingo-oophorectomy was associated with lower all-cause mortality (10% vs 3%; HR, 0.40 [95% CI, 0.26-0.61]), breast cancer–specific mortality (6% vs 2%; HR, 0.44 [95% CI, 0.26-0.76]), and ovarian cancer–specific mortality (3% vs 0.4%; HR, 0.21 [95% CI, 0.06-0.80]). Conclusions: Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer–specific mortality, and ovarian cancer–specific mortality. doi:10.1001/jama.2010.1237.

Revised Bethesda Guidelines: compliance in identifying HNPCC affected families

IntroductionHereditary non-polyposis colorectal cancer (HNPCC) causes approximately 3% of colorectal cancer cases in the UK and has significant implications for screening families with multiple affected members. It is usually caused...

Association of Risk-Reducing Surgery in &lt;emph type="ital"&gt;BRCA1&lt;/emph&gt; or &lt;emph type="ital"&gt;BRCA2&lt;/emph&gt; Mutation Carriers With Cancer Risk and Mortality

Mastectomy and salpingo-oophorectomy are widely used by carriers of BRCA1 or BRCA2 mutations to reduce their risks of breast and ovarian cancer. To estimate risk and mortality reduction stratified by mutation and prior cancer status. Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. The study was conducted at 22 clinical and research genetics centers in Europe and North America to assess the relationship of risk-reducing mastectomy or salpingo-oophorectomy with cancer outcomes. The women were followed up until the end of 2009. Breast and ovarian cancer risk, cancer-specific mortality, and overall mortality. No breast cancers were diagnosed in the 247 women with risk-reducing mastectomy compared with 98 women of 1372 diagnosed with breast cancer who did not have risk-reducing mastectomy. Compared with women who did not undergo risk-reducing salpingo-oophorectomy, women who underwent salpingo-oophorectomy had a lower risk of ovarian cancer, including those with prior breast cancer (6% vs 1%, respectively; hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.04-0.59) and those without prior breast cancer (6% vs 2%; HR, 0.28 [95% CI, 0.12-0.69]), and a lower risk of first diagnosis of breast cancer in BRCA1 mutation carriers (20% vs 14%; HR, 0.63 [95% CI, 0.41-0.96]) and BRCA2 mutation carriers (23% vs 7%; HR, 0.36 [95% CI, 0.16-0.82]). Compared with women who did not undergo risk-reducing salpingo-oophorectomy, undergoing salpingo-oophorectomy was associated with lower all-cause mortality (10% vs 3%; HR, 0.40 [95% CI, 0.26-0.61]), breast cancer-specific mortality (6% vs 2%; HR, 0.44 [95% CI, 0.26-0.76]), and ovarian cancer-specific mortality (3% vs 0.4%; HR, 0.21 [95% CI, 0.06-0.80]). Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality.

Comparison of prenatal ultrasound findings and autopsy findings in fetuses terminated after prenatal diagnosis of malformations: An experience of a clinical genetics center

To compare antenatal diagnosis with post mortem examination findings in the pregnancies terminated after prenatal detection of anomalies and to evaluate the potential benefits of post mortem examination for counseling regarding the risk of recurrence. This is a retrospective study over a 7-year period from 2001 to 2007. Pregnancies terminated after prenatal identification of fetal malformation were evaluated by post mortem examination of 91 fetuses. Fetal autopsy provided a definite diagnosis in 72/91 (79.1%) of the cases. Fetal autopsy confirmed the sonographic findings in 89 of 91 cases (97.8%). In 66 (72.5%) cases there was complete concordance between prenatal and autopsy findings, while in 23 cases there was major concordance. There were 49 cases with isolated malformations, 41 cases with multiple (89) malformations, and, in one case, no malformation was found at autopsy. Of the 89 associated malformations, 39 (43.8%) were detected prenatally and 50 (56.2%) were detected on fetal autopsy. The additional malformations detected on autopsy included 38 major and 12 minor malformations Additional findings helped in redefining the diagnosis and the risk of recurrence in 30 of 91 (33%) cases. The present study emphasizes the importance of autopsy in providing accurate etiologic diagnosis necessary for genetic counseling.

Recommendations to improve identification of hereditary and familial colorectal cancer in Europe

Familial colorectal cancer (CRC) accounts for 10-15% of all CRCs. In about 5% of all cases, CRC is associated with a highly penetrant dominant inherited syndrome. The most common inherited form of non-polyposis CRC is the Lynch syndrome which is responsible for about 2-4% of all cases. Surveillance of individuals at high risk for CRC prevents the development of advanced CRC. About 1 million individuals in Western Europe are at risk for Lynch syndrome. We performed a survey to evaluate the strategies currently used to identify individuals at high risk for CRC in 14 Western European countries. Questionnaires were distributed amongst members of a European collaborative group of experts that aims to improve the prognosis of families with hereditary CRC. The survey showed that in all countries obtaining a family history followed by referral to clinical genetics centres of suspected cases was the main strategy to identify familial and hereditary CRC. In five out of seven countries with a (regional or national) CRC population screening program, attention was paid in the program to the detection of familial CRC. In only one country were special campaigns organized to increase the awareness of familial CRC among the general population. In almost all countries, the family history is assessed when a patient visits a general practitioner or hospital. However, the quality of family history taking was felt to be rather poor. Microsatellite instability testing (MSI) or immunohistochemical analysis (IHC) of CRC are usually recommended as tools to select high-risk patients for genetic testing and are performed in most countries in patients suspected of Lynch syndrome. In one country, IHC was recommended in all new cases of CRC. In most countries there are no specific programs on cancer genetics in the teaching curriculum for medical doctors. In conclusion, the outcome of this survey and the discussions within an European expert group may be used to improve the strategies to identify individuals at high risk of CRC. More attention should be given to increasing the awareness of the general population of hereditary CRC. Immunohistochemical analysis or MSI-analysis of all CRCs may be an effective tool for identifying all Lynch syndrome families. The cost-effectiveness of this approach should be further evaluated. All countries with a CRC population screening program should obtain a full family history as part of patient assessment.