Female Mutation Carriers Research Articles

Predictors of long-term cancer-related distress among female BRCA1 and BRCA2 mutation carriers without a cancer diagnosis: an international analysis

BackgroundWomen with a BRCA1 or BRCA2 mutation have high lifetime risks of developing breast and ovarian cancers. We sought to estimate the prevalence of cancer-related distress and to identify predictors of distress in an international sample of unaffected women with a BRCA mutation.MethodsWomen with a BRCA1/2 mutation and no previous cancer diagnosis were recruited from the United States, Canada, the United Kingdom, Australia and from a national advocacy group. Using an online survey, we asked about cancer risk reduction options and screening, and we measured cancer-related distress using the Impact of Event Scale.ResultsAmong 576 respondents, mean age was 40.8 years (SD = 8.1). On average 4.9 years after a positive test result, 16.3% of women reported moderate-to-severe cancer-related distress. Women who had undergone risk-reducing breast and ovarian surgery were less likely to have (moderate or severe) cancer-related distress compared to other women (22.0% versus 11.4%, P value = 0.007). Women recruited from the advocacy group were more likely to have cancer-related distress than other women (21.6% versus 5.3%, P value = 0.002).ConclusionsApproximately 16% of women with a BRCA1 or BRCA2 mutation experience distress levels comparable to those of women after a cancer diagnosis. Distress was lower for women who had risk-reducing surgery.

Mental Problems in Cases with Duchenne Muscular Dystrophy Mutation: Not Only Males, but also Females

Dystrophin, the pathogenic variants of which can cause muscular diseases, is a protein mainly distributed under the sarcolemma. However, the protein also exists in the central nervous system and many reports have described neural comorbidities in patients with dystrophinopathy. Duchenne muscular dystrophy (DMD) has been described as being associated with neurodevelopmental disorders, including intellectual developmental disorders, communication disorders, autism spectrum disorders, and attention deficit/hyperactivity disorders. Patients with dystrophinopathy have also been reported to have depression, anxiety, or obsessive-compulsive disorders. Female carriers of DMD mutations exhibit a wide variety of clinical features from asymptomatic high serum creatine kinase level to severe muscle weakness or dilated cardiomyopathy, and mental disorders including cognitive impairment. Since the mental disorders in female carriers of DMD mutations can be easily overlooked, it is necessary to pay close attention for correct diagnosis

Functional performance and muscular strength in symptomatic female carriers of Duchenne muscular dystrophy.

To investigate the motor and functional impairments of 10 female patients with dystrophinopathy diagnosed with clinical, pathological, genetic and immunohistochemical studies. A descriptive study of a sample of symptomatic female carriers of DMD mutations. The studied variables were muscular strength and functional performance. The prevalence was 10/118 (8.4%) symptomatic female carriers. Deletions were found in seven patients. The age of onset of symptoms in female carriers of DMD was quite variable. Pseudohypertrophy of calf muscles, muscular weakness, compensatory movements and longer timed performance on functional tasks were observed in most of the cases. Differently from males with DMD, seven female patients showed asymmetrical muscular weakness. The asymmetric presentation of muscle weakness was frequent and affected posture and functionality in some cases. The functional performance presents greater number of compensatory movements. Time of execution of activities was not a good biomarker of functionality for this population, because it does not change in the same proportion as the number of movement compensations. Clinical manifestation of asymmetrical muscle weakness and compensatory movements, or both can be found in female carriers of DMD mutations, which can adversely affect posture and functional performance of these patients.

Circulating cell-free DNA (cfDNA) levels in BRCA1 and BRCA2 mutation carriers: A preliminary study.

Female carriers of BRCA1 or BRCA2 germline mutations are at a substantially increased risk for developing breast and ovarian cancer. The lack of effective early detection schemes for ovarian cancer, mandate surgical removal of adnexa at age 35-40 years in these high-risk women. The role of circulating cell-free DNA (cfDNA) levels as a marker for early detection in high-risk women has rarely been reported. To quantify cfDNA levels in BRCA1BRCA2 carriers. Serum cfDNA levels, measured by direct fluorometric assay in cancer-free female BRCA1BRCA2 mutation carriers were compared with cancer-free controls recruited from among women undergoing breast biopsy or routine colonoscopy. Overall, 10 BRCA1 (185delAG) and 10 BRCA2 (6174delT) mutation carriers, 20 breast biopsy controls, and 20 colonoscopy controls participated. cfDNA levels [Median (95% CI)], were 472 (317-589) ng/ml and 525 (339-621) ng/ml in breast biopsy and colonoscopy controls, respectively. Median levels of cfDNA in BRCA1 and BRCA2 mutation carriers combined were 921 (835-1087) ng/ml, significantly higher than in both controls (P< 0.0001). cfDNA levels are significantly higher in BRCA1 and BRCA2 mutation carriers compared with non-carriers. This finding, if validated, may facilitate development of early detection breast/ovarian cancer biomarker in high-risk women.

How to support patients with BRCA genetic mutation? Research review.

Aim of the studyAccording to research conducted so far, the detection of a genetic mutation that increases the risk of developing cancer may be associated with feelings of discomfort, anxiety and apprehension, so it is important to know the needs and expectations externalized by those patients who face the challenge of coping with information about cancer risk. This analyzes the results obtained on this subject in recent studies.Subject or material and methodsThe results of 11 studies conducted in the years 2000-2018 were analyzed. To achieve this aim, the EBSCO, PubMed, PsychARTICLES and MEDLINE databases were searched through.ResultsThe results obtained show that both male and female carriers of BRCA mutations have specific support needs. They usually look for valuable content, including information on the procedure for conducting the genetic test and the consequences of obtaining a positive result. Social as well as therapeutic support are also significant. Patients who participated in psychotherapy assessed this form of help as valuable and necessary, especially in relation to the decision making process regarding surgical treatment.DiscussionSupport programs for patients with BRCA mutations implemented in different countries have a chance to become an inspiration for introducing similar solutions in Poland.ConclusionsThis could possibly lead to increased patient involvement in preventive activities or could contribute to the reduction of anxiety or distress that results from having a genetic mutation.

Effectiveness of decision aids for female BRCA1 and BRCA2 mutation carriers: a systematic review

BackgroundFemale BRCA1 and BRCA2 mutation carriers have an increased lifetime risk of developing breast and/or ovarian cancer. Hence, they face the difficult decision of choosing a preventive strategy such as risk-reducing surgeries or intensified breast screening. To help these women during their decision process, several patient decision aids (DA) were developed and evaluated in the last 15 years. Until now, there is no conclusive evidence on the effectiveness of these DA. This study aims 1) to provide the first systematic literature review about DA addressing preventive strategy decisions for female BRCA1 and BRCA2 mutation carriers, 2) to analyze the quality of the existing evidence, 3) to evaluate the effects of DA on decision and information related outcomes, on the actual choice for preventive measure and on health outcomes.MethodsA systematic literature review was conducted using six electronic databases (inclusion criteria: DA addressing preventive strategies, female BRCA1 and BRCA2 mutation carriers, 18 to 75 years, knowledge of test result). The quality of the included randomized controlled trials (RCT) was evaluated with the Cochrane Collaboration’s risk of bias tool. The quality of included one-group pretest-posttest design studies was evaluated with the ROBINS-I tool. Outcomes of included studies were extracted and qualitatively summarized.ResultsA total of 2093 records were identified. Six studies were included for further evaluation (5 RCT, 1 one-group pretest-posttest design study). One RCT was formally included, but data presentation did not allow for further analyses. The risk of bias was high in three RCT and unclear in one RCT. The risk of bias in the one-group pretest-posttest study was serious. The outcome assessment showed that the main advantages of DA are linked to the actual decision process: Female BRCA1 and BRCA2 mutation carriers using a DA had less decisional conflict, were more likely to reach a decision and were more satisfied with their decision.ConclusionsDecision aids can support female BRCA1 and BRCA2 mutation carriers during their decision process by significantly improving decision related outcomes. More high-quality evidence is needed to evaluate possible effects on information related outcomes, health outcomes and the actual choice for preventive measures.

Inflammation-induced fibrosis in skeletal muscle of female carriers of Duchenne muscular dystrophy

Female carriers of DMD gene mutations may be symptomatic and show variable skeletal as well as cardiac muscle symptoms. Skeletal muscle can exhibit morphological alterations. However, inflammatory, degenerative and fibrotic changes as seen in Duchenne boys have not been specifically analysed yet, so we addressed the question whether skeletal muscle of female carriers show such alterations. Thirteen carriers with an age range of 3 to 50 years were studied retrospectively. Five out of 13 women had clinically affected relatives. Clinically, most women showed mild muscle weakness, while the CK levels were increased in nine of them. Histomorphological analyses highlighted the typical mosaic pattern of dystrophin-positive and -negative fibres. Regenerating fibres were diffusely scattered and focally pronounced, while endo- and perimysial fibrosis was a variable but constant feature. Infiltration of CD206+TGFß+ macrophages and scattered T cells was noted in the endomysium. TGFb and CCL18, were significantly increased. However, gene expression of markers involved in Th1/Th2 immunity did not reach statistical significance compared to non-diseased controls. In summary, skeletal muscle of clinically manifest female DMD gene mutation carriers shows mild fibrosis and increased regeneration associated with endomysial CD206+TGFβ+ and STAT6+ macrophages, which are most likely involved in fibrotic remodelling.

International trends in the uptake of cancer risk reduction strategies in women with a BRCA1 or BRCA2 mutation

BackgroundWomen with a BRCA1 or BRCA2 mutation face high risks of breast and ovarian cancer. In the current study, we report on uptake of cancer screening and risk-reduction options in a cohort of BRCA mutation carriers from ten countries over two time periods (1995 to 2008 and 2009 to 2017).MethodsEligible subjects were identified from an international database of female BRCA mutation carriers and included women from 59 centres from ten countries. Subjects completed a questionnaire at the time of genetic testing, which included past use of cancer prevention options and screening tests. Biennial follow-up questionnaires were administered.ResultsSix-thousand two-hundred and twenty-three women were followed for a mean of 7.5 years. The mean age at last follow-up was 52.1 years (27–96 years) and 42.3% of the women had a prior diagnosis of breast cancer. In all, 27.8% had a prophylactic bilateral mastectomy and 64.7% had a BSO. Screening with breast MRI increased from 70% before 2009 to 81% at or after 2009. There were significant differences in uptake of all options by country.ConclusionFor women who received genetic testing more recently, uptake of prophylactic mastectomy and breast MRI is significantly higher than those who received genetic testing more than 10 years ago. However, uptake of both BSO and breast MRI is not optimal, and interventions to increase uptake are needed.

Understanding BRCA Mutation Carriers’ Preferences for Communication of Genetic Modifiers of Breast Cancer Risk

Refined estimates of risk based on genetic risk modifiers could assist BRCA mutation carriers in understanding their risk, but it is not clear whether carriers are interested in receiving these estimates or how they might benefit from them. Using qualitative interviews, we investigated female BRCA1 and BRCA2 mutation carriers’ (N = 20) reactions to numerical and verbal presentations of breast cancer risk based on risk modifiers and assessed women’s preferences regarding visual formats for communicating risk. Our results show carriers are interested in receiving refined risk estimates and suggest the estimates may influence decision-making regarding cancer prevention, depending on the nature of the risk assessment. Although accurate and precise estimates of breast cancer risk are most important to women, they preferred quantitative risk estimates expressed as a proportion with or without a population comparison; however, women noted that comparisons to other BRCA mutation carriers were less useful given their high risk. Participants also preferred communication of a risk as a specific percentage versus a range of risk, but a clear preference regarding visual displays was not expressed. Results support many existing recommendations for genetic risk communication and provide guidance for the development of tools incorporating genetic risk modifiers.

Complex Neurological Phenotype in Female Carriers of NHE6 Mutations

Mutations in NHE6 (also termed SLC9A6) cause the X-linked neurological disorder Christianson syndrome (CS) in males. The purpose of this study was to examine the phenotypic spectrum of female carriers of NHE6 mutations. Twenty female carriers from 9 pedigrees were enrolled, ranging from approximately age 2 to 65. A subset of female carriers was assessed using standardized neuropsychological measures. Also, the association of NHE6 expression with markers of brain age was evaluated using 740 participants in the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). A majority, but not all, female carriers demonstrated a deficit in at least one neurocognitive domain (85%). A recognizable neuropsychological profile emerged, revealing impairments in visuospatial function, attention, and executive function. Common neuropsychiatric diagnoses included: intellectual disability/developmental delay (20%), learning difficulties (31%), speech/language delays (30%), and attention-deficit/hyperactivity disorder (20%). Notable neurological diagnoses in aging CS female carriers include corticobasal degeneration and atypical parkinsonism. In postmortem brains from the ROS/MAP dataset of normal and pathological aging, decreased NHE6 expression was correlated with greater tau deposition. Our study provides an examination of the phenotypic range in female carriers of NHE6 mutations. The findings indicate that NHE6-related disease in females represents a new neurogenetic condition.

The clinical impact of MRI screening for BRCA mutation carriers: the first report in Japan

BackgroundThere is no consensus on the appropriate surveillance for high-risk women with breast cancer in Japan. We investigated their imaging features and pathological characteristics to build a proper surveillance system for asymptomatic high-risk individuals in the future.MethodsWe retrospectively reviewed 93 female (median age 43 years) BRCA1 and BRCA2 mutation carriers from our institutional clinical database from 2011 to 2017. The study population was composed of 112 breast cancers. Mammography and MRI were reviewed by examiners blinded to patients’ clinical history. Final surgical or biopsy histopathology served as the reference standard in all the patients.ResultsFifty-nine breast cancers met selection criteria; of these, 30 were BRCA1-associated tumors, and 29 were BRCA2-associated tumors. Invasive ductal carcinoma was the most prevalent type in both BRCA1 and BRCA2. There were statistically significant differences in phenotype, nuclear grade, and Ki-67 labeling index between BRCA1 and BRCA2 mutation carriers. Additionally, imaging findings on mammography and MRI were statistically different. Tumors in BRCA2 carriers demonstrated mammographic calcifications more frequently, while those in BRCA1 carriers demonstrated a mass or architectural distortion (P < 0.001). Enhancement pattern on MRI also significantly differed between the two subgroups (P = 0.006). The size of MRI-detected lesions was statistically smaller than the size of those detected by other modalities (P = 0.004).ConclusionsThe imaging and histological characteristics of BRCA1/2 mutation carriers were consistent with other countries’ studies. MRI-detected lesions were significantly smaller than lesions detected by non-MRI modality. All lesions in BRCA1 mutation carriers could be detected by MRI.

Behavioural and psychiatric phenotypes in female carriers of genetic mutations associated with X-linked ichthyosis.

