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Preconception and pregnancy represent a unique window of opportunity for women to engage with the health care system. This article explores the possibility of offering testing for cancer‐associated pathogenic variants on obstetrical carrier screening panels. [ABSTRACT FROM AUTHOR]

Hereditary cancer syndromes associated with gynecologic malignancies account for up to 18% of all cases of ovarian, uterine, and cervical cancers, and identification of these syndromes has implications for cancer screening and risk reduction techniques in affected patients. The associated cancer risks with moderate-penetrance genes are rapidly evolving and present variable risks for the provider counseling the patient. In this review, we detail the cancer risk and management of patients with germline PV in the moderate-risk hereditary cancer genes ATM , BRIP1 , RAD51C , RAD51D , and PALB2. [ABSTRACT FROM AUTHOR]

Hereditary cancer syndromes (HCS) are responsible for up to 10% of all cancers. At present, the majority of cancer susceptibility testing is initiated after a cancer diagnosis. There exists a significant opportunity for primary care providers including general obstetrician-gynecologists to engage in hereditary cancer risk assessment through adequate family history evaluation, initiation of genetic testing, and following the recommendations of national organizations. Identifying hereditary cancer genes may prompt primary prevention efforts such as enhanced screening, prevention, or personalized care strategies. We will review the literature regarding the approach and assessment of the most common gynecologic HCS. [ABSTRACT FROM AUTHOR]

PURPOSE: Patients with hereditary cancer syndromes (HCS) have a high lifetime risk of developing cancer. Historically underserved populations have lower rates of genetic evaluation. We sought to characterize demographic factors that are associated with undergoing HCS evaluation in an urban safety-net patient population. METHODS: All patients who met inclusion criteria for this study from 2016 to 2021 at an urban safety-net hospital were included in this analysis. Inclusion criteria were pathologically confirmed breast, ovarian/fallopian tube, colon, pancreatic, and prostate cancers. Patients also qualified for hereditary breast and ovarian cancers or Lynch syndrome on the basis of National Comprehensive Cancer Network guidelines. Institutional review board approval was obtained. Demographic and oncologic data were collected through retrospective chart review. Univariable and multivariable logistic regression models were constructed. RESULTS: Of the 637 patients included, 40% underwent genetic testing. Variables associated with receiving genetic testing on univariable analysis included patients living at the time of data collection, female sex, Latinx ethnicity, Spanish language, family history of cancer, and referral for genetic testing. Patients identifying as Black, having Medicare, having pancreatic or prostate cancer, having stage IV disease, having Eastern Cooperative Oncology Group (ECOG) prognostic score ≥1, having medium or high Charlson comorbidity index, with current or previous cigarette use, and with previous alcohol use were negatively associated with testing. On multivariable modeling, family history of cancer was positively associated with testing. Patients identifying as Black, having colon or prostate cancer, and having ECOG score of 2 had significantly lower association with genetic testing. CONCLUSION: Uptake of HCS was lower in patients identifying as Black, those with colon or prostate cancer, and those with an ECOG score of 2. Efforts to increase HCS testing in these patients will be important to advance equitable cancer care. [ABSTRACT FROM AUTHOR]

PURPOSE: Paired tumor-germline sequencing can identify somatic variants for targeted therapy and germline pathogenic variants (GPVs) causative of hereditary cancer/tumor predisposition syndromes. It is unknown how patients/families in pediatric oncology use information about an identified GPV. We assessed recall of germline results and actions taken on the basis of findings. METHODS: We completed phone surveys with patients (and/or their parent) with GPVs identified via a single academic medical center's paired tumor-germline sequencing study. Seven hundred forty pediatric (aged 0-25 years) oncology patients were enrolled in this sequencing study between May 2012 and August 2021. Ninety-six participants (13.0%) had at least one GPV identified and were therefore eligible for this survey. The parent/guardian (for patients younger than 18 years or deceased patients) or patients themselves (if 18 years or older) were contacted. Survey topics included germline result recall, experience with genetic counseling, changes to patient's cancer treatment/screening, sharing of results with family members, and lifestyle changes. RESULTS: Fifty-three surveys (response rate, 55.2%) were completed between October 2021 and June 2022. Thirty-seven (69.8%) respondents correctly recalled the identified GPV. Discussing results with a genetic counselor (P =.0001), having a GPV related to the cancer/tumor diagnosis (P =.002), and non-Hispanic White race/ethnicity (P =.02) were associated with accurate recall. Twenty-five respondents (47.2%) reported a change in the child's cancer treatment and/or screening recommendations, 17 respondents (32.1%) made a lifestyle change on the basis of the results, and 44 respondents (83.0%) shared results with at least one family member. CONCLUSION: While most respondents remembered that a GPV was identified in the patient, some did not recall having a GPV found, and others recalled germline findings incorrectly. Future work may determine patient/family preferences for timing/method of result return to optimize patient recall and use of germline results. Pediatric oncology family recall of germline findings varies by age of onset of hereditary cancer risk. [ABSTRACT FROM AUTHOR]

The article discusses a case of a patient with a rare genetic condition called familial paraganglioma and pheochromocytoma syndrome (familial PGL/PCC) who developed multiple cancers, including neuroblastoma, renal cancer, and gastrointestinal stromal tumor (GIST). The patient underwent various treatments and surgeries over the years, and genetic testing revealed a germline and mosaic SDHA mutation associated with the syndrome. The study highlights the importance of genetic testing for patients with GISTs and a history of cancer, as well as the need for further research on treatment options and screening recommendations for individuals with SDHA mutations. [Extracted from the article]

PURPOSE: Identification of those at risk of hereditary cancer syndromes using electronic health record (EHR) data sources is important for clinical care, quality improvement, and research. We describe diagnostic processes, previously seldom reported, for a common hereditary cancer syndrome, Lynch syndrome (LS), using EHR data within a community-based, multicenter, demographically diverse health system. METHODS: Within a retrospective cohort enrolled between 2015 and 2020 at Kaiser Permanente Northern California, we assessed electronic diagnostic domains for LS including (1) family history of LS-associated cancer; (2) personal history of LS-associated cancer; (3) LS screening via mismatch repair deficiency (MMRD) testing of newly diagnosed malignancy; (4) germline genetic test results; and (5) clinician-entered diagnostic codes for LS. We calculated proportions and overlap for each diagnostic domain descriptively. RESULTS: Among 5.8 million individuals, (1) 28,492 (0.49%) had a family history of LS-associated cancer of whom 3,635 (13%) underwent genetic testing; (2) 100,046 (1.7%) had a personal history of a LS-associated cancer; and (3) 8,711 (0.1%) were diagnosed with colorectal cancer of whom 7,533 (86%) underwent MMRD screening and of the positive screens (486), 130 (27%) underwent germline testing. One thousand seven hundred and fifty-seven (0.03%) were diagnosed with endometrial cancer of whom 1,613 (92%) underwent MMRD screening and of the 195 who screened positive, 55 (28%) underwent genetic testing. (4) 30,790 (0.05%) had LS germline genetic testing with 707 (0.01%) testing positive; and (5) 1,273 (0.02%) had a clinician-entered diagnosis of LS. CONCLUSION: It is feasible to electronically characterize the diagnostic processes of LS. No single data source comprehensively identifies all LS carriers. There is underutilization of LS genetic testing for those eligible and underdiagnosis of LS. Our work informs similar efforts in other settings for hereditary cancer syndromes. Our work demonstrates feasible methods for identifying people with genetic diseases using electronic health records. [ABSTRACT FROM AUTHOR]

Introduction Heterogenous clinical manifestations, overlapping phenotypes, and complex genetic backgrounds are common in patients with endocrine tumors. There are no comprehensive recommendations for genetic testing and counseling of these patients compared to other hereditary cancer syndromes. The application of multigene panel testing is common in clinical genetic laboratories, but their performance for patients with endocrine tumors has not been assessed. Methods As a national reference center, we prospectively tested the diagnostic utility and cost-efficiency of a multigene panel covering 113 genes representing genetic susceptibility for solid tumors; 1279 patients (including 96 cases with endocrine tumors) were evaluated between October 2021 and December 2022 who were suspected to have hereditary tumor syndromes. Results The analytical performance of the hereditary cancer panel was suitable for diagnostic testing. Clinical diagnosis was confirmed in 24% (23/96); incidental findings in genes not associated with the patient's phenotype were identified in 5% (5/96). A further 7% of pathogenic/likely pathogenic variants were detected in genes with potential genetic susceptibility roles but currently no clear clinical consequence. Cost-benefit analysis showed that the application of a more comprehensive gene panel in a diagnostic laboratory yielded a shorter turnaround time and provided additional genetic results with the same cost and workload. Discussion Using comprehensive multigene panel results in faster turnaround time and cost-efficiently identifies genetic alterations in hereditary endocrine tumor syndromes. Incidentally identified variants in patients with poor prognoses may serve as a potential therapeutic target in tumors where therapeutic possibilities are limited. [ABSTRACT FROM AUTHOR]

Lynch syndrome (LS) is one of the most common hereditary cancer syndrome in human populations, associated with germline variants in MLH1, MSH2/EPCAM, MSH6 and PMS2 genes. The advent of next generation sequencing has proven a significant impact in germline variant detection in the causative genes; however, a large proportion of patients with clinical criteria still receive uncertain or negative results. PMS2 is the least frequent reported gene, associated with up to 15% of LS cases with late-onset disease and low penetrance phenotype; however, the proportion of PMS2-LS cases is considered to be highly underestimated. In this context, our analysis aimed to improve the current diagnostic yield by focusing on missense and intronic PMS2 variants available in public clinical databases (ClinVar, LOVD). We performed an in silico assessment of the wild-type DNA sequence and the reported genetic variants, employing splicing bioinformatics tools known for their effectiveness in other genes. Splicing variants were predicted in silico and using GTEx short-read RNA expression data. Out of the 2384 missense variants discovered, 90% were classified with uncertain significance (VUS). 4.9% of missense variants were shown to have a potential splicing consequence (DS > 0.2) using SpliceAI. As described in the original publication, SpliceAI-visual was proven effective in annotation of short intronic variants (< 50 bp). Four short intronic variants were identified using SpliceAI-visual as potentially splicing disturbing, in spite of using a lower threshold (DS > 0.1). Exons 2, 3, 4, 5, 6, 7, 8, 11, 12 and 14 were consistently predicted in at least three out of eight software with weak canonical splice sites. Additionally, we noted that both Exonic Splicing Enhancers (ESEs) and Exonic Splicing Silencers (ESSs) contribute significantly to alternative splicing and exonic selection in PMS2 gene. Specifically, ESE motifs were consistently more abundant in highly expressed exons 5, 11 and 14, while ESS motifs played a fundamental role in exons 6, 7 and 10. Computational analysis performed in our study serves as a valuable filtering step for guiding further RNA experiments. Additional functional data is necessary to validate our findings. [ABSTRACT FROM AUTHOR]

Prostate cancer remains a lethal disease for many men. Knowledge of genetic contributions to this condition has increasingly been used in its management. In this narrative review, we summarize various genetic alterations and syndromes associated with prostate cancer, including hereditary breast and ovarian cancer syndrome, Lynch syndrome, and hereditary prostate cancer, among others. Indications for germline testing are reviewed, as well as incorporation of genetic data at different phases of management for prostate cancer, such as screening and monitoring, and treatment of localized and metastatic disease. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusions Whether the progression of precursor lesions or the occurrence of cancer is influenced by lifestyle factors in carriers of genetic mutations has not been fully investigated, especially in Asian patients of hereditary colorectal cancer (CRC) syndrome.Patients at a high risk of hereditary CRC were included. For polyposis CRC syndromes, colorectal polyp burden was measured using at least 60 images per colonoscopy in each patient and classified into five stages using the International Society for Gastrointestinal Hereditary Tumours staging system according to the polyp number and size. Increase in tumor burden stage for polyposis CRC syndrome and the occurrence of CRC or any cancer for Lynch syndrome were analyzed according to lifestyle factors.Ninety‐six patients with suspected hereditary polyposis CRC syndrome and 106 patients with Lynch syndrome were recruited. For polyposis CRC syndromes, multivariate analysis showed that exposure to smoking and > 100 polyps independently predicted a high risk of increased polyp burden (p = 0.008 and p = 0.012, respectively). Significant genetic mutations or phenotype of polyposis syndromes were significantly associated with an increased polyp burden. For Lynch syndrome, smokers showed to be diagnosed with CRC in younger age than never‐smokers (42.2 years vs. 49.0 years; p = 0.021), and heavy drinkers had high risk for occurrence of CRC (HR, 2.381, 95% CI, 1.338–4.236; p = 0.003) and any cancer (HR, 2.254; 95% CI, 1.334–3.806; p = 0.002).The lifestyle factors (smoking and alcohol consumption) were associated with increasing precursor lesions and occurrence of cancer in patients with hereditary CRC syndrome. Lifestyle modifications may reduce the risk of hereditary CRC in carriers. [ABSTRACT FROM AUTHOR]

Introduction: Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome primarily caused by germline TP53 pathogenic/likely pathogenic (P/LP) variants. Soft tissue and bone sarcomas are among the most frequently occurring of the many LFS-associated cancer types. Cancer screening recommendations for LFS are centered around annual whole-body MRI (wbMRI), the interpretation of which can be challenging. This study aims to characterize sarcoma topography in LFS. Methods: Study subjects included individuals from clinically and genetically ascertained cohorts of germline TP53 variant-carriers, namely the National Cancer Institute's LFS longitudinal cohort study (NCI-LFS), the NCI Genetic Epidemiology of Osteosarcoma (NCI-GEO) study, and the germline TP53 Database. Results: Data was aggregated for a total of 160 sarcomas that had detailed topography available. Abdominal sarcomas and extremity osteosarcomas were among the most frequent locations of sarcomas. Chi-squared analyses showed no statistical differences in sarcoma topography based on age (pediatric vs adult) or sex (male vs female). A case series of sarcomas from the NCI-LFS study highlights the diagnostic challenges due to topography-related imaging. Discussion: While LFS-related sarcomas frequently occur in expected locations such as the extremities, they also occur in less typical sites, leading to difficulties in discerning between differential diagnoses on wbMRI and imaging. Prospective collection of detailed cancer topography in individuals with LFS will further aid in recommendations for radiologic interpretation and personalized screening in individuals with LFS. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumors in soft tissue and bones are rare, and there is limited knowledge about how they occur. Better knowledge about inherited predisposition to tumor syndromes increases the chance for the medical community to detect cancer early through targeted screening programs and to choose the most appropriate cancer treatment. In our study, we show that some inherited mutations can increase the risk for these tumors. We applied a novel approach, in which we analyzed a blood sample in tandem with a tumor sample from participants, and we found especially interesting inherited mutations. Some of the mutations we found were already known to increase the risk of cancer, although not proven to be connected to soft tissue and bone tumors before. Other mutations we present have not been shown to be connected to tumors at all before. Our findings can guide further genetic investigations of soft tissue and bone tumors. Background: The etiology of most mesenchymal tumors is unknown, and knowledge about syndromes with an increased risk of tumors in bone or soft tissue is sparse. Methods: We present a prospective germline analysis of 312 patients with tumors suspected of being sarcomas at a tertiary sarcoma center. Germline and tumor whole genome sequencing, tumor transcriptome, and methylome analyses were performed. Results: Germline pathogenic or likely pathogenic variants associated with an increased risk of tumors were detected in 24 patients (8%), of which 11 (4%) harbored a detectable second hit in the tumor. Second hits were confirmed in genes with (NF1, RB1, TP53, EXT2, and SDHC) and without (ATM, CDC73, MLH1, MSH6, POLG, and KCNQ1) known association with mesenchymal tumor predisposition. Sarcomas from two Lynch syndrome patients showed mismatch repair deficiency, predicting a treatment response to immune checkpoint inhibitors (Level 1 biomarker according to the FDA (Federal Drug Administration) and ESMO (European Society for Medical Oncology)). None of the three CHEK2 carriers had a second hit in the tumor, suggesting a weak link to sarcoma. Conclusions: We conclude that second-hit analyses can be used in standard of care to identify syndrome-related tumors. This approach can help distinguish true manifestations of tumor syndromes from unrelated germline findings and enhance the understanding of germline predisposition in soft tissue tumors. Prospective screening using germline whole genome sequencing should be considered when comprehensive somatic sequencing is introduced into clinical practice. [ABSTRACT FROM AUTHOR]

The editorial discusses the controversial relationship between acromegaly, a rare endocrine disorder, and cancer risk. While some studies suggest an increased risk of certain cancers, others do not. Advances in acromegaly treatment have improved disease control and reduced mortality rates. Current data do not support extensive cancer screening beyond standard guidelines, but clinical attention is crucial, especially for elderly patients and those with diabetes mellitus. Further research is needed to understand the impact of acromegaly on cancer risk and refine screening protocols. [Extracted from the article]

Introduction: Restorative proctocolectomy (RPC) and total colectomy with ileorectal anastomosis (TC-IRA) are traditional surgical options for individuals with familial adenomatous polyposis (FAP). Re-appraisal and modification to these techniques, such as near-total colectomy with ileo-distal sigmoid anastomosis (NT-IDSA) and RPC with robotic intracorporeal single-stapled anastomosis (RPC-RiSSA), have been implemented in recent years. This study aimed to evaluate the early postoperative outcomes associated with novel techniques employed in a single centre for restorative surgery in patients with FAP. Methods: A retrospective analysis was conducted using data from patients with FAP who underwent prophylactic restorative surgery between January 2008 and December 2022 at St Mark's Hospital. Results: Two hundred fifty-three individuals underwent restorative surgery over the 15-year period; 102/253 (40.3%) underwent TC-IRA, 84 (33.2%) had NT-IDSA, and 67 (26.5%) underwent RPC. Laparoscopic approach was the most common (88.2%) operative access. Seventeen patients (6.7%) underwent robotic operations. For robotic-assisted procedures, no conversions were reported. No anastomotic leaks or 30-day reoperations were reported in the NT-IDSA group compared to 8% (0/84 vs 8/102, p = 0.009) and 11% (0/84 vs 11/102, p = 0.002), respectively, in the TC-IRA group. Regarding RPC, following the introduction of robotic RPC-RiSSA in 2019, no anastomotic leakage was observed compared with 9% (0/11 vs 5/56, p = 0.3) in those undergoing conventional RPC. Conclusion: Our institution has transitioned from TC-IRA to NT-IDSA since 2014 and conventional RPC to RPC-RiSSA in 2019. To date, since refinement of the techniques there have been no anastomotic failures amongst these cohorts. The reported results may offer future horizons for patients undergoing similar procedures for alternative colorectal diseases. [ABSTRACT FROM AUTHOR]

Background: Efficient and scalable solutions are needed to identify patients who qualify for germline cancer genetic testing. We evaluated the clinical validity of a brief, patient-administered hereditary cancer risk assessment digital tool programmed to assess if patients meet criteria for germline genetic testing, based on personal and family history, and in line with national guidelines. Methods: We applied the tool to cases seen in a nationwide telehealth genetic counseling practice. Validity of the tool was evaluated by comparing the tool's assessment to that of the genetic counselor who saw the patient. Patients' histories were extracted from genetic counselor-collected pedigrees and input into the tool by the research team to model how a patient would complete the tool. We also validated the tool's assessment of which specific aspects of the personal and family history met criteria for genetic testing. Descriptive statistics were used. Results: Of the 152 cases (80% female, mean age 52.3), 56% had a personal history of cancer and 66% met genetic testing criteria. The tool and genetic counselor agreed in 96% of cases. Most disagreements (4/6; 67%) occurred because the genetic counselor's assessment relied on details the tool was not programmed to collect since patients typically don't have access to the relevant information (pathology details, risk models). We also found complete agreement between the tool and research team on which specific aspects of the patient's history met criteria for genetic testing. Conclusion: We observed a high level of agreement with genetic counselor assessments, affirming the tool's clinical validity in identifying individuals for hereditary cancer predisposition testing and its potential for increasing access to hereditary cancer risk assessment. [ABSTRACT FROM AUTHOR]

Cascade testing for hereditary cancer syndromes allows relatives to estimate cancer risk and pursue prevention and early detection strategies. The current paradigm relies on patient coordinated care, resulting in only one-third of relatives successfully completing testing. Studies suggest that team-based approaches, where clinicians facilitate testing, can increase uptake. As institutions consider implementing such programs, understanding patient characteristics associated with interest is crucial for resource allocation. We aim to assess interest in clinician-facilitated testing and evaluate barriers. Patients with cancer-associated pathogenic variants seen at a gynecologic oncology clinic were offered clinician-facilitated cascade testing. Patient interest and demographic variables were recorded and patients that declined were interviewed regarding the decision. From 11/2023–4/2024, 139 patients were offered clinician-facilitated cascade testing. Median patient age was 43 years (IQR 17), 97 (69.8 %) self-identified as White and 101 (72.7 %) as non-Hispanic. Fifty-six (40.3 %) patients harbored a BRCA1 pathogenic variant, 37 (26.6 %) BRCA2, and 46 (33.1 %) other cancer-associated genes. Fifty-seven (41.0 %) patients expressed interest in the intervention. Interested patients were more likely to have been diagnosed in the prior year vs. patients who were not interested on univariate (OR 4.6, 95 % CI 2.0–10.2, P = 0.0002) and multivariable analyses (adjusted OR 3.8, 95 % CI 1.622–9.009, P = 0.0022). Our study demonstrates that patients are almost five time more likely to be interested in cascade genetic testing within the first year of diagnosis of a pathogenic variant. Given the utility of such programs and their resource requirements, targeting this population could maximize effectiveness and uptake of cascade services. [ABSTRACT FROM AUTHOR]

Genetic counseling aims to identify hereditary cancer syndromes that potentially concern all primary tumors of the digestive tract but which are dominated by hereditary forms of colorectal cancers. The identification of a germline pathogenic variant in the index case makes it possible to confirm the diagnosis of genetic predisposition and to offer genetic testing to its relatives. This approach can also lead to a "theranostic" issue due to a particular tumor molecular phenotype likely to impact the natural history of tumors and their sensitivity to different therapies. Recent years have been marked by the identification of new predisposition syndromes, particularly in the field of colorectal adenomatous polyposis, but also by technological evolutions (NGS, New Generation Sequencing) and by the significant development of tumor genetics which led to modification of both the genetic testing strategy and the criteria for referring patients to oncogenetic clinic. The objective of this review is to describe the « fundamentals » of the different syndromes but also to highlight new data as well as the current dynamics in our discipline in close interaction with tumor genetics, medical oncology and gastroenterology. [ABSTRACT FROM AUTHOR]

Simple Summary: This study reports the results of genetic testing to identify germline variants in the main genes (APC, BMPR1A, MUTYH, PTEN, SMAD4, STK11) associated with hereditary polyposis syndromes in 75 index cases with colorectal polyps and a personal/family history of cancer that had been referred to genetic counseling at the Medical Genetics Unit of the National Institute of Gastroenterology "Saverio de Bellis", Castellana Grotte, Bari, Italy. In the screened patients, some of which did not meet the recommended eligibility criteria of current National Comprehensive Cancer Network (NCCN) guidelines for genetic testing, we identified 14 pathogenic variants and 6 variants of uncertain significance. Of note, by combining the results of multigene panel tests with the evaluation of patients' clinical phenotype and family history, we were able to confirm the diagnosis of hereditary polyposis syndrome for pathogenic variant carriers and assign them to specific clinical surveillance and management programs. Background: Hereditary polyposis syndromes are clinically and genetically heterogeneous conditions associated with increased colorectal cancer risk. They are classified based on polyp histology, inheritance mode, causal gene, and colonic and extracolonic manifestations. Their diagnosis is challenging due to overlapping and heterogeneous clinical presentations. Methods: A multigene next-generation sequencing panel was used to screen 75 index cases with colorectal polyps and a personal/family history of cancer for key hereditary polyposis-associated genes (APC, BMPR1A, MUTYH, PTEN, SMAD4, and STK11) in order to identify germline genetic variants. Results: In the screened index cases, we found 14 pathogenic variants involving APC, MUTYH, SMAD4, and STK11 and 6 variants of uncertain significance involving APC, BMPR1A, and SMAD4. In this cohort, four patients not fulfilling the recommended eligibility criteria of current National Comprehensive Cancer Network (NCCN) guidelines for genetic testing were molecularly diagnosed with a hereditary polyposis syndrome. Conclusions: Our findings indicate that stringent NCCN eligibility criteria for molecular screening may lead to missing some of the patients affected by hereditary polyposis syndromes. This highlights the need for a careful evaluation of patients' clinical manifestations, polyp number, age of polyp onset, and family history to select appropriate candidates for molecular diagnosis of these conditions. [ABSTRACT FROM AUTHOR]

Background: Lynch syndrome (LS) is a hereditary cancer syndrome caused by pathogenic germline variants in mismatch repair (MMR) genes, which predisposes to various types of cancers showing deficient MMR (dMMR). Identification of LS probands is crucial to reduce cancer-related deaths in affected families. Although universal screening is recommended for colorectal and endometrial cancers, and age-restricted screening is proposed as an alternative, LS screening covering a broader spectrum of cancer types is needed. In the current study, we elucidated the rate of dMMR tumors and evaluated the outcome of LS screening in young-onset extra-colorectal LS-associated cancers. Methods: Immunohistochemistry for MMR proteins were retrospectively performed in a total of 309 tissue samples of endometrial, non-mucinous ovarian, gastric, urothelial, pancreatic, biliary tract, and adrenal cancers in patients < 50 years of age. Clinicopathological information and the results of genetic testing were obtained from medical charts. Results: There were 24 dMMR tumors (7.8%) including 18 endometrial, three ovarian, two urothelial, and one gastric cancer. Co-occurrence of colorectal cancer and family history of LS-associated cancers was significantly enriched in patients with dMMR tumors. Among the 16 patients with dMMR tumors who were informed of the immunohistochemistry results, five with endometrial and one with urothelial cancer were diagnosed as LS with positive pathogenic variants in MMR genes. Conclusions: We report the outcome of immunohistochemistry for MMR proteins performed in multiple types of young-onset extra-colorectal LS-associated cancers. Our study demonstrates the feasibility of a comprehensive LS screening program incorporating young-onset patients with various types of extra-colorectal LS-associated cancers. [ABSTRACT FROM AUTHOR]

The document delves into the intersection of communication and genetic testing in hereditary cancer syndromes, emphasizing the importance of tailored communication strategies and resources to facilitate informed decision-making and improve access to genetic services. Long-term outcome data from a psychosocial study within the IMPACT study revealed that targeted prostate cancer screening for men with pathogenic germline mutations in BRCA1 or BRCA2 led to positive psychosocial outcomes, including low levels of anxiety and depression, cancer-related distress, and good quality of life. The findings underscore the significance of addressing psychosocial well-being in the context of genetic predispositions to cancer and highlight the need for personalized approaches to support individuals and families navigating genetic testing and hereditary cancer risks. [Extracted from the article]

TP53 pathogenic variants cause Li-Fraumeni syndrome (LFS), with some variants causing an attenuated phenotype. Herein, we describe the clinical phenotype and genetic characteristics of carriers of NM_000546.6 (TP53): c.541C > T, (p.Arg181Cys) treated at Hadassah Medical Center. We retrospectively examined our genetic databases to identify all carriers of TP53 p.Arg181Cys. We reached out to carriers and their relatives and collected clinical and demographic data, lifestyle factors, carcinogenic exposures as well as additional blood samples for genetic testing and whole exome sequencing. Between 2005 and 2022 a total of 2875 cancer patients underwent genetic testing using genetic panels, whole exome sequencing or targeted TP53 assays. A total of 30 cancer patients, all of Arab-Muslim descent, were found to be carriers of TP53 p.Arg181Cys, the majority from Jerusalem and Hebron, two of which were homozygous for the variant. Carriers were from 24 distinct families of them, 15 families (62.5%) met updated Chompret criteria for LFS. Median age of diagnosis was 35 years-old (range 1–69) with cancers characteristic of LFS (16 Breast cancer; 6 primary CNS tumors; 3 sarcomas) including 4 children with choroid plexus carcinoma, medulloblastoma, or glioblastoma. A total of 21 healthy carriers of TP53 p.Arg181Cys were identified at a median age of 39 years-old (range 2–54)—19 relatives and 2 additional pediatric non-cancer patients, in which the finding was incidental. We report a shared haplotype of 350kb among carriers, limited co-morbidities and low BMI in both cancer patients and healthy carriers. There were no demographic factors or carcinogenic exposures unique to carriers who developed malignancy. Upon exome analysis no other known pathogenic variants in cancer predisposing genes were identified. TP53 p.Arg181Cys is a founder pathogenic variant predominant to the Arab-Muslim population in Jerusalem and Hebron, causing attenuated-LFS. We suggest strict surveillance in established carriers and encourage referral to genetic testing for all cancer patients of Arab-Muslim descent in this region with LFS-associated malignancies as well as family members of established carriers. [ABSTRACT FROM AUTHOR]

Serrated polyposis syndrome (SPS) presents with multiple sessile serrated lesions (SSL) in the large intestine and confers increased colorectal cancer (CRC) risk. However, the etiology of SPS is not known. SSL-derived organoids have not been previously studied but may help provide insights into SPS pathogenesis and identify novel biomarkers and chemopreventive strategies. This study examined effects of EGFR and COX pathway inhibition in organoid cultures derived from uninvolved colon and polyps of SPS patients. We also compared with organoids representing the hereditary gastrointestinal syndromes, Familial Adenomatous Polyposis (FAP) and Lynch syndrome (LS). Eighteen total organoid colon cultures were generated from uninvolved colon and polyps in SPS, FAP, LS, and non-syndromic screening colonoscopy patients. BRAF and KRAS mutation status was determined for each culture. Erlotinib (EGFR inhibitor) and sulindac (COX inhibitor) were applied individually and in combination. A 44-target gene custom mRNA panel (including WNT and COX pathway genes) and a 798-gene microRNA gene panel were used to quantitate organoid RNA expression by NanoString analysis. Erlotinib treatment significantly decreased levels of mRNAs associated with WNT and MAPK kinase signaling in organoids from uninvolved colon from all four patient categories and from all SSL and adenomatous polyps. Sulindac did not change the mRNA profile in any culture. Our findings suggest that EGFR inhibitors may contribute to the chemopreventive treatment of SSLs. These findings may also facilitate clinical trial design using these agents in SPS patients. Differentially expressed genes identified in our study (MYC, FOSL1, EGR1, IL33, LGR5 and FOXQ1) may be used to identify other new molecular targets for chemoprevention of SSLs. [ABSTRACT FROM AUTHOR]

PTEN hamartoma tumor syndrome (PHTS) has a broad clinical spectrum including various benign and malignant tumors at varying age of diagnosis. Many patients remain unrecognized, unaware of their increased cancer risk. We aimed to describe the cancer spectrum, age of onset and histopathological cancer characteristics to assess whether specific cancer characteristics could improve PHTS recognition. Genetic testing results and pathology reports were collected for patients tested for germline PTEN variants between 1997 and 2020 from the diagnostic laboratory and the Dutch nationwide pathology databank (Palga). The cancer spectrum and age of onset were assessed in patients with (PTENpos) and without (PTENneg) a germline PTEN variant. Histopathological cancer characteristics were assessed in a nested cohort. 341 PTENpos patients (56% females) and 2882 PTENneg patients (66% females) were included. PTENpos patients presented mostly with female breast (BC, 30%), endometrial (EC, 6%), thyroid (TC, 4%) or colorectal cancer (4%). PTENpos were significantly younger at cancer onset (43 vs. 47 years) and had more often (46% vs. 18%) a second BC than PTENneg. PTEN detection rates were highest for BC <40 years (9%), TC <20 years (15%) and EC <50 years (28%), and dropped to 6%, 4%, and 15% by age 60. Histopathological characteristics were similar between groups. No histopathological cancer characteristics were distinctive for PHTS. However, PTENpos were significantly younger at cancer onset. Therefore early‐onset BC, EC, or TC warrants consideration of PHTS diagnostics either through a pre‐screen for other PHTS features or direct germline testing. [ABSTRACT FROM AUTHOR]

Despite evidence supporting genetic testing's utility in hereditary cancer risk management, uptake remains low among at-risk relatives of a hereditary cancer patient. The qualitative systematic review aims to identify the psychosocial barriers and facilitators associated with the uptake of genetic counselling services and/or genetic testing (GC/GT). A systematic literature search was performed across six databases in June 2023, limited to studies published in English from 2010 onwards. Qualitative studies interviewing hereditary cancer patients, their relatives, and/or healthcare providers to identify the psychosocial barriers and facilitators associated with the uptake of genetic testing for hereditary cancer syndrome were eligible for inclusion. A thematic analysis was conducted on the extracted data from 41 eligible qualitative studies. 54% of the studies were from the United States and 75% of the participants were female. 14 psychosocial barriers and nine facilitators to the uptake of genetic testing services were identified. The most frequently cited psychosocial barriers to genetic testing uptake were ‘emotional roller coaster’, ‘threat of genetic discrimination’, and ‘no perceived benefit of genetic testing’. In contrast, the most common facilitators were ‘concern for family’, ‘easing personal worries’, and ‘knowledge is empowering’. Our findings reveal complex factors affecting GC/GT service uptake, some with dual effects. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Lynch syndrome (LS) is an autosomal‐dominant, hereditary cancer predisposition syndrome caused by pathogenic variants (PVs) in one of the mismatch‐repair genes MLH1, MSH2/EPCAM, MSH6, or PMS2. Individuals who have MLH1 PVs have high lifetime risks of colorectal cancer (CRC) and endometrial cancer (EC). There is controversy regarding whether a younger age at diagnosis (or anticipation) occurs in MLH1‐associated LS. The objective of this study was to assess anticipation in families with MLH1‐associated LS by using statistical models while controlling for potential confounders.Data from 31 families with MLH1 PVs were obtained from an academic registry. Wilcoxon signed‐rank tests on parent–child‐pairs as well as parametric Weibull and semiparametric Cox proportional hazards and Cox mixed‐effects models were used to calculate hazard ratios or to compare mean ages at CRC/EC diagnosis by generation. Models were also corrected for ascertainment bias and birth‐cohort effects.A trend toward younger ages at diagnosis of CRC/EC in successive generations, ranging from 3.2 to 15.7 years, was observed in MLH1 PV carrier families. A greater hazard for cancer in younger generations was not precluded by the inclusion of birth cohorts in the model. Individuals who had MLH1 variants with no Mlh1 activity were at a 78% greater hazard for CRC/EC than those who retained Mlh1 activity.The current results demonstrated evidence in support of anticipation in families with MLH1‐associated LS across all statistical models. Mutational effects on Mlh1 activity influenced the hazard for CRC/EC. Screening based on the youngest age of cancer diagnosis in MLH1‐LS families is recommended. [ABSTRACT FROM AUTHOR]

While renal cell carcinoma (RCC) is often linked to smoking, obesity, and hypertension, hereditary forms also account for about 3% of RCC cases. Notably, NCCN guidelines identify 7 major hereditary syndromes associated with an increased RCC risk. Inherited mutations in DNA repair genes, such as ATM, BRCA, and TP53, significantly increase the risk of various cancers. Biallelic pathogenic mutations in ATM cause Ataxia-Telangiectasia (A-T) syndrome, while heterozygous germline pathogenic ATM mutations, present in about 1% of the population, also elevate cancer risk. RCC has not traditionally been associated with germline pathogenic ATM mutations, only limited retrospective analyses have identified such mutations. This case report presents a 68-year-old woman with a germline pathogenic ATM mutation (c.8786+1 G>A) who developed high-risk clear cell RCC followed by an acquired somatic VHL mutation in RCC and a 3-cm serous cystadenoma, illustrating the double-hit phenomenon. Her brother, who shares the same germline pathogenic mutation, was diagnosed with pancreatic cancer and prostate cancer. This case highlights the potential use for enhanced screening protocols for RCC in patients who have germline pathogenic ATM mutations and the importance of research in targeted treatments for tumors driven by dual genetic mechanisms. Increased awareness and vigilant screening for RCC are crucial in managing hereditary cancer syndromes effectively. [ABSTRACT FROM AUTHOR]

Phaeochromocytomas and paragangliomas (collectively termed PPGL) are rare yet highly heritable neuroendocrine tumours, with over one-third of cases associated with germline pathogenic variants (PVs) in numerous genes. PVs in the succinate dehydrogenase subunit-A gene (SDHA) were initially implicated in hereditary PPGL in 2010, and SDHA has since become an important susceptibility gene accounting for up to 2.8% of cases. However, it remains poorly understood, particularly regarding the clinical nature of SDHA PPGL, rates of recurrence and metastasis, and the nature of metastatic disease. We present a narrative review of SDHA-related PPGL, covering pathophysiology, relevance to current clinical practice, and considerations for clinical genetics. We analyse a pool of 107 previously reported cases of SDHA-associated PPGL to highlight the spectrum of SDHA-related PPGL. Our analysis demonstrates that SDHA PPGL occurs across a wide age range (11-81 years) and affects men and women equally. SDHA PPGL typically presents as single tumours (91%), usually occurring in the head and neck (46%) or abdomen (43%, including 15% with phaeochromocytomas). Metastatic disease was reported in 25.5% of cases, with bone (82%) and lymph nodes (71%) being the most common sites of metastasis, often identified many years after the initial diagnosis. A family history of SDHA-related neoplasia was rare, reported in only 4% of cases. Understanding the clinical nature and risks associated with SDHA PVs is essential for facilitating the optimal management of patients and their families. [ABSTRACT FROM AUTHOR]

Lynch syndrome, also called hereditary non‐polyposis colorectal cancer, is an autosomal dominant disorder characterized by germline pathogenic mutations in DNA mismatch repair genes—resulting in increased susceptibility to colorectal, endometrial, and other tumors. This case report presents an incidental finding of endometrial cancer with Lynch syndrome during investigation for primary infertility. A 34‐year‐old woman presented to the fertility clinic with unexplained primary infertility. Investigations showed possible endometrial polyp, 13 × 11 mm in size. Hysteroscopic polypectomy and endometrial biopsy revealed complex endometrial hyperplasia amounting to endometroid adenocarcinoma. The case was discussed at the West of Scotland Gynecology‐Oncology MDT meeting—management options including fertility‐sparing treatment or radical surgery were presented to the patient and she opted for the latter. A total laparoscopic hysterectomy with bilateral salpingo‐oophorectomy was performed with pathology results consistent with well‐differentiated endometroid adenocarcinoma Stage 1A. Peritoneal washings showed no malignant cells. Genetic testing confirmed a diagnosis of Lynch syndrome. On further questioning, it was revealed that the patient had a strong family history of colon cancer but had not previously met the criteria for genetic testing. She was referred to colorectal surgeons and underwent colonoscopy. This showed no abnormality; she was therefore scheduled for 2‐yearly colonoscopic surveillance. Synopsis: Asymptomatic presentation of endometrial cancer in a patient found to have Lynch syndrome, discovered incidentally through workup for primary infertility. [ABSTRACT FROM AUTHOR]

Hereditary or familial cancer syndromes are caused by inherited pathogenic variants in cancer susceptibility genes and are associated with an increased risk of developing malignancies occurring at an earlier age. BRCA-associated Hereditary Breast and Ovarian Cancer and Lynch Syndromes are the most common conditions encountered in gynaecology. Identification presents opportunities to prevent or reduce the risk of cancer, or to detect cancers at earlier stages with improved outcomes. When cancer does occur, there may be options for personalized therapeutic approaches. Cancer prevention invariably requires risk-reducing surgical treatment, which may result in irreversible loss of fertility and premature menopause; issues which must be addressed through a personalized management approach. Regular review with adjustments to plans are required as individuals pass through different reproductive life-stages. Comprehensive management requires a multi-professional approach including specialist genetics input, prevention of cancer by education, modification of risk factors and specific interventions, in addition to psychosocial support. [ABSTRACT FROM AUTHOR]

The article discusses the success of ENDO 2024, an international conference held in Seoul, South Korea, with 3200 delegates from 85 countries participating. The event featured live demonstrations, hands-on training, educational courses, symposia, and industry sessions. The article also highlights the recipients of the 2024 WEO Awards, recognizing outstanding leaders in the field of endoscopy. Additionally, the document mentions the transition of WEO Presidency from Professor Hisao Tajiri to Professor Lars Aabakken. [Extracted from the article]

With the development of genetics and advances in genetic testing technology, the demand for cancer genetic counseling has increased dramatically. Advanced practice nurses play a key role in personalized health care delivery. The oncology genetic nurse-led genetic counseling services in foreign countries are becoming more and more mature, but in China, the work of oncology genetic counseling started late, and the combination of genetics/genomics with nursing is still in its infancy. There is still a lack of relevant research on oncology genetic nurses. This article introduced the qualification certification, core competence and clinical practice content of foreign oncology genetic nurses, and summarized the clinical practice effect of oncology genetic nurses and the enlightenment to China’s advanced nursing practice, which provided references for the construction of oncology genetic nurses training programs and clinical service models suitable for China’s national conditions, so as to meet the needs of the development of advanced nursing practice and the growing demand for precision oncology and high-quality genetic medical care. [ABSTRACT FROM AUTHOR]

We present a family in which four individuals have been identified with the same likely pathogenic genetic alteration in the PIK3CA gene at the germinal level; specifically, c.1145G>A p.(Arg382Lys) missense type. The index case patient was diagnosed with multinodular goiter and breast cancer at 61 years old. Among the other three carrier relatives: one has been diagnosed with serous cystadenoma of the ovary and a thyroid nodule with no radiological suspicion of malignancy; the other two present multinodular goiter. Additionally, a sister of three of the carriers suffered from an ovarian teratoma, follicular thyroid carcinoma on multinodular goiter, and high-grade serous ovarian carcinoma. No direct mutation study was performed on her as she had died due to ovarian carcinoma. This finding suggests that the PIK3CA gene should be considered in Cowden-like families when no other gene mutations have been found. Furthermore, this report contributes to characterization of the clinical phenotype caused by mutations in PIK3CA, which may be shared with other hereditary breast and ovarian cancer syndromes. [ABSTRACT FROM AUTHOR]

Pheochromocytoma and paragangliomas (PPGLs) are rare chromaffin cell tumors arising from neural crest tissue. The majority of these tumors are nonmetastatic, with complete cure achieved through surgical resection. PPGLs have been associated with several hereditary cancer syndromes, including von Hippel-Lindau (VHL). We present the case of a 10-year-old patient with VHL and a history of 2 asynchronous pheochromocytomas requiring bilateral adrenalectomies who presented with a new 1.2 cm × 1.3 cm × 1.5 cm nodular structure between the superior pole of the right kidney and the intrahepatic inferior vena cava. The patient was noted to have hypertension but was otherwise asymptomatic. Positron emission tomography-DOTA-(Tyr)3-octreotate revealed a metabolically active retrocrural lymph node. Based on these imaging findings and laboratory studies showing elevated plasma normetanephrine, clinical suspicion was highest for metastatic pheochromocytoma. The patient underwent surgical resection of multiple abdominal tumors. Pathology ultimately favored a diagnosis of multiple primary paragangliomas rather than metastatic disease. With this shift in diagnosis, the patient was managed with surgery alone. One year later, he has no signs of disease recurrence. Long-term surveillance imaging and screening with fractionated plasma metanephrines is indicated to monitor for new tumors in the setting of VHL and 3 prior endocrine tumors. [ABSTRACT FROM AUTHOR]

In the age of telehealth medicine, an individual's facial features may provide the only physical clues signaling the presence of a heritable cancer predisposition syndrome. These syndromes include APC -associated polyposis, Birt-Hogg-Dubé syndrome, CYLD cutaneous syndrome, hereditary leiomyomatosis and renal cell cancer, multiple endocrine neoplasia, neurofibromatosis type 1, Peutz-Jeghers syndrome, PTEN hamartoma tumor syndrome, and tuberous sclerosis complex 1 and 2, among others. Correctly identifying characteristic features is important for genetic and nongenetic specialists as early detection can enable prompt intervention, improving patient outcomes. Advancements in the availability of genetic testing allow patients and their relatives to have more information about their genetic risk profile than before. These changes in clinical pathways, combined with improvements in screening and risk-reducing treatment, highlight the need to outline the cutaneous and morphologic features of high-risk cancer syndromes for clinicians. In this review, we describe the important facial features of hereditary cancer predisposition, with emphasis on diagnosis, cutaneous and extracutaneous manifestations, and screening. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) comprises various histologically distinct subtypes, each characterized by specific genetic alterations, necessitating individualized management and treatment strategies for each subtype. An exhaustive search of the PubMed database was conducted without any filters or restrictions. Inclusion criteria encompassed original English articles focusing on molecular mechanisms of kidney cancer. On the other hand, all non-original articles and articles published in any language other than English were excluded. Hereditary kidney cancer represents 5–8% of all kidney cancer cases and is associated with syndromes such as von Hippel–Lindau syndrome, Birt–Hogg–Dubè syndrome, succinate dehydrogenase-deficient renal cell cancer syndrome, tuberous sclerosis complex, hereditary papillary renal cell carcinoma, fumarate hydratase deficiency syndrome, BAP1 tumor predisposition syndrome, and other uncommon hereditary cancer syndromes. These conditions are characterized by distinct genetic mutations and related extra-renal symptoms. The majority of renal cell carcinoma predispositions stem from loss-of-function mutations in tumor suppressor genes. These mutations promote malignant advancement through the somatic inactivation of the remaining allele. This review aims to elucidate the main molecular mechanisms underlying the pathophysiology of major syndromes associated with renal cell carcinoma. By providing a comprehensive overview, it aims to facilitate early diagnosis and to highlight the principal therapeutic options available. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) ranks third in terms of cancer incidence worldwide and is responsible for 8% of all deaths globally. Approximately 10% of CRC cases are caused by inherited pathogenic mutations in driver genes involved in pathways that are crucial for CRC tumorigenesis and progression. These hereditary mutations significantly increase the risk of initial benign polyps or adenomas developing into cancer. In recent years, the rapid and accurate sequencing of CRC-specific multigene panels by next-generation sequencing (NGS) technologies has enabled the identification of several recurrent pathogenic variants with established functional consequences. In parallel, rare genetic variants that are not characterized and are, therefore, called variants of uncertain significance (VUSs) have also been detected. The classification of VUSs is a challenging task because each amino acid has specific biochemical properties and uniquely contributes to the structural stability and functional activity of proteins. In this scenario, the ability to computationally predict the effect of a VUS is crucial. In particular, in silico prediction methods can provide useful insights to assess the potential impact of a VUS and support additional clinical evaluation. This approach can further benefit from recent advances in artificial intelligence-based technologies. In this review, we describe the main in silico prediction tools that can be used to evaluate the structural and functional impact of VUSs and provide examples of their application in the analysis of gene variants involved in hereditary CRC syndromes. [ABSTRACT FROM AUTHOR]

Lynch syndrome, a hereditary cancer susceptibility syndrome, arises from pathogenic mutations in mismatch repair genes. This syndrome is strongly linked to colorectal and endometrial cancers, as well as an elevated risk for other cancers such as gastric, ovarian, renal pelvis/ureter, and prostate. Notably, Lynch syndrome is rarely associated with cholangiocarcinoma (CCA). In this case study, we present a unique instance of Lynch syndrome-related CCA resulting from a singular MSH6 mutation. Notably, our findings reveal discrepancies between immunohistochemistry (IHC) and microsatellite stability results compared to genetic testing outcomes. This discrepancy underscores the limitations of solely relying on IHC analysis and microsatellite stability testing for the detection of hereditary tumors, emphasizing the crucial role of genetic testing in such cases. This insight enhances our comprehension of the mechanisms involved in cancer development and underscores the significance of thorough analysis integrating immunohistochemistry and genetic testing for diagnosing Lynch syndrome-related cancers. [ABSTRACT FROM AUTHOR]

Individuals with inherited cancer syndromes, such as Li-Fraumeni syndrome (LFS), may be motivated to adopt health-protective behaviors, such as eating more fruits and vegetables and increasing physical activity. Examining these health behaviors among young people with high lifetime genetic cancer risk may provide important insights to guide future behavioral interventions that aim to improve health-related quality of life (HRQOL). We used a self-regulatory framework to investigate relationships among diet and physical activity behaviors and psychosocial constructs (e.g., illness perceptions, coping, HRQOL) in adolescents and young adults (AYAs; aged 15–39 years) with LFS. This longitudinal mixed-methods study included 57 AYAs aged 16–39 years at enrollment), 32 (56%) of whom had a history of one or more cancers. Participants completed one or two telephone interviews and/or an online survey. We thematically analyzed interview data and conducted regression analyses to evaluate relationships among variables. AYAs described adopting healthy diet and physical activity behaviors to assert some control over health and to protect HRQOL. More frequent use of active coping strategies was associated with greater reported daily fruit and vegetable intake. Greater reported physical activity was associated with better quality of psychological health. Healthy diet and physical activity behaviors may function as LFS coping strategies that confer mental health benefits. Clinicians might emphasize these potential benefits and support AYAs in adopting health behaviors that protect multiple domains of health. Future research could use these findings to develop behavioral interventions tailored to AYAs with high genetic cancer risk. [ABSTRACT FROM AUTHOR]

Purpose: Oncology clinicians are appropriately positioned to facilitate discussions of assisted reproductive technologies including preimplantation genetic testing for monogenic disease (PGT-M), in the context of cancer treatment or surveillance. Yet, reproductive services, including PGT-M, remain one of the least implemented services in oncology. No studies to date have explored which practice resources the clinicians need to increase knowledge of PGT-M. The objective of this study was to explore the specific needs of oncology clinicians to help maximize the reproductive potential of young adult patients with hereditary cancers. Methods: Participants were recruited through notices circulated on social media platforms and snowball sampling. Participants completed a brief online survey to confirm eligibility. Eligible participants completed a virtual, semi-structured interview. Interviews focused on clinician experiences with PGT-M and initiating referrals to fertility specialists. Thematic analysis was conducted using a constant comparative approach to identify current clinical practices. Results: This study found that PGT-M discussions are not necessarily within the scope of responsibilities for oncology clinicians owing to prioritization of cancer treatment and overall lack of knowledge. Participants need accessible resources and timely support for reproductive planning in the context of cancer treatment. Participants desire a streamlined referral pathway to professionals trained in oncofertility to help address their patient's reproductive needs. Conclusion: Our study identified that educational and referral resources to reproductive specialists are needed to maximize reproductive potential across the cancer continuum. These findings provide a foundation for larger studies that can inform standard-of-care recommendations in the emerging field of oncofertility. [ABSTRACT FROM AUTHOR]

In the 1990s, as prevention became a central strategy in the battle against cancer and the molecular genetics revolution uncovered the genetic basis of numerous hereditary cancer syndromes, there were no options available for patients at increased risk of developing pancreatic cancer. When surveillance efforts for those at familial and hereditary risk of pancreatic cancer emerged in the late 1990s, it was uncertain if early detection was achievable. In this introduction to the special issue, we offer an overview of the history of surveillance for pancreatic cancer, including the first reports of familial pancreatic cancer in the medical literature, the initial results of surveillance in the United States and the initiation of surveillance programs for hereditary pancreatic cancer in the Netherlands. This special issue features a collection of 18 articles written by prominent experts in the field, focusing specifically on refining surveillance methodologies with the primary objective of improving care of high-risk individuals. Several reviews in this collection highlight improved survival rates associated with pancreas surveillance, underlying the potential of early detection and improved management in the continuing fight against pancreatic cancer. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at an advanced stage, resulting in poor prognosis and low 5-year survival rates. While early evidence suggests increased long-term survival in those with screen-detected resectable cancers, surveillance imaging is currently only recommended for individuals with a lifetime risk of PDAC ≥ 5%. Identification of risk factors for PDAC provides opportunities for early detection, risk reducing interventions, and targeted therapies, thus potentially improving patient outcomes. Here, we summarize modifiable and non-modifiable risk factors for PDAC. We review hereditary cancer syndromes associated with risk for PDAC and their implications for patients and their relatives. In addition, other biologically relevant pathways and environmental and lifestyle risk factors are discussed. Future work may focus on elucidating additional genetic, environmental, and lifestyle risk factors that may modify PDAC risk to continue to identify individuals at increased risk for PDAC who may benefit from surveillance and risk reducing interventions. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the most common malignancy in female patients with Li-Fraumeni syndrome (LFS), a condition associated with an increased risk of various malignancies, including radiation therapy (RT)–induced malignancies (RIM) within previously irradiated areas. Our study aimed to assess the incidence of RIM in patients with LFS and early-stage BC treated with adjuvant RT, including the effect of RT dose and technique. We examined patients with a germline pathogenic/likely pathogenic TP53 variant diagnosed with early-stage BC and monitored by a hereditary cancer team at a single cancer center. The study endpoints included RIM frequency, the association of RIM with the dose and type of RT (2-dimensional [2D] RT, 3-dimensional [3D] RT, and intensity modulated RT [IMRT]), and BC recurrence. We analyzed 48 patients with a median age of 39 years (range, 21-62). The majority (71%) had the TP53 R337H variant, and 87% were unaware of their LFS diagnosis at the time of BC treatment. Treatment modalities included mastectomy (62%), (neo)adjuvant chemotherapy (66%), and RT (62%), with RT being more common after breast-conserving surgery (87% vs 46% with mastectomy, P =.010). Among the 30 patients treated with RT, 10% developed RIM in the irradiated field, consisting of 3 soft tissue malignancies. RT dose (≤40.8 or >40.8 Gy) did not influence RIM occurrence, but the type of RT did. RIM was observed in 100% of cases with 2D RT (2/2), 50% with IMRT (1/2), and 0% with 3D RT (0/16) (P =.004). Our study underscores a concerning rate of RIM after adjuvant RT, emphasizing the importance of a thorough risk-benefit evaluation before recommending RT, with preference for its avoidance if possible. Although subgroup sizes were limited, the risk of RIM appeared to be influenced by the RT technique, with higher rates observed with 2D RT and IMRT compared with 3D RT. Early TP53 testing is essential to guide the BC treatment plan. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PrCa) is the most frequently diagnosed cancer in men. Variants in known moderate- to high-penetrance genes explain less than 5% of the cases arising at early-onset (< 56 years) and/or with familial aggregation of the disease. Considering that BubR1 is an essential component of the mitotic spindle assembly checkpoint, we hypothesized that monoallelic BUB1B variants could be sufficient to fuel chromosomal instability (CIN), potentially triggering (prostate) carcinogenesis. Methods: To unveil BUB1B as a new PrCa predisposing gene, we performed targeted next-generation sequencing in germline DNA from 462 early-onset/familial PrCa patients and 1,416 cancer patients fulfilling criteria for genetic testing for other hereditary cancer syndromes. To explore the pan-cancer role of BUB1B, we used in silico BubR1 molecular modeling, in vitro gene-editing, and ex vivo patients' tumors and peripheral blood lymphocytes. Results: Rare BUB1B variants were found in ~ 1.9% of the early-onset/familial PrCa cases and in ~ 0.6% of other cancer patients fulfilling criteria for hereditary disease. We further show that BUB1B variants lead to decreased BubR1 expression and/or stability, which promotes increased premature chromatid separation and, consequently, triggers CIN, driving resistance to Taxol-based therapies. Conclusions: Our study shows that different BUB1B variants may uncover a trigger for CIN-driven carcinogenesis, supporting the role of BUB1B as a (pan)-cancer predisposing gene with potential impact on genetic counseling and treatment decision-making. [ABSTRACT FROM AUTHOR]

Background: In the last decade, technical innovations have resulted in the development of several minimally invasive diagnostic cancer tools. Within women at high risk of developing ovarian or endometrial cancer (EC) due to hereditary cancer syndrome, there is an urgent need for minimally invasive and patient‐friendly methods to detect ovarian cancer and EC at an early stage. Materials and Methods: We performed a systematic search of studies using DNA methylation or mutation analysis, microbiome, or proteomics performed on cervicovaginal specimens (smear, swab, or tampon) intended to detect ovarian and EC published until January 2024. Results: Included studies (n = 36) showed high heterogeneity in terms of biomarkers used and outcomes, and only a few studies reported on the detection of biomarkers in high‐risk subgroups. Conclusion: Based on the findings in this review, DNA methylation techniques seem to be the most promising for detecting ovarian and EC at early stages in the general population. Future validation of cervicovaginal DNA methylation techniques is needed to determine whether this technique might be beneficial in hereditary high‐risk subgroups. [ABSTRACT FROM AUTHOR]

Introduction: Approximately 10% of breast cancer (BC) cases result from hereditary causes. Genetic testing has been widely implemented in BC care to determine hereditary cancer syndromes and personalized medicine. Thus, identification of individuals carrying germline pathogenic variants could be useful to provide appropriate prophylactic or screening measures for each BC subtype, however, there are few formal recommendations for genetic testing in this sense so far. In this study, we assessed rare germline variants in a specific group of genes in order to determine the association with human epidermal growth factor 2 enriched (HER2+) BC phenotype through a systematic review and meta-analysis comparing subtypes overexpressing HER2 with other clinically recognized subtypes of BC. This review was registered with PROSPERO (ID: CRD42023447571). Methods: We conducted an online literature search in PubMed (MEDLINE), Scopus, and EMBASE databases. We included original studies that investigated germline variants in HER2+ BC patients and selected the studies that reported only rare and/or pathogenic germline variants. We assessed the risk of bias and quality of the studies using the Joanna Briggs Institute Critical Appraisal checklists and the Modified Newcastle-Ottawa Scale for Genetic Studies, respectively. Considering hormone receptor and HER2 expression status, we compared gene-based risks initially in HR-HER2-, HR+HER2-, HR+HER2+, and HR-HER2+ groups, conducting separate meta-analyses using the random effects model for each comparison, and within them for each gene. Results: Of the total 36 studies describing germline variants, 11 studies provided information on the prevalence of variants in the different clinically relevant BC subtypes and allowed comparisons. Germline variants within eight genes showed significant differences when meta-analyzed between the BC groups: BRCA1, BRCA2, TP53, ATM, CHEK2, PALB2, RAD51C, and BARD1. Notably, TP53, ATM, and CHEK2 germline variants were identified as predisposing factors for HER2+ subtypes, whereas BRCA1, BRCA2, PALB2, RAD51C, and BARD1 germline variants were associated with a predisposition to low HER2 expression. Main concerns about bias and quality assessment were the lack of confounding factors control; and comparability or outcome assessment, respectively. Discussion: Our findings underscore the connection between germline variants and differential expression of the HER2 protein and BC subtypes. [ABSTRACT FROM AUTHOR]

Introduction: Although hereditary male neoplasms are quite rare, individuals harbouring germline BRCA1/2 pathogenic variants (PVs) may have a risk of developing tumours associated with Hereditary Breast and Ovarian Cancer (HBOC) syndrome, including male breast (MBC), prostate (PCa) and pancreatic (PC) cancers, and melanoma. Women and men showed a comparable genetic architecture of cancer susceptibility, but there are some gender-specific features. Since little is known about cancer genetic susceptibility in male population, our study was aimed at investigating the frequency of BRCA1/2 PVs in men with HBOC syndrome-associated tumors, in order to understand whether differences in gender may reflect in the prevalence and spectrum of germline alterations. Patients and methods: We retrospectively collected and analysed clinical information of 352 HBOC-associated male cancer patients genetically tested for germline BRCA1/2 PVs by Next-Generation Sequencing analysis, enrolled, from February 2018 to January 2024, at the "Regional Center for the prevention, diagnosis and treatment of rare and heredo-familial tumors of adults" of the University-Hospital Policlinico "P. Giaccone" of Palermo (Italy). Results: Our investigation revealed that 7.4% of patients was carrier of a germline BRCA PV, with an almost total prevalence of BRCA2 alterations. In particular, 65.4% of BRCA-positive patients developed MBC, 19.2% had PC, 11.6% developed PCa, and only 3.8% had melanoma. Specifically, MBC individuals showed a BRCA-associated genetic predisposition in 17% of cases, whereas patients with PCa or PC exhibited a lower frequency of BRCA2 PVs, taking into account the current national criteria for access to germline genetic testing. Discussion: Our study showed a high heterogeneity in prevalence of germline BRCA2 PVs among men which could reflect a potential gender-specific genetic heterogeneity. Therefore, BRCA-associated male tumours could be due to BRCA2 PVs different from those usually detected in women. In the event that it is demonstrated, in future, that male cancers are genetically distinct entities from those female this could improve personalized risk evaluation and guide therapeutic choices for patients of both sexes, in order to obtain a gender equality in cancer care. [ABSTRACT FROM AUTHOR]

Fertility-related concerns cause significant anxiety among patients with Hereditary Breast and Ovarian Cancer Syndrome (HBOC). The Society of Gynecologic Oncology and the American Society for Reproductive Medicine recommend patients diagnosed with HBOC receive early referral to a reproductive endocrinologist. However, evidence about fertility trends in this patient population are limited and guidelines are scarce. The aim of this study is to compare fertility preservation among patients with HBOC to control patients undergoing fertility treatment without a diagnosis of infertility. This retrospective study included patients who presented to a single academic institution for fertility preservation in the setting of diagnosis of HBOC. In this study, HBOC patients are referred to as those who had tested positive for pathogenic mutations in BRCA1, BRCA2 or were at high-risk for HBOC based on a strong family history (defined as >3 family members diagnosed with HBOC) without a genetic mutation. HBOC patients were matched in a 1:1 fashion to a control group undergoing fertility preservation without a diagnosis of infertility or HBOC. All analysis was done using SPSS version 9.4 (SAS Institute, Cary, NC). Between August 1st, 2016 and August 1st, 2022, 81 patients presented to the study center for consultation in the setting of HBOC. Of those who presented, 48 (59.2%) ultimately underwent oocyte cryopreservation and 33 (40.7%) underwent embryo cryopreservation. Patients who underwent oocyte cryopreservation due to BRCA1 status were more likely to present for fertility consultation at a younger age compared to control patients (32.6 vs. 34.7 years, p = 0.03) and were more likely to undergo oocyte cryopreservation at a younger age (32.1 vs. 34.6 years, p = 0.007). There was no difference in age at initial consultation or age at procedure for patients with BRCA2 or patients with a strong family history compared to control patients (p > 0.05). There was no difference in the mean age of patients with HBOC at presentation for consultation for embryo cryopreservation or the mean age the patient with HBOC underwent embryo cryopreservation compared to control patients (p > 0.05). Patients with BRCA1 or BRCA2 did not have expedited time from consultation to first cycle start (p > 0.05). After adjusting for factors including anti-Müllerian hormone (AMH) level and age, patients considered in the HBOC group due to family history had less time between consultation and oocyte cryopreservation cycle compared to control patients. (179 vs. 317 days, p = 0.045). There was no difference in time from consultation to starting cycle for embryo cryopreservation for patients with HBOC compared to controls (p > 0.05). Patients with HBOC did not undergo expedited fertility treatment compared to control patients undergoing oocyte and embryo cryopreservation for non-infertility reasons. Patients diagnosed with BRCA1 had more oocytes retrieved compared to the control population which is possibly due to earlier age of presentation in the setting of recommended age of risk reducing surgery being age 35–40. When age matched, cycle outcomes did not differ between HBOC and control patients. Given the known cancer prevention benefit and recommendations for risk-reducing surgery, future studies should focus on guidelines for fertility preservation for patients with HBOC. • Patients with Hereditary Breast and Ovarian Cancer Syndrome did not undergo expedited fertility treatment. • Patients with BRCA1 presented for fertility consultation at an earlier age and had more oocytes retrieved during oocyte cryopreservation. • Cycle outcomes did not differ in patients with Hereditary Breast and Ovarian Cancer Syndrome. [ABSTRