Familial Cancer Risk Research Articles

Proactive familial cancer risk assessment: a service development study in UK primary care.

Family history assessment can identify individuals above population-risk for cancer to enable targeted Screening, Prevention, and Early Detection (SPED). Family History Questionnaire Service (FHQS) is a resource-efficient patient-facing online tool to facilitate this. In the UK, cancer risk assessment is usually only offered to concerned individuals proactively self-presenting to their GP, leading to inequity in accessing SPED in the community. To improve access to community cancer genetic risk assessment and explore barriers to uptake. Service development project of a digital pathway using the FHQS for cancer risk assessment across four general practices within the clinical remit of the South West Thames Centre for Genomics (SWTCG). 3100 individuals aged 38-50 years were invited to complete the FHQS through either text message or email. A random selection of 100 non-responders were contacted to determine barriers to uptake. In total, n = 304/3100 (10%) registered for the FHQS. Responders were more likely to be British (63% vs 47%, P<0.001), speak English as their main language (92% vs 76%, P<0.001), and not require an interpreter (99.6% vs 94.9%, P = 0.001). Of 304 responders, 158 (52%) were automatically identified as at population-risk without full family history review. Of the remaining 146 responders, 52 (36%) required either additional screening referral (n = 23), genetics referral (n = 15), and/or advice to relatives (n = 18). Of 100 non-responders contacted, eight had incorrect contact details and 53 were contactable. Reasons for not responding included not receiving invitation details (n = 26), losing the invitation (n = 5), or forgetting (n = 4). The FHQS can be used as part of a low-resource primary care pathway to identify individuals in the community above population-risk for cancer requiring action. This study highlighted barriers to uptake requiring consideration to maximise impact and minimise inequity.

IKNOWgynetics - A web-based learning concept to empower primary care gynecologists to participate in the care of patients with a family history of breast and ovarian cancer.

Familial cancer burden and genetics play an increasingly important role in the early detection and prevention of gynecological cancers. However, people with hereditary cancer risks are often identified late when they already have cancer. We aimed at developing and evaluating a training concept for primary care gynecologists-iKNOWgynetics-to improve their knowledge and awareness of genetic cancer syndromes and their ability to identify patients with increased familial cancer risks based on up-to-date evidence and current guidelines (in Germany, primary care includes all doctors treating patients on an outpatient basis without a clear separation of the expertise of the doctor or of their specialty). Starting off with a needs assessment among primary care gynecologists, we developed and evaluated an online training concept-using a web-based learning platform in combination with a live virtual seminar-to convey practice-relevant knowledge about familial cancer. After registration, participants get access to the web-based learning platform (www.iknowgynetics.de) to prepare for the virtual seminars and to use it as online reference to re-access the contents after the training. Evaluation included multiple-choice (MC) questions on knowledge and participants' self-efficacy to implement the acquired knowledge, which were administered in a pre-post design. Of 109 participants, 103 (94.5%) filled out pre- and post-questionnaires. Eighty-five participants were gynecologists in primary care from Berlin (81.2%) and Brandenburg (18.8%) and had an average of 24.1 years (SD = 8.5 years) of professional experience. After the training, participants answered significantly more knowledge questions correctly (M = 15.2 of 17, SD = 1.3) than before (M = 13.8 of 17, SD = 1.7) (p < 0.01) and felt more confident to be able to apply referral criteria for specialized counseling in practice (p < 0.001). The online-based training iKNOWgynetics considers the busy schedule of primary care gynecologists and supports them in acquiring practice-relevant information on familial cancer risks and on how to identify healthy persons at risk, which may ultimately help to improve the prevention of gynecological cancers. In future studies, the reported concept could be transferred to other entities.