X-linked ichthyosis (XLI) is a rare X-linked dermatological condition arising from deficiency for the enzyme steroid sulfatase (STS). STS is normally expressed in the brain, and males with XLI exhibit personality differences from males in the general population, and are at increased risk of developmental and mood disorders. As the STS gene escapes X-inactivation, female carriers of XLI-associated genetic mutations have reduced STS expression/activity relative to non-carrier females, and could manifest similar behavioural phenotypes to males with XLI. Additionally, as STS activity normally increases in female tissues towards late pregnancy and into the puerperium, carrier females could theoretically present with increased rates of postpartum psychopathology. Using a worldwide online survey comprising custom-designed demographic questionnaires and multiple validated psychological questionnaires, we collected detailed self-reported information on non-postpartum and postpartum behaviour in confirmed adult (>16yrs) female carriers of genetic mutations associated with XLI (n = 94) for statistical comparison to demographically-matched previously-published normative data from female controls (seven independent studies, 98≤n≤2562), adult males with XLI (n = 58), and to newly-obtained online survey data from a general population sample of mothers from the United Kingdom and United States of America (n = 263). The pattern of results in carrier females relative to controls was remarkably similar to that previously observed in males with XLI, with evidence for increased rates of developmental and mood disorders, and elevated levels of inattention, impulsivity, autism-related traits and general psychological distress. Carrier females exhibited a significantly elevated rate of postpartum mental health conditions (notably mild depression) relative to controls which could not be accounted for by social factors. Our data confirm the psychological profile associated with XLI-associated mutations, and suggest that female carriers may be at increased risk of psychopathology, including in the postpartum period. These findings are relevant to families affected by XLI, to clinicians involved in the care of these families, and to genetic counsellors.

Exploring the Variable Phenotypes of RPGR Carrier Females in Assessing their Potential for Retinal Gene Therapy.

Inherited retinal degenerations are the leading cause of blindness in the working population. X-linked retinitis pigmentosa (XLRP), caused by mutations in the Retinitis pigmentosa GTPase regulator (RPGR) gene is one of the more severe forms, and female carriers of RPGR mutations have a variable presentation. A retrospective review of twenty-three female RPGR carriers aged between 8 and 76 years old was carried out using fundoscopy, autofluorescence imaging (AF), blue reflectance (BR) imaging and optical coherence tomography (OCT). Confirmation of the genetic mutation was obtained from male relatives or Sanger genetic sequencing. Fundus examination and AF demonstrate phenotypic variability in RPGR carriers. The genetic mutation appears indeterminate of the degree of change. We found four distinct classifications based on AF images to describe RPGR carriers; normal (N) representing normal or near-normal AF appearance (n = 1, 4%); radial (R) pattern reflex without pigmentary retinopathy (n = 14, 61%); focal (F) pigmentary retinopathy (n = 5, 22%) and; male (M) phenotype (n = 3, 13%). The phenotypes were precisely correlated in both eyes (rs = 1.0, p < 0.0001). Skewed X-inactivation can result in severely affected carrier females—in some cases indistinguishable from the male pattern and these patients should be considered for RPGR gene therapy. In the cases of the male (M) phenotype where the X-inactivation was skewed, the pattern was similar in both eyes, suggesting that the mechanism is not truly random but may have an underlying genetic basis.

Co-Existence of Novel PDE6A Mutations and A Recurrent RPGR Mutation: A Potential Explanation for Phenotypic Diversity in Female RPGR Mutation Carriers.

To report the co-existence of novel biallelic PDE6A mutations and heterozygous RPGR mutation in a Chinese female patient with retinitis pigmentosa (RP), and to analyze the intrafamilial phenotypic diversity. Three patients with retinopathy and four healthy family members were included in genetic and clinical analyses. Personal medical records were obtained from another four unaffected female family members who refused blood donation. Family history was carefully recorded. Each patient received comprehensive ophthalmic tests. Targeted next-generation sequencing (NGS) approach was performed on the proband to determine the retinopathy causative mutation for this family. In silico analysis was also applied to analyze the pathogenesis of identified mutations. The two recruited male patients were diagnosed with RP, and the female patient RP sine pigmento (RPSP). Genetic assessments revealed a recurrent RPGR mutation, c.1926_1927insA, carried by all three patients and segregated the disease status. Three other unaffected female family members were confirmed as carriers for the identified RPGR mutation, and another four as obligate carriers. Interestingly, of all the eight female RPGR mutation carriers in this family, only one female developed retinal dystrophy. Comprehensive genetic analysis of this patient unraveled additional biallelic PDE6A mutations, c.[1066-9delT];[2324delG], carried solely by this individual. Taken together, we hypothesize that the phenotypic variability presented by female RPGR mutation carriers may be attributed to the co-existence of other disease-causative mutations. Our study also emphasizes the importance of comprehensive genetic analysis in these female carriers, which will contribute to better diagnosis, prognosis, and treatment for these patients.

