Ovarian Cancer Syndrome Research Articles

Unexpected Findings in Hereditary Breast and Ovarian Cancer Syndrome: Low-Level Constitutional Mosaicism in BRCA2.

Hereditary breast and ovarian cancer syndrome (HBOC) is a clinical entity characterized by an increased risk of developing breast and ovarian cancer. The genetic diagnosis is based on the identification of heterozygous germinal variants in HBOC susceptibility genes. However, it has recently been described that constitutional mosaic variants can contribute to the aetiology of HBOC. In constitutional mosaicism, individuals have at least two genotypically distinct populations of cells that arise from an early post-zygote event. The mutational event occurs early enough in development to affect several tissues. It is detected in germinal genetic studies as low variant allele frequency (VAF) variants (<30%) that are generally overlooked during the prioritization process. Constitutional mosaic variants can affect both somatic and germinal cells, and thus can be passed to the offspring and have important consequences for genetic counselling. In this work, we report the c.9648+1G>A mosaic variant in the BRCA2 gene and propose a diagnostic algorithm to deal with potential mosaic findings identified by Next Generation Sequencing (NGS).

Genetically engineered mouse models for hereditary cancer syndromes.

Advances in molecular diagnostics have led to improved diagnosis and molecular understanding of hereditary cancers in the clinic. Improving the management, treatment, and potential prevention of cancers in carriers of predisposing mutations requires preclinical experimental models that reflect the key pathogenic features of the specific syndrome associated with the mutations. Numerous genetically engineered mouse (GEM) models of hereditary cancer have been developed. In this review, we describe the models of Lynch syndrome and hereditary breast and ovarian cancer syndrome, the two most common hereditary cancer predisposition syndromes. We focus on Lynch syndrome models as illustrative of the potential for using mouse models to devise improved approaches to prevention of cancer in a high-risk population. GEM models are an invaluable tool for hereditary cancer models. Here, we review GEM models for some hereditary cancers and their potential use in cancer prevention studies.

Exposure to Di-(2-Ethylhexyl) phthalate drives ovarian dysfunction by inducing granulosa cell pyroptosis via the SLC39A5/NF-κB/NLRP3 axis

Endocrine-disrupting chemicals (EDCs) have been reported to affect populations by disrupting the human endocrine system. Di-(2-ethylhexyl) phthalate (DEHP) is an EDC that is present in various consumer products. Exposure to DEHP could contribute to reproductive system dysfunction, with subsequent adverse female reproductive outcomes. Granulosa cells (GCs) play essential roles in ovarian function and fertility. To further reveal the underlying mechanism by which DEHP impairs female fertility and affects the normal function of GCs, in vivo and in vitro experiments were performed. Transcript sequencing was used to identify genes that were differentially expressed in GCs after DEHP treatment. SLC39A5 was shown to be overexpressed in the DEHP group compared to the normal control group. DEHP treatment and overexpression of SLC39A5 activated NF-κB-related factors, followed by an increase in the transcript expression level of NLRP3. NLRP3 inflammasomes play crucial roles in pyroptosis by acting as sensors. Pyroptosis is a type of inflammation-related cell death associated with various diseases, including ovarian cancer and polycystic ovary syndrome. Activation of NF-κB contributed to the upregulation of pyroptosis in GCs, while pyroptosis factors were downregulated after the inhibition of NF-κB with JSH-23. The same phenomenon was also observed in a mouse model in which DEHP-treated mice had higher expression levels of NF-κB and pyroptosis markers in GCs. Moreover, this phenomenon could be partially reversed by the NF-κB inhibitor JSH-23. DEHP treatment also disrupted the normal expression of ovarian function-related genes and inhibited the proliferation of GCs. Reproductive system impairment was observed in mice exposed to DEHP. DEHP-treated mice had a lower body weight, smaller reproductive organs, fewer healthy follicles, and diminished ovarian reserve. Thus, DEHP contributes to ovarian dysfunction by inducing pyroptosis via the SLC39A5/NF-κB/NLRP3 axis in GCs.

22MO Homologous recombination gene mutations in uterine serous cancer: A phenotype of the hereditary breast and ovarian cancer syndrome?

To determine the prevalence of somatic homologous recombination (HR) gene mutations in uterine serous cancer (USC) and compare these with rates among high-grade serous ovarian cancer (HGSOC). The American Association for Cancer Research’s (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database version 12.0 was queried via cBioPortal (http://genie.cbioportal.org). This is a publicly available, multi-institutional database of next-generation sequencing genomic profiles of tumor samples. Mutation frequencies for 8 homologous recombination deficiency (HRD) genes are reported and compared between uterine serous cancer (USC) and high-grade serous ovarian cancer (HGSOC) samples using chi-squared or Fisher's exact tests. The threshold used for statistical significance was a two-sided alpha of 0.05. Table: 22MOComparison of mutation frequencies of HR genes between tumor samples from uterine serous cancer and high-grade serous ovarian cancerMutation frequency among USCMutation frequency among HGSOCP-valueBRCA112/776, 1.5%313/3125, 10.0%p<0.001BRCA240/776, 5.2%218/3125, 7.0%p<0.001BRIP14/752, 0.5%57/2974, 1.9%p<0.01CHEK26/768, 0.8%19/3040, 0.6%0.82BARD112/664, 1.8%55/2615, 2.1%0.74RAD51C3/671, 0.4%27/2663, 1.0%0.25RAD51D4/671, 0.6%24/2658, 0.9%0.59PALB212/766, 1.6%37/3045, 1.2%0.58 Open table in a new tab Among 844 USC samples, the most prevalent somatic HR gene mutations were BRCA2 (5.2%), BARD1 (1.8%), PALB2 (1.6%) and BRCA1 (1.5%). When compared to 3304 HGSOC samples, higher HR gene mutation frequencies among HGSOC were only found for BRCA1 (10.0% vs 1.5%, p<0.001), BRCA2 (7.0% vs 5.2%, p<0.001) and BRIP1 (1.9% vs 0.5%, p<0.01); however, there was no difference between HGSOC and USC samples in mutation frequencies of BARD1, CHEK2, RAD51C, RAD51D or PALB2. Genomic profiling of USC tumor samples demonstrates a substantial rate of somatic gene mutations conferring HR deficiency, with rates for most HR gene mutations similar to those found among HGSOC samples. This demonstrates the need for genetically targeted clinical trials of poly-ADP ribose polymerase (PARP) inhibitors in patients with USC, and further research into the germline genetic profile of these patients to establish if this rare uterine cancer could be a phenotype of the hereditary breast and ovarian cancer syndrome.

Identification of Germline Variants in Patients with Hereditary Cancer Syndromes in Northeast Mexico.

Hereditary cancer syndromes (HCS) are genetic diseases with an increased risk of developing cancer. This research describes the implementation of a cancer prevention model, genetic counseling, and germline variants testing in an oncologic center in Mexico. A total of 315 patients received genetic counseling, genetic testing was offered, and 205 individuals were tested for HCS. In 6 years, 131 (63.90%) probands and 74 (36.09%) relatives were tested. Among the probands, we found that 85 (63.9%) had at least one germline variant. We identified founder mutations in BRCA1 and a novel variant in APC that led to the creation of an in-house detection process for the whole family. The most frequent syndrome was hereditary breast and ovarian cancer syndrome (HBOC) (41 cases with BRCA1 germline variants in most of the cases), followed by eight cases of hereditary non-polyposic cancer syndrome (HNPCC or Lynch syndrome) (with MLH1 as the primarily responsible gene), and other high cancer risk syndromes. Genetic counseling in HCS is still a global challenge. Multigene panels are an essential tool to detect the variants frequency. Our program has a high detection rate of probands with HCS and pathogenic variants (40%), compared with other reports that detect 10% in other populations.

Predicting Openness of Communication in Families With Hereditary Breast and Ovarian Cancer Syndrome: Natural Language Processing Analysis.

In health care research, patient-reported opinions are a critical element of personalized medicine and contribute to optimal health care delivery. The importance of integrating natural language processing (NLP) methods to extract patient-reported opinions has been gradually acknowledged over the past years. One form of NLP is sentiment analysis, which extracts and analyses information by detecting feelings (thoughts, emotions, attitudes, etc) behind words. Sentiment analysis has become particularly popular following the rise of digital interactions. However, NLP and sentiment analysis in the context of intrafamilial communication for genetic cancer risk is still unexplored. Due to privacy laws, intrafamilial communication is the main avenue to inform at-risk relatives about the pathogenic variant and the possibility of increased cancer risk. The study examined the role of sentiment in predicting openness of intrafamilial communication about genetic cancer risk associated with hereditary breast and ovarian cancer (HBOC) syndrome. We used narratives derived from 53 in-depth interviews with individuals from families that harbor pathogenic variants associated with HBOC: first, to quantify openness of communication about cancer risk, and second, to examine the role of sentiment in predicting openness of communication. The interviews were conducted between 2019 and 2021 in Switzerland and South Korea using the same interview guide. We used NLP to extract and quantify textual features to construct a handcrafted lexicon about interpersonal communication of genetic testing results and cancer risk associated with HBOC. Moreover, we examined the role of sentiment in predicting openness of communication using a stepwise linear regression model. To test model accuracy, we used a split-validation set. We measured the performance of the training and testing model using area under the curve, sensitivity, specificity, and root mean square error. Higher "openness of communication" scores were associated with higher overall net sentiment score of the narrative, higher fear, being single, having nonacademic education, and higher informational support within the family. Our results demonstrate that NLP was highly effective in analyzing unstructured texts from individuals of different cultural and linguistic backgrounds and could also reliably predict a measure of "openness of communication" (area under the curve=0.72) in the context of genetic cancer risk associated with HBOC. Our study showed that NLP can facilitate assessment of openness of communication in individuals carrying a pathogenic variant associated with HBOC. Findings provided promising evidence that various features from narratives such as sentiment and fear are important predictors of interpersonal communication and self-disclosure in this context. Our approach is promising and can be expanded in the field of personalized medicine and technology-mediated communication.

Occurrence of variants of unknown clinical significance in genetic testing for hereditary breast and ovarian cancer syndrome and Lynch syndrome: a literature review and analytical observational retrospective cohort study

Background and purposeOver the last decade, the implementation of multigene panels for hereditary tumor syndrome has increased at our institution (Inselspital, University Hospital Berne, Switzerland). The aim of this study was to determine the prevalence of variants of unknown significance (VUS) in patients with suspected Lynch syndrome and suspected hereditary breast and ovarian cancer syndrome, the latter in connection with the trend toward ordering larger gene panels.ResultsRetrospectively collected data from 1057 patients at our institution showed at least one VUS in 126 different cases (11.9%). In patients undergoing genetic testing for BRCA1/2, the prevalence of VUS was 6%. When < 10 additional genes were tested in addition to BRCA1/2, the prevalence increased to 13.8%, and 31.8% for > 10 additional genes, respectively. The gene most frequently affected with a VUS was ATM. 6% of our patients who were tested for Lynch syndrome had a VUS result in either MLH1, MSH2 or MSH6.ConclusionsOur data demonstrate that panel testing statistically significantly increases VUS rates due to variants in non-BRCA genes. Good genetic counseling before and after obtaining results is therefore particularly important when conducting multigene panels to minimize patient uncertainty due to VUS results.