Family history and breast cancer risk for Asian women: a systematic review and meta-analysis

BackgroundStudies of women of European ancestry have shown that the average familial relative risk for first-degree relatives of women with breast cancer is approximately twofold, but little is known for Asian women. We aimed to provide evidence for the association between family history and breast cancer risk for Asian women by systematically reviewing published literature.MethodsStudies reporting the familial relative risk of breast cancer for Asian women were searched in three online databases and complemented by a manual search. Odds ratios (ORs) for the association between family history and breast cancer risk were pooled across all included studies and by subgroups in terms of the type of family history, age, menopausal status and geographical region.ResultsThe pooled OR for women who have a first-degree relative with breast cancer was 2.46 (95% confidence interval [CI]: 2.03, 2.97). There was no evidence that the familial risk differed by the type of affected relative (mother versus sisters), the woman’s age (< 50 years versus ≥ 50 years), menopausal status (pre versus post) and geographical region (East and Southeast Asia versus other regions) (all P > 0.3). The pooled ORs for women of Asian ancestry with a family history in any relative were similar for those living in non-Asian countries (2.26, 95% CI: 1.42, 3.59) compared with those living in Asian countries (2.18, 95% CI: 1.85, 2.58).ConclusionsFamily history of breast cancer is associated with an approximately twofold relative risk of breast cancer for Asian women, which is of similar magnitude to that observed for women of European ancestry. This implies that similar familial factors are implicated in breast cancer risk between women of European and Asian ancestries. Genetic factors are likely to play a substantial role in explaining the breast cancer familial risk for Asian women, as similar risks were observed across different living environments and cultures.

Detection of germline variants with pathogenic potential in 48 patients with familial colorectal cancer by using whole exome sequencing

BackgroundHereditary genetic mutations causing predisposition to colorectal cancer are accountable for approximately 30% of all colorectal cancer cases. However, only a small fraction of these are high penetrant mutations occurring in DNA mismatch repair genes, causing one of several types of familial colorectal cancer (CRC) syndromes. Most of the mutations are low-penetrant variants, contributing to an increased risk of familial colorectal cancer, and they are often found in additional genes and pathways not previously associated with CRC. The aim of this study was to identify such variants, both high-penetrant and low-penetrant ones.MethodsWe performed whole exome sequencing on constitutional DNA extracted from blood of 48 patients suspected of familial colorectal cancer and used multiple in silico prediction tools and available literature-based evidence to detect and investigate genetic variants.ResultsWe identified several causative and some potentially causative germline variants in genes known for their association with colorectal cancer. In addition, we identified several variants in genes not typically included in relevant gene panels for colorectal cancer, including CFTR, PABPC1 and TYRO3, which may be associated with an increased risk for cancer.ConclusionsIdentification of variants in additional genes that potentially can be associated with familial colorectal cancer indicates a larger genetic spectrum of this disease, not limited only to mismatch repair genes. Usage of multiple in silico tools based on different methods and combined through a consensus approach increases the sensitivity of predictions and narrows down a large list of variants to the ones that are most likely to be significant.

Homologous recombination pathway gene variants identified by tumor-only sequencing assays in lung carcinoma patients.

The homologous recombination (HR) repair pathway plays a key role in double-stranded DNA break repair, and germline HR pathway gene variants are associated with increased risk of several cancers, including breast and ovarian cancer. HR deficiency is also a therapeutically targetable phenotype. Somatic (tumour-only) sequencing was performed on 1,109 cases of lung tumors, and the pathological data were reviewed to filter for lung primary carcinomas. Cases were filtered for variants (disease-associated or of uncertain significance) in 14 HR pathway genes, including BRCA1, BRCA2, and ATM. The clinical, pathological and molecular data were reviewed. Sixty-one HR pathway gene variants in 56 patients with primary lung cancer were identified. Further filtering by variant allele fraction (VAF) of ≥30% identified 17 HR pathway gene variants in 17 patients. ATM gene variants were most the commonly identified (9/17), including two patients with c.7271T>G (p.V2424G), a variant in the germline that is associated with increased familial cancer risk. Four (4/17) patients had a family history of lung cancer, among which three patients had ATM gene variants suspected to be germline in origin. In three other patients with BRCA1/2 or PALB2 gene variants who had undergone germline testing, the variants were confirmed to be germline; lung cancer was the sentinel cancer in two of these patients with a BRCA1 or PALB2 variant. Genomic variants in the HR repair pathway identified in tumor-only sequencing and occurring at higher VAFs (i.e., ≥30%) may suggest a germline origin. Correlating with personal and family history, a subset of these variants is also suggested to be associated with familial cancer risks. Patient age, smoking history and driver mutation status are expected to be a poor screening tool in identifying these patients. Finally, the relative enrichment for ATM variants in our cohort suggests a possible association between ATM mutation and lung cancer risk.

Real life use of biomarkers of homologous recombination deficiency (HRD) status beyond BRCA to predict the effectiveness of PARP inhibitors in ovarian cancer patients.

10592 Background: Testing for BRCA mutations (BRCAm) and genomic instability can identify epithelial ovarian cancer (OC) patients most likely to benefit from PARP-inhibitors (PARPi). However, current biomarkers of non- BRCA Homologous Recombination Repair (HRR) mutations are insufficient for guiding use of PARPi in the clinic. Despite non- BRCA HRR pathway gene mutations are rare, these patients may benefit from PARPi. Furthermore, recent preclinical findings showed that sensitivity to PARPi could be associated also with mutations in mismatch repair (MMR) genes, although sensitivity in the clinic is not proven. Methods: We report our real-life experience to assess the HRD status beyond BRCAm in newly-diagnosed OC patients, with the use of HRR gene panel and HRD genomic instability tests. After primary diagnosis, tumor and germline BRCA (g BRCA) status were assessed and, if BRCA WT, tumor HRR deficiency status were centrally determined by myChoiceCDx (Myriad) assay. NGS panel evaluating 20 MMR and HRR-genes beyond BRCA1/2 was proposed to patients with significant personal and/or family history of cancer, resulted negative to g BRCA testing. Results: From January 2017 to January 2023, 540 unselected epithelial OC patients, aging 27 to 81, were tested for tumor and g BRCA status; 109 were carriers of germline pathogenic or likely pathogenic variants (PVs) in BRCA1/2 genes (20.2%): 72 in BRCA1 (66.1%) and 37 in BRCA2 gene (33.9%). Additional 19 patients showed somatic PVs confined to tumor samples (3.5%).In the population of 70 BRCA WT patients tested by multigene panel testing, 14 germline PVs in HRR-associated (7.1%) or MMR-associated genes (12.8%) were found, including 5 in MUTYH (35.7%), 2 in ATM (14.3%), 2 in MLH1 (14.3%), 2 in PMS2 (14.3%), 1 in RAD51C (7.14%), 1 in RAD51D (7.14%), and 1 in CHEK2 gene (7.14%).Out of 72 samples analyzed by HRD genomic instability test, 23 cases were identified as HRD positive (31.9%), with a median GIS score of 65.5 (44-83). Median GIS were 35 (1-72) in the 6 cases of non- BRCA mutated tumors (8.3%), 40 (4-82) in the 17 tumor with non- BRCA variant of uncertain significance (VUS) (23.6%), and 27 (2-83) in the WT samples. Median GIS were significantly higher in tumors with PVs/VUS of RAD51 than BRIP1 (55.5 vs 35). Conclusions: HRRm gene panel and HRD genomic instability tests are not interchangeable to study HRR deficiency beyond BRCAm. HRD genomic instability test is effective to identify patients most likely to gain benefit from PARPi, but not for predicting familial risk of cancer. In our population, NGS panel evaluating HRR genes, beyond BRCA1/2, improved the detection rate of HRRm by 7%, with additional finding of MMR germline mutations, and important clinical implications for family members. Prospective data are expected to evaluate the effectiveness of PARPi in these population.

Familial aggregation of esophageal cancer.

Familial aggregation of esophageal cancer.