DUCHENNE MUSCULAR DYSTROPHY - GENETICS: P.220A neuropsychological and neuroimaging study of female carriers of DMD mutations

Dystrophinopathies are caused by DMD mutations and include Duchenne/Becker dystrophies. Men are typically affected, but subtle clinical signs have been increasingly reported in female carriers of DMD mutations (fcDMD) as well. Cognitive and cerebral abnormalities are major findings in affected men, but have not yet been assessed in fcDMD. Objectives: To investigate cognitive and neuroanatomical abnormalities in fcDMD. Fourteen fcDMD were submitted to neurological and neuropsychological examination, employing either the Addenbrooke's Cognitive Examination – Revised (ACE-R) test or the Montreal Cognitive Assessment (MoCA). For each subject, volumetric T1 cerebral sequences were obtained in a 3T MRI scanner. A control group of 14 age-matched healthy women was used for comparison. We computed cortical thickness measurements using the FreeSurfer software. Between-group comparisons were performed with GLM taking total intracranial volumes as covariates. Pearson coefficients explored associations between cognitive tests and MRI results. P values <0.05 were considered significant. Mean age and education of the fcDMD were 37.3±6.4 years and 8.5±3.6 years, respectively. None of the fcDMD presented muscular weakness or ECG abnormalities. Mean ACE-R and MOCA scores were 73.7±9.6 and 24.5±2.1. Half of patients (n=7) scored below the expected Brazilian and schooling-adjusted reference levels. Abnormal domains included attention/temporal orientation, language and visuospatial skills. MRI analyses revealed right inferior temporal cortical thinning in fcDMD, but it did not correlate with cognitive scores. fcDMD have cognitive and neuroanatomical abnormalities. Temporal regions look particularly vulnerable, but further studies are needed to fully characterize the structural pattern of damage in fcDMD.

DUCHENNE MUSCULAR DYSTROPHY - GENETICS: P.218Heart and skeletal muscle affection in female carriers of a dystrophin gene mutation

Female carriers of mutations associated with Duchenne (DMD) and Becker (BMD) muscular dystrophies are typically considered unaffected. However, different degrees of symptomatic carriers have been reported. Through an observational, prospective, cross-sectional study, female carriers of a DMD mutation were examined to investigate the frequency and extent of heart and muscle involvement. Genetically verified female carriers of a DMD mutation were examined by Magnetic Resonance Imaging (MRI) of the heart and the lower extremity muscles, by isokinetic muscle dynamometry of legs, echocardiography, 24-h Holter monitoring, ECG and blood concentrations of creatine kinase (CK) and cardiac biomarkers. Dixon MRI was used to determine muscle fat fractions of the lower extremity muscles and was correlated to muscle strength measurements. MRI late gadolinium enhancement was used to examine the presence of heart muscle fibrosis. A total of 52 subjects were included and data analysis is ongoing. We found that 71% of subjects had higher fat fractions (mean+2SD) than the 19 age- and gender-matched healthy controls in one or more lower extremity muscle groups. Subjects had significantly lower maximum voluntary force in dynamometry in all muscle groups. Fifty-six percent of subjects had elevated CK. Furthermore, the normal linear relationship between lean muscle mass and force, as seen in healthy controls, was not present in the carriers, indicating an overall contractile dysfunction of skeletal muscles. Preliminary cardiovascular results show that 11 of 48 subjects (23%) had reduced left ventricular systolic function. Female carriers of dystrophin gene mutations have higher fat fractions in skeletal muscles, lower maximal voluntary force, and impaired contractility of their lean muscle mass, compared to healthy controls. A subset of carriers had reduced cardiac contractility. Final results from both skeletal and heart muscle analysis will be presented at the conference.

The Spectrum of Structural and Functional Abnormalities in Female Carriers of Pathogenic Variants in the RPGR Gene.

The purpose of this study was to investigate the phenotype and long-term clinical course of female carriers of RPGR mutations. This was a retrospective cohort study of 125 heterozygous RPGR mutation carriers from 49 families. Eighty-three heterozygotes were from retinitis pigmentosa (RP) pedigrees, 37 were from cone-/cone-rod dystrophy (COD/CORD) pedigrees, and 5 heterozygotes were from pedigrees with mixed RP/CORD or unknown diagnosis. Mutations were located in exon 1-14 and in ORF15 in 42 of 125 (34%) and 83 of 125 (66%) subjects, respectively. The mean age at the first examination was 34.4 years (range, 2.1 to 86.0 years). The median follow-up time in heterozygotes with longitudinal data (n = 62) was 12.2 years (range, 1.1 to 52.2 years). Retinal pigmentary changes were present in 73 (58%) individuals. Visual symptoms were reported in 51 (40%) cases. Subjects with both symptoms and pigmentary fundus changes were older than the other heterozygotes (P = 0.01) and had thinner foveal outer retinas (P = 0.006). Complete expression of the RP or CORD phenotype was observed in 29 (23%) heterozygotes, although usually in milder forms than in affected male relatives. Best-corrected visual acuity (BCVA) was <20/40 and <20/400 in at least one eye in 45 of 116 (39%) and 11 of 116 (9%) heterozygotes, respectively. Myopia was observed in 74 of 101 (73%) subjects and was associated with lower BCVA (P = 0.006). Increasing age was associated with lower BCVA (P = 0.002) and decreasing visual field size (P = 0.012; I4e isopter). RPGR mutations lead to a phenotypic spectrum in female carriers, with myopia as a significantly aggravating factor. Complete disease expression is observed in some individuals, who may benefit from future (gene) therapeutic options.

Reducing the Risk of Gynecologic Cancer in Hereditary Breast Ovarian Cancer Syndrome Mutation Carriers: Moral Dilemmas and the Principle of Double Effect.

Hereditary breast ovarian cancer (HBOC) syndrome is an autosomal dominant disease linked to mutations in the BRCA1 and BRCA2 genes in 90 percent of affected families. Female mutation carriers are highly susceptible to aggressive, often disseminated, usually fatal pelvic-abdominal carcinomatosis. This cancer risk can be markedly reduced by surgical removal of the internal gynecologic organs before the end of the fourth decade of life and by using estrogen-progestin formulations marketed for many years as combined oral contraceptives (COCs). Both risk-reducing methods are associated with unfavorable effects. Relying on the principle of double effect, this essay argues for the ethical justification of prophylactic surgery and the use of COC to reduce the risk of gynecologic cancer in HBOC syndrome mutation carriers. Summary: Hereditary breast ovarian cancer syndrome is an autosomal dominant disease linked to mutations in the BRCA1 and BRCA2 genes in most affected families. Female mutation carriers are highly susceptible to aggressive, often disseminated, usually fatal pelvic-abdominal carcinomatosis. This cancer risk can be markedly reduced by surgical removal of the internal gynecologic organs before the end of the fourth decade of life and by using estrogen-progestin formulations marketed for many years as combined oral contraceptives. Both risk-reducing methods are associated with unfavorable effects. Relying on the principle of double effect, this essay argues for the ethical justification for those unfavorable effects.

Abstract 1410: Pedigree analysis equally identifies cases of pancreatic cancer in families with BRCA1 and BRCA2 mutations

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in western countries, although lifetime risk is estimated at only 1.3% in the general population. BRCA2 mutations, however, have been attributed with a lifetime risk for PDAC development of 5-10%, while the risk for PDAC development in BRCA1 mutation carriers has been the subject of an ongoing scientific discussion, with current estimates of an increased PDAC risk of only 2-4-fold. We retrospectively analyzed 180 pedigrees for occurrence of PDAC. All families were counselled for hereditary breast and ovarian cancer (HBOC) within three years (2015 to 2017) at the Center for Hereditary Breast and Ovarian Cancer in Dresden. The pedigrees of 111 families with a pathogenic BRCA1 germline mutation and of 69 families with a pathogenic BRCA2 germline mutation were available for analysis. Whenever possible genetic testing (NGS or targeted sequencing) was performed using blood and/or tumor tissue of affected individuals. 14 “BRCA1 families” were identified to have at least one family member affected by PDAC (12.6% of families). Three of the patients were available for testing and carrier status could be confirmed in all of them. According to formal genetic risk calculation 6 of the PDAC patients had a mutation carrier risk of 50%, 5 of 25% and 1 of 12.5%. Age of onset (AO) of the disease was known in 13 of the families and the mean AO, calculated for these patients, was 58.7 years. Interestingly, two female Mutation carriers had both breast- and pancreatic cancer and one family with a BRCA1 mutation presented with two sisters with PDAC. Tumor tissue was available from one of them and sequencing indicated loss-of-heterozygosity, supporting the assumption that the BRCA1 mutation might have been causative for tumorigenesis. Of the “BRCA2 families” 10 (14,5%) were identified to have one family member each with PDAC. To date, however, none of them was available for genetic testing. 3 of the patients had a mutation carrier risk calculated at 50%, 5 at 25%, 1 at 12.5% and 1 at 6.25%. The mean AO was calculated to be 60.1 years. One female PDAC patient additionally had breast cancer and one of the male patients also suffered from prostate cancer. While the number of families represented in this retrospective study is limited, our observations indicate that BRCA1 mutations might be underdiagnosed in PDAC, especially in patients with an earlier AO. Extensive genetic analyses of PDAC patients will be necessary in order to elucidate this presumption and could also indicate whether additional genetic risk modifiers play a role in PAC development in BRCA1/2 families. Citation Format: Evelin Schrock, Karl Hackmann, Franziska Kuhlee, Arne Jahn, Johannes Wagner, Anne-Karin Kahlert, Joseph Porrmann, Andreas Tzschach, Daniela Aust, Gustavo Baretton, Karin Kast, Pauline Wimberger, Michael Laniado, Christoph Kahlert, Thilo Welsch, Jürgen Weitz, Barbara Klink, Andreas Rump, Laura Gieldon. Pedigree analysis equally identifies cases of pancreatic cancer in families with BRCA1 and BRCA2 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1410.

Uptake of Preimplantation Genetic Diagnosis in Female BRCA1 and BRCA2 Mutation Carriers.

Women with a germline pathogenic variant in the BReast CAncer susceptibility genes (BRCA1 or BRCA2) have an increased risk of early-onset breast and ovarian cancer. In addition to weighing cancer screening and risk-reduction options, healthy BRCA mutation carriers of childbearing age may choose to preclude passing the mutation to the next generation. In the current study, we report on preimplantation genetic diagnosis (PGD) practices in BRCA-positive Israeli women who were offered PGD at no cost. Methods: we measured PGD uptake, decision satisfaction or regret, and predictors of uptake. Of the 70 participant female carriers, only 25.7% chose to use PGD to prevent transmission of the mutation, and were not predicted by age or religious affiliation. For those who chose IVF/PGD, satisfaction with the decision regarding IVF and PGD was significantly higher than those who did not have IVF and PGD (p < 0.04). Experiencing previous infertility was the only significant predictor of uptake of IVF/PGD (p < 0.001), which may suggest that BRCA status is secondary to infertility in the decision-making process for PGD in women with a BRCA mutation.