P443: Genetic screening of a reportedly healthy population for familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome

P443: Genetic screening of a reportedly healthy population for familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome

Abstract P017: Early detection of ovarian cancer in high-risk individuals using circulating miRNAs: The MiDe study

Abstract Background: Epithelial ovarian cancers generally carry a poor prognosis due to late-stage presentation and a high rate of disease recurrence. In contrast, diagnosis of early-stage disease is associated with a high rate of durable remission. Prior studies using archival samples have suggested that a neural network analysis of circulating miRNA expression levels may be an informative biomarker for early-stage ovarian cancer diagnosis. Methods: The miRNA Detection Study (MiDe Study) is a prospective, observational clinical trial open to individuals in all 50 U.S. states. Persons with at least one ovary classified as being at high-risk for ovarian cancer, either due to known genetic predisposition or family history suggestive of possible hereditary breast and ovarian cancer syndrome or Lynch syndrome, are eligible to enroll. Study subjects will submit a blood sample every 6 months for up to 5 years. Neural network analysis of serum miRNA profiles will be correlated with the subsequent diagnosis of ovarian cancer or serous tubal intraepithelial carcinoma, either clinically or at the time of risk-reducing salpingectomy or salpingo-oophorectomy. The primary outcomes are the sensitivity and specificity of the neural network for anticipating a diagnosis of epithelial ovarian cancer or a cancer precursor within 2 years of the index blood sample. The goal recruitment is 1000 study subjects. Based on a presumed cancer incidence of 0.5-1% per year among this population, approximately 25 incident cancers or precursors are expected to be diagnosed over the timespan of the study. Results: Enrollment began in September 2019. As of August 1, 2022, 372 subjects had consented to the study. Among study subjects, 270/372 (72.5%) carry a known mutation in BRCA1/2, 63/372 (16.9%) carry a known mutation in a different high-risk gene (e.g., PALB2, BRIP1), and 39/372 (10.5%) are considered high-risk due to a mutation in a gene potentially related to ovarian cancer (e.g., ATM, CHEK2) or based on family history alone. To date, 215 (57.8%) participants have contributed at least one sample, among whom 90/215 (41.9%) of subjects have contributed multiple blood samples. Among the study subjects who have given a sample, 2/215 (0.9%) have been later diagnosed with ovarian cancer. Conclusions: The MiDe Study seeks to establish the feasibility of a circulating miRNA-based test for early diagnosis of epithelial ovarian cancer among high-risk individuals. The results of this study will clarify the performance of the neural network test among a high-risk population and inform subsequent interventional trials. Citation Format: Kevin M. Elias, Dipanjan Chowdhury, Judy Garber, Ryan C. Buehler. Early detection of ovarian cancer in high-risk individuals using circulating miRNAs: The MiDe study. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P017.

Abstract P027: Interest and uptake rates for cancer risk genetic testing in the AHEAD early detection program

Abstract Genetic testing for hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome have both been defined as Tier 1 genomic applications for their significant potential for positive impact on public health, as early cancer interception could greatly reduce mortality among the millions of people at increased risk. However, the integration of this genetic screening into standard-of-care workflows has proven to be challenging due to factors such as clinical resources, patient access, cost and insurance, or patient education and perceptions. More recently, alternative care-delivery models such as tele genetics or “mainstreaming” genetic testing have been popularized as a route to providing more access and less burden that the traditional referral-based pre-test counseling model. This study analyzed the uptake of recommended genetic testing for hereditary cancer from the Adventist Health Early All-Around Detection (AHEAD) program, which is a system-wide initiative aimed at expanding access to genetic screening for cancer risk. The purpose of this analysis is to understand associations between the uptake of genetic testing, and factors such as population demographics, socioeconomics, or care-delivery models, in order to inform and improve the implementation design of the AHEAD program and similar efforts, ultimately improving care and outcomes for the whole patient population. A retrospective data analysis was performed from January 2021 to July 2022 of individuals from 48 clinical locations across California, Oregon, and Hawaii, who went through the AHEAD screening program. A total of 4,922 out of 19,258 individuals met NCCN criteria for HBOP and Lynch syndrome. Of these “high-risk” individuals, 2,666 (54.2%) were interested in genetic testing and of those, 2,313 (86.8%) underwent testing. The analysis demonstrated that interest in genetic testing differed among patient age groups (243, 49.4% in Under 30; 426, 58% in 30-40; 597, 60% in 40-50; 574, 56.7% in 50-60; 501, 50% in 60-70 and 325, 47.6% in 70 and above) and clinic types (1549, 62.5% RHC vs. 663, 52.5% non-RHC). Of patients that were interested, those who went through a single-appointment, point-of-care testing (POCT) model were more likely to follow through with testing than a multiple-appointment, non-POCT model (odds ratio of 1.5, 95% confidence interval of 1.18 to 1.91). The study results showed that interest and uptake of genetic testing may be influenced by demographic or socioeconomic factors, as well as care-delivery models. The difference in testing follow through may indicate that POCT could be a more effective model for increasing genetic testing in certain populations. These results from the AHEAD program suggest that alternative care-delivery models such as telegenetics or "mainstreaming" can provide patients access to genetic screening. Future work should focus on understanding barriers and attitudes among different groups and designing targeted strategies for increasing genetic testing uptake across all groups. Citation Format: Candace Theal Westgate. Interest and uptake rates for cancer risk genetic testing in the AHEAD early detection program. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P027.

Emotions of patients with hereditary breast and ovarian cancer syndrome after risk reducing salpingo-oophorectomy

Emotions of patients with hereditary breast and ovarian cancer syndrome after risk reducing salpingo-oophorectomy

Diverse genetic spectrum among patients who met the criteria of hereditary breast, ovarian and pancreatic cancer syndrome.

Genetic high-risk assessment combines hereditary breast, ovarian and pancreatic cancer into one syndrome. However, there is a lack of data for comparing the germline mutational spectrum of the cancer predisposing genes between these three cancers. Patients who met the criteria of the hereditary breast, ovarian and pancreatic cancer were enrolled and received multi-gene sequencing. We enrolled 730 probands: 418 developed breast cancer, 185 had ovarian cancer, and 145 had pancreatic cancer. Out of the 18 patients who had two types of cancer, 16 had breast and ovarian cancer and 2 had breast and pancreatic cancer. A total of 167 (22.9%) patients had 170 mutations. Mutation frequency in breast, ovarian and pancreatic cancer was 22.3%, 33.5% and 17.2%, respectively. The mutation rate was significantly higher in patients with double cancers than those with a single cancer (p<0.001). BRCA1 and BRCA2 were the most dominant genes associated with hereditary breast and ovarian cancer, whereas ATM was the most prevalent gene related to hereditary pancreatic cancer. Genes of hereditary colon cancer such as lynch syndrome were presented in a part of patients with pancreatic or ovarian cancer but seldom in those with breast cancer. Families with a history of both ovarian and breast cancer were associated with a higher mutation rate than those with other histories. The mutation spectrum varies across the three cancer types and family histories. Our analysis provides guidance for physicians, counsellors, and counselees on the offer and uptake of genetic counseling.

Development of a comprehensive approach to adult hereditary cancer testing in Ontario

BackgroundGenetic testing for hereditary cancer susceptibility has advanced over time due to the discovery of new risk genes, improved technology and decreased cost. In the province of Ontario, testing eligibility...

Cancer prevention in cancer predisposition syndromes: A protocol for testing the feasibility of building a hereditary cancer research registry and nurse navigator follow up model.

Monogenic, high penetrance syndromes, conferring an increased risk of malignancies in multiple organs, are important contributors to the hereditary burden of cancer. Early detection and risk reduction strategies in patients with a cancer predisposition syndrome can save their lives. However, despite evidence supporting the benefits of early detection and risk reduction strategies, most Canadian jurisdictions have not implemented programmatic follow up of these patients. In our study site in the province of Newfoundland and Labrador (NL), Canada, there is no centralized, provincial registry of high-risk individuals. There is no continuity or coordination of care providing cancer genetics expertise and no process to ensure that patients are referred to the appropriate specialists or risk management interventions. This paper describes a study protocol to test the feasibility of obtaining and analyzing patient risk management data, specifically patients affected by hereditary breast ovarian cancer syndrome (HBOC; BRCA 1 and BRCA 2 genes) and Lynch syndrome (LS; MLH1, MSH2, MSH6, and PMS2 genes). Through a retrospective cohort study, we will describe these patients' adherence to risk management guidelines and test its relationship to health outcomes, including cancer incidence and stage. Through a qualitative interviews, we will determine the priorities and preferences of patients with any inherited cancer mutation for a follow up navigation model of risk management. Study data will inform a subsequent funding application focused on creating and evaluating a research registry and follow up nurse navigation model. It is not currently known what proportion of cancer mutation carriers are receiving care according to guidelines. Data collected in this study will provide clinical uptake and health outcome information so gaps in care can be identified. Data will also provide patient preference information to inform ongoing and planned research with cancer mutation carriers.

The neglected role of preimplantation genetic testing for Lynch syndrome

Preimplantation genetic testing for monogenic/single-gene disorders (PGT-M) is a procedure employed in the field of assisted reproductive technology to avoid the transmission of genetic diseases to the offspring. Hereditary cancer syndromes represent a diffuse and accepted indication for PGT-M, but take-up differs among the different disorders. Its use is markedly lower for the genes causing Lynch syndrome compared with the breast cancer type 1 or 2 susceptibility genes (BRCA1/2), despite the similar prevalence and severity of the two conditions. Reasons to explain this difference have not been explored. First, Lynch syndrome may be more frequently undiagnosed compared with hereditary breast and ovarian cancer syndrome. In addition, the different take-up may be due to different patient perceptions of the conditions and of the management options. Finally, this distinct attitude may depend on the awareness and sensibility of the professionals caring for affected patients. The authors’ considerations are, however, speculative, and specific studies aimed at disentangling the causes of the different receptions of PGT-M are warranted to understand how to tackle this gap. In the meantime, we believe that empowerment regarding PGT-M of all individuals with hereditary cancer syndromes, including Lynch syndrome, is ethically due, and plead for a more active involvement of caregivers.

Metastatic colorectal cancer as the primary phenotype in a hereditary breast and ovarian cancer patient with Germline BRCA1 mutation: a case report

Hereditary breast and ovarian cancer (HBOC) syndrome has increased predisposition to breast and/or ovarian cancer, and 24% of families with HBOC were associated with the germline pathogenic variants in BRCA1/2. Timely diagnosis and identification of mutation carriers is of utmost importance to improve survival benefit and quality of life. Cancers that have been included into screening of BRCA1/2 associated HBOC included prostate and pancreatic cancers etc. In this case, we reported a patient who firstly presented symptoms of CRC and was finally diagnosed as BRCA1 associated HBOC with advanced peritoneal carcinoma. With strategies of cetuximab based treatment and olaparib, and debulking surgeries, she has achieved an overall survival (OS) > 35 months. The aim was to indicate that HBOC might also first present as CRC, and comprehensive next-generation sequencing analysis might be a key complement for screening and diagnose of HBOC.

EE217 Population Genomic Screening for Tier 1 Genomic Applications: A Cost-Effectiveness Analysis

To assess the impact and cost-effectiveness of offering population genomic screening to all young adults in Australia to detect heterozygous familial hypercholesterolemia (FH), hereditarian breast and ovarian cancer and Lynch Syndrome.

BRCAShare-Assessment of an animated digital message for intrafamilial communication of pathogenic variant positive test results: A feasibility study.

While genetic testing for hereditary breast and ovarian cancer syndrome (HBOC) is well-established in the field of medicine, family members' uptake of cascade genetic testing for known familial pathogenic variants remains low. Probands often become responsible for initiating familial communication about their testing results, and barriers to communication may include difficulty in conveying information to relatives and a lack of communication resources for probands' use. In this study, we tested a two-minute animated digital message (ADM) intervention guided by the Health Belief Model (HBM) in an unselected sample to determine hypothetical individual perceptions of susceptibility and severity and behavioral intention to act on the information provided in the ADM. We recruited genetic testing naïve adults from the United States with no personal history of cancer through Amazon Mechanical Turk to participate in this study. Participants were presented a hypothetical scenario describing a relative's recent HBOC diagnosis, viewed the ADM, and answered a questionnaire assessing participants' perception of the HBM constructs in relation to the hypothetical scenario and participants' intentions to pursue cascade genetic testing, talk to a healthcare professional, or talk to family members after ADM viewing. Participants (n=373) largely perceived HBOC as serious and believed that they could benefit from the information provided by genetic testing; 76% hypothetically intended to pursue genetic testing at a cost of $100 or less, and 90% intended to either pursue testing or talk to a healthcare provider or family members. This feasibility study in an unaffected population could mimic the experience of distant/less-engaged relatives in HBOC families after receiving unexpected information about cascade genetic testing. Most participants demonstrated behavioral intention toward cascade testing, at a rate higher than literature would suggest is typical in high-risk families, indicating that a theory-supported, simple to use intervention may be useful in clinical practice.

Overview of familial syndromes with increased skin malignancies.

The vast majority of skin cancers can be classified into two main types: melanoma and keratinocyte carcinomas. The most common keratinocyte carcinomas include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Multiple familial syndromes have been identified that can increase the risk of developing SCC, BCC, and/or melanoma. The major syndromes include oculocutaneous albinism for SCC, basal cell nevus syndrome for BCC, familial atypical multiple mole-melanoma syndrome, and hereditary breast and ovarian cancer syndrome for melanoma. In addition, familial syndromes that can predispose individuals to all three major skin cancers include xeroderma pigmentosum and Li-Fraumeni syndrome. This review highlights the epidemiology, risk factors, pathogenesis, and etiology of the major and minor syndromes to better identify and manage these conditions. Current investigational trials in genomic medicine are making their way in revolutionizing the clinical diagnosis of these familial syndromes for earlier preventative measures and improvement of long-term prognosis in these patients.

Relatives from Hereditary Breast and Ovarian Cancer and Lynch Syndrome Families Forgoing Genetic Testing: Findings from the Swiss CASCADE Cohort.

Cascade genetic testing of relatives from families with pathogenic variants associated with hereditary breast and ovarian cancer (HBOC) or Lynch syndrome (LS) has important implications for cancer prevention. We compared the characteristics of relatives from HBOC or LS families who did not have genetic testing (GT (−) group) with those who had genetic testing (GT (+) group), regardless of the outcome. Self-administered surveys collected cross-sectional data between September 2017 and December 2021 from relatives participating in the CASCADE cohort. We used multivariable logistic regression with LASSO variable selection. Among n = 115 relatives who completed the baseline survey, 38% (n = 44) were in the GT (−) group. Being male (OR: 2.79, 95% CI: 1.10–7.10) and without a previous cancer diagnosis (OR: 4.47, 95% CI: 1.03–19.42) increased the odds of being untested by almost three times. Individuals from families with fewer tested relatives had 29% higher odds of being untested (OR: 0.71, 95% CI: 0.55–0.92). Reasons for forgoing cascade testing were: lack of provider recommendation, lack of time and interest in testing, being afraid of discrimination, and high out-of-pocket costs. Multilevel interventions designed to increase awareness about clinical implications of HBOC and LS in males, referrals from non-specialists, and support for testing multiple family members could improve the uptake of cascade testing.