PD18-02 DESCRIBING PATTERNS OF FAMILIAL CANCER RISK IN SUBFERTILE MEN USING POPULATION PEDIGREE DATA

You have accessJournal of UrologyCME1 Apr 2023PD18-02 DESCRIBING PATTERNS OF FAMILIAL CANCER RISK IN SUBFERTILE MEN USING POPULATION PEDIGREE DATA Joemy Ramsay, Joshua Horns, Benjamin Emery, Kenneth Aston, and James Hotaling Joemy RamsayJoemy Ramsay More articles by this author , Joshua HornsJoshua Horns More articles by this author , Benjamin EmeryBenjamin Emery More articles by this author , Kenneth AstonKenneth Aston More articles by this author , and James HotalingJames Hotaling More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003273.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Subfertile men and their relatives show increased risk for certain cancers including testis, pediatric leukemia/lymphoma, thyroid, and prostate. We assessed risk for multiple cancers simultaneously to identify distinct familial multicancer patterns (FMPs) in azoospermic and oligozoospermic men. METHODS: We identified azoospermic (N=809) and oligozoospermic (N=669) men in the Subfertility, Health and Assisted Reproduction (SHARE) cohort and their family members out to third-degree relatives (azoo: N=27,148; oligo: N=23,626). Cancer cases were identified using the Utah Cancer Registry, a population-based SEER registry with statewide cancer records from 1966. Families with ≥10 individuals who lived in Utah for ≥1 year 1966-2017 were included in the analysis (azoo: N=426 families, 21,361 individuals; oligo: N=360 families, 18,818 individuals). The famcluster R package was used to cluster families on familial standardized incidence ratios (FSIRs). FSIRs were calculated across 34 cancer types and a weighted Gower distance with k-mediods clustering (k=2:20) was used to identify FMPs. k was selected using silhouette plots and consensus clusters with 1,000 bootstrap replicates. FMPs were assessed separately for azoospermia and oligospermia families. RESULTS: 13 FMPs were identified in azoospermia families and 12 FMPs in oligozoospermia families. Distinct overall patterns of familial cancer were observed between azoospermia and oligozoospermia families (Table 1). 12 out of 13 FMPs (36% of families) showed significantly increased risk for ≥1 cancer in azoospermia families and 11 out of 12 FMPs (40% of the families) showed significantly increased cancer risk in oligozoospermia families (Figure 1). CONCLUSIONS: This analysis described FMPs for subfertile men, with 36-40% of families showing elevated risk for ≥1 cancer. FMPs were unique between azoospermia and oligozoospermia families, suggesting heterogeneity in familial cancer risk by both type of subfertility and within subfertility type. Source of Funding: GEMS: Genomic approach to connecting Elevated germline Mutation rates with male infertility and Somatic health NICHD: R01 HD106112 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e502 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joemy Ramsay More articles by this author Joshua Horns More articles by this author Benjamin Emery More articles by this author Kenneth Aston More articles by this author James Hotaling More articles by this author Expand All Advertisement PDF downloadLoading ...

Clinical case study meets population cohort: identification of a BRCA1 pathogenic founder variant in Orcadians

We multiply ascertained the BRCA1 pathogenic missense variant c.5207T > C; p.Val1736Ala (V1736A) in clinical investigation of breast and ovarian cancer families from Orkney in the Northern Isles of Scotland, UK. We sought to investigate the frequency and clinical relevance of this variant in those of Orcadian ancestry as an exemplar of the value of population cohorts in clinical care, especially in isolated populations. Oral history and birth, marriage and death registrations indicated genealogical linkage of the clinical cases to ancestors from the Isle of Westray, Orkney. Further clinical cases were identified through targeted testing for V1736A in women of Orcadian ancestry attending National Health Service (NHS) genetic clinics for breast and ovarian cancer family risk assessments. The variant segregates with female breast and ovarian cancer in clinically ascertained cases. Separately, exome sequence data from 2088 volunteer participants with three or more Orcadian grandparents, in the ORCADES research cohort, was interrogated to estimate the population prevalence of V1736A in Orcadians. The effects of the variant were assessed using Electronic Health Record (EHR) linkage. Twenty out of 2088 ORCADES research volunteers (~1%) carry V1736A, with a common haplotype around the variant. This allele frequency is ~480-fold higher than in UK Biobank participants. Cost-effectiveness of population screening for BRCA1 founder pathogenic variants has been demonstrated at a carrier frequency below the ~1% observed here. Thus we suggest that Orcadian women should be offered testing for the BRCA1 V1736A founder pathogenic variant, starting with those with known Westray ancestry.

Abstract P6-02-08: Identifying preferences that may motivate choice of ovarian cancer risk prevention strategies using a discrete choice experiment

Abstract Background: Women with a familial or hereditary risk for ovarian cancer are at a much greater risk of developing ovarian cancer compared with women in the general population. This high risk demands prevention strategies to reduce ovarian cancer incidence and mortality. Currently there is little information about how women with a hereditary risk for ovarian cancer make trade-offs when choosing among prevention strategies and their associated risks. In anticipation of the likelihood that when given more personalized risk estimates, patients may have different preferences based on their mutation specific cancer risk as well as demographic and clinical factors, it is critical that we have the necessary information to develop counseling models that are tailored to individual patients’ preferences for cancer risk reduction and tolerance of associated risks. Methods: We performed a discrete choice experiment to investigate how women at higher risk of ovarian cancer weigh benefits (e.g. reduced risk of ovarian) versus costs (e.g. increased risk of heart disease) in choosing a treatment strategy. N=396 pre-menopausal women with a personal history of breast cancer or familial history suggestive of increased breast and/or ovarian cancer risk were surveyed from August, 2019, to January, 2022. Participants were asked to choose between two sets of attributes that specified type of surgery (risk-reducing salpingo-oophorectomy [RRSO], risk reducing salpingectomy [RRS] vs. non-surgical surveillance), age of menopause (natural versus immediate), quality of menopausal symptoms (mild, moderate, severe), and risk of ovarian cancer, heart disease, or osteoporosis. Risks of disease varied in discrete intervals. We fit a Bradley-Terry logistic regression to estimate preferences. The binary response was the randomly generated choice set selected versus the set not selected. Results: Women were more likely to choose sets with either surveillance (odds ratio [OR]= 1.28, 95% confidence interval [CI] 0.98, 1.67) or RRSO (OR= 1.39, 95% CI 1.07, 1.81) over RSS. In weighing trade-offs in the choice sets that included type of surgery, women had a stronger independent preference for reducing the risk of ovarian cancer (OR= 0.66 of choosing set per 10% increase in risk, 95% CI 0.62, 0.71) than in reducing the risk of osteoporosis (OR= 0.82 per 10% increase, 95% CI 0.75, 0.90) or heart disease (OR = 0.82 per 10% increase, 95% CI 0.76,0.88). Women also had a strong preference for delaying the expected age of ovarian cancer (OR= 1.34 per 10-year increase in age, 95% CI 1.19, 1.51). Women had strong preferences for having a natural age of menopause (OR= 1.58 compared to immediate menopause post-treatment, 95% CI 1.27, 1.95), and better less severe symptoms (OR= 0.65 for each ordinal increase in the severity of symptoms, 95% CI 0.60, 0.70). Conclusions: Our results suggest that women may prefer either surveillance or the most extensive type of surgery (RRSO) over more limited surgery (RRS). In weighing trade-offs, reducing the risk of ovarian cancer seemed to be more important than reducing the risk of osteoporosis or heart disease. Still, having a natural age of menopause and reducing the severity of symptoms could motivate the choice of treatment. Our work will allow us to estimate thresholds of measured factors that may motivate women to choose a specific treatment strategy. Citation Format: Mary Daly, Brian Egleston, Kaitlyn Lew, Lisa Bealin, Alexander Husband, Jill Stopfe, Pawel Przybysz, Olga Tchuvatkina, Yu-Ning Wong, Judy Garber, Timothy Rebbeck. Identifying preferences that may motivate choice of ovarian cancer risk prevention strategies using a discrete choice experiment. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-08.

Long-term effects of premenopausal risk-reducing salpingo-oophorectomy on cognition in women with high familial risk of ovarian cancer: A cross-sectional study.

To examine the effect of a premenopausal risk-reducing salpingo-oophorectomy (RRSO) in women at increased risk of ovarian cancer on objective and subjective cognition at least 10 years after RRSO. A cross-sectional study with prospective follow-up, nested in a nationwide cohort. Multicentre in the Netherlands. 641 women (66% BRCA1/2 pathogenic variant carriers) who underwent either a premenopausal RRSO ≤ age 45 (n=436) or a postmenopausal RRSO ≥ age 54 (n=205). All participants were older than 55 years at recruitment. Participants completed an online cognitive test battery and a questionnaire on subjective cognition. We used multivariable regression analyses, adjusting for age, education, breast cancer, hormone replacement therapy, cardiovascular risk factors and depression. The influence of RRSO on objective and subjective cognition of women with a premenopausal RRSO compared with women with a postmenopausal RRSO. After adjustment, women with a premenopausal RRSO (mean time since RRSO 18.2 years) performed similarly on objective cognitive tests compared with women with a postmenopausal RRSO (mean time since RRSO 11.9 years). However, they more frequently reported problems with reasoning (odds ratio [OR] 1.8, 95% confidence interval [95% CI] 1.1-3.1) and multitasking (OR 1.9, 95% CI 1.1-3.4) than women with a postmenopausal RRSO. This difference between groups disappeared in an analysis restricted to women of comparable ages (60-70 years). Reassuringly, approximately 18 years after RRSO, we found no association between premenopausal RRSO and objective cognition.

Familial pancreatic cancer syndrome

In contrast to many other malignant entities the risk factors for pancreatic cancer are mostly unknown. Hereditary factors are causative in about 3-6% of all pancreatic cancers. In addition to hereditary tumor disposition syndromes and hereditary pancreatitis, the familial pancreatic cancer syndrome accounts for about 75% of all hereditary pancreatic cancers. Afamilial pancreatic cancer syndrome is present when at least two first-degree relatives in afamily have histologically proven pancreatic cancer and there are no criteria for another hereditary syndrome. An underlying uniform monogenetic gene defect in familial pancreatic cancer syndrome is currently unknown and agermline mutation in the BRCA2 gene is so far the most frequently identified genetic alteration. Patients at risk for familial pancreatic cancer should be offered participation in registry studies with associated early detection programs (e.g., the FaPaCa registry). These enable the detection of high-grade neoplasms and pancreatic cancer in the early stages, which appears to reduce mortality; however, the detected pancreatic lesions are often incorrectly diagnostically classified, and patients undergo complex pancreatic resection despite benign findings. Finally, studies have so far not been able to clearly clarify whether patients at risk benefit from an early detection program. According to current data, prophylactic operations are not indicated for familial pancreatic cancer syndrome and should only be performed if there is evidence of asuspicious finding that requires resection.

Prostate cancer prevention clinic for men with risk of familial prostate cancer (profam-risk)

Prostate cancer prevention clinic for men with risk of familial prostate cancer (profam-risk)

Your Family Connects: A Theory-Based Intervention to Encourage Communication about Possible Inherited Cancer Risk among Ovarian Cancer Survivors and Close Relatives

Introduction: Encouraging family communication about possible genetic risk has become among the most important avenues for achieving the full potential of genomic discovery for primary and secondary prevention. Yet, effective family-wide risk communication (i.e., conveying genetic risk status and its meaning for other family members) remains a critical gap in the field. We aim to describe the iterative process of developing a scalable population-based communication outreach intervention, Your Family Connects, to reach ovarian cancer survivors and close relatives to communicate the potential for inherited risk and to consider genetic counseling. Methods: Relational-level theories (e.g., interdependence theory) suggest that interventions to promote family cancer risk communication will be most effective if they consider the qualities of specific relationships and activate motives to preserve the relationship. Informed by these theories, we collaborated with 14 citizen scientists (survivors of ovarian cancer or relatives) and collected 261 surveys and 39 structured interviews over 12 weeks of citizen science activities in 2020. Results: The citizen science findings and consideration of relational-level theories informed the content and implementation of Your Family Connects (<ext-link ext-link-type="uri" xlink:href="http://www.yourfamilyconnects.org/" xmlns:xlink="http://www.w3.org/1999/xlink">www.yourfamilyconnects.org</ext-link>). CS results showed survivors favor personal contact with close relatives, but relatives were open to alternative contact methods, such as through health professionals. Recognizing the need for varied approaches based on relationship dynamics, we implemented a relative contact menu to enable survivors identify at-risk relatives and provide multiple contact options (i.e., survivor contact, health professional contact, and delayed contact). In line with relational autonomy principles, we included pros and cons for each option, assisting survivors in choosing suitable contact methods for each relative. Discussion: Our developed intervention represents a novel application of relational-level theories and partnership with citizen scientists to expand genetic services reach to increase the likelihood for fair distribution of cancer genomic advances. The Your Family Connects intervention as part of a randomized trial in collaboration with the Georgia Cancer Registry compared with standard outreach.

CO4 How Can the Long-Term Benefits and Harms of Screening Be Transparently Quantified and Contrasted for Informed Decision-Making? Colorectal Cancer Screening for Persons at Familial Risk (FARKOR)

Our aim was to systematically evaluate and compare the long-term benefit-harm balance of different screening strategies (colonoscopy or immunologic fecal blood testing (iFOBT) for individuals younger than age 50 with identified familial colorectal cancer (CRC) risk in Germany.

Sex-specific familial aggregation of cancers in Finland

Despite the fact that the effect of sex on the occurrence of cancers has been studied extensively, it remains unclear whether sex modifies familial aggregation of cancers. We explored sex-specific familial aggregation of cancers in a large population-based historical cohort study. We combined cancer and population registry data, inferring familial relationships from birth municipality-surname-sex (MNS) combinations. Our data consisted of 391,529 incident primary cancers in 377,210 individuals with 319,872 different MNS combinations. Cumulative sex-specific numbers of cancers were compared to expected cumulative incidence. Familial cancer risks were similar between the sexes in our population-wide analysis. Families with concordant cancer in both sexes exhibited similar sex-specific cancer risks. However, some families had exceptionally high sex-specific cumulative cancer incidence. We identified six families with exceptionally strong aggregation in males: three families with thyroid cancer (ratio between observed and expected incidence 184.6; 95% credible interval (95% CI) 33.1–1012.7, 173.4 (95% CI 65.4–374.3), and 161.4 (95% CI 29.6–785.7), one with stomach (ratio 14.4 (95% CI 6.9–37.2)), colon (ratio 15.5 (95% CI 5.7–56.3)) cancers and one with chronic lymphocytic leukaemia (ratio 33.5 (95% CI 17.2–207.6)). Our results imply that familial aggregation of cancers shows no sex-specific preference. However, the atypical sex-specific aggregation of stomach cancer, colon cancer, thyroid cancer and chronic lymphocytic leukaemia in certain families is difficult to fully explain with present knowledge of possible causes, and could yield useful knowledge if explored further.

Low-level constitutional mosaicism of BRCA1 in two women with young onset ovarian cancer

Germline pathogenic variants in BRCA1 and BRCA2 cause hereditary breast and ovarian cancer. The vast majority of these variants are inherited from a parent. De novo constitutional pathogenic variants are rare. Even fewer cases of constitutional mosaicism have been reported and these have mostly been described in women with breast cancer. Here we report low-level constitutional mosaicism identified by Next Generation Sequencing in two women with ovarian cancer. A BRCA1 c.5074G > A p.(Asp1692Asn) variant detected in the first female at 42 years, classed as likely pathogenic, was found in ~ 52% of reads in DNA extracted from tumour, ~ 10% of reads in DNA extracted from peripheral blood leukocytes and ~ 10% of reads in DNA extracted from buccal mucosa. The second BRCA1 c.2755_2758dupCCTG p.(Val920AlafsTer6) variant was detected in a female aged 53 years, classed as pathogenic, and was found in ~ 59% of reads in DNA extracted from tumour, ~ 14% of reads in DNA extracted from peripheral blood leukocytes and similarly in ~ 14% of reads in both DNA extracted from buccal mucosa and urine sample. Sanger sequencing confirmed the presence of these variants at a corresponding low level consistent with mosaicism that may not have been detected by this method alone. This report demonstrates the clinical benefit for two women of BRCA1/BRCA2 germline NGS testing at a depth that can detect low-level mosaicism. As well as informing appropriate treatments, tumour sequencing results may facilitate the detection and interpretation of low-level mosaic variants in the germline. Both results have implications for other cancer risks and for relatives when providing a family cancer risk assessment and reproductive risk. The implications for laboratory practice, clinical genetics management and genetic counselling for constitutional mosaicism of BRCA1/BRCA2 are discussed.

Experience with a nurse-driven genetic counseling pathway of Italian women with uninformative BRCA test result.

Several models of genetic counseling have been proposed to tackle the increasing volume of individuals requiring access to BRCA testing. Few data are available on patient experience and retention of information with nurse-driven genetic counseling. We evaluated the experience and retention of information in women with an uninformative BRCA test result and who were not considered at high risk due to their personal/family history of cancer who underwent geneticist-supervised nurse-driven genetic counseling and who received their test result by phone. Women who received an uninformative BRCA test result between May 2017 and September 2019 were administered a questionnaire exploring experience with genetic counseling and retention of information provided. Of 366 eligible women, 299 (273 breast cancer patients and 26 women without breast cancer) completed the interview. Overall, 280 women (93.6%) positively valued their experience with genetic counseling and 287 (96.0%) considered it helpful with 57.5% of them feeling reassured for themselves and their family. Information on the clinical implications of the test result was correctly retained and women acted accordingly. Overall, 252 women (87.8%) accurately reported their test result as normal/negative. Only 67 (22.4%) recognized that despite a normal BRCA test result, a low probability of a hereditary syndrome remains. Most women showed a poor ability to estimate cancer risk in BRCA mutation carriers and in the general population. Geneticist-supervised nurse-driven genetic counseling process for women with uninformative BRCA test result is associated with a positive patient experience and an adequate retention of information concerning the management of their personal and familial cancer risk. The design and implementation of nurse-driven genetic counseling models may contribute to efficient and timely access to BRCA genetic testing.

Long-Term Adaptation Among Adolescent and Young Adult Children to Familial Cancer Risk.

It is important to examine adolescent and young adult (AYA) children's long-term psychosocial and behavioral adaptation to disclosure of maternal BRCA-positive carrier status (BRCA+) to inform approaches for familial cancer risk communication, education, and counseling. Mothers underwent BRCA genetic testing 1 to 5 years earlier. Group differences in AYAs' self-reported outcomes were analyzed by maternal health and carrier status, and child age and sex. A total of N = 272 AYAs were enrolled: 76.1% of their mothers were breast or ovarian cancer survivors and 17.3% were BRCA+. AYAs' cancer risk behavior (tobacco and alcohol use, physical activity) and psychologic distress levels did not vary by maternal status. In bivariate analyses, AYAs of cancer-surviving mothers believed themselves to be at greater risk for, and were more knowledgeable about, cancer than AYAs of mothers without cancer. AYAs of BRCA+ mothers were more concerned about cancer, held stronger beliefs about genetic risk, and placed a higher value on learning about genetics. In adjusted models, maternal cancer history (not BRCA+) remained associated with AYAs' greater perceptions of cancer risk (P = .002), and knowledge about cancer (P = .03) and its causes (P = .002). Disclosing maternal BRCA+ status did not influence children's lifestyle behavior or adversely affect quality of life long term. AYAs of BRCA+ mothers were more aware of and interested in genetic risk information. Such families may benefit from support to promote open communication about genetic testing choices.

Topical issues of prevention of stomach cancer: A review

Prevention of gastric cancer, both primary and secondary, is an extremely important component of the management of gastroenterological patients. The correct collection of anamnesis with an assessment of the hereditary (family) cancer risk, the action of risk factors (eating disorders, habitual/chronic intoxication, obesity, Helicobacter pylori infection, etc.), as well as the use of gastroprotectors (in particular, the drug Regastim Gastro), especially in persons with potentially precancerous the condition is chronic atrophic gastritis. According to the data of a double-blind placebo-controlled randomized study Regastim Gastro (active ingredient alpha-glutamyl tryptophan) in the treatment of chronic atrophic gastritis, it was found that this drug has a powerful anti-inflammatory effect and regenerative activity. Taking the drug Regastim Gastro, compared with placebo, statistically significantly contributed to a decrease in the number of inflammatory infiltration cells per 1 mm2 of the gastric mucosa. Regastim Gastro decreases in eosinophilic (3 times) and neutrophilic (4 times) infiltration of the gastric mucosa and also reduced the number of macrophages, lymphocytes and plasmocytes. In addition to anti-inflammatory properties, the drug also had a pronounced regenerative effect. Taking of Regastim Gastro statistically significant (p=0.028) increases in the number of glands per 1 mm2 of the gastric mucosa by 26.1% compared with the initial screening indicators. In the group of patients taking placebo, on the contrary, there was a further progression of the pathological process, accompanied by a decrease in the number of glands per 1 mm2 of the gastric mucosa after the end of treatment in comparison with the initial indicators. After the course of therapy, the number of glands per 1 mm2 of the gastric mucosa in patients taking the drug Regastim Gastro was statistically significantly higher in comparison with the results in the placebo group (p=0.013). After the course of Regastim Gastro, there was an improvement in acid production: a shift in the acidic side of the average pH value (1.6 times) and an increase in the value of the acidity index, both when compared with the initial values (5.4 times) and in comparison with the placebo group (2.9 times). The intake of Regastim Gastro to patients with gastritis, both H. pylori (+) and H. pylori (-) before the development of atrophy of the gastric mucosa can reduce the inflammatory factor, prevent the occurrence of atrophy and may have maximum anti-carcinogenic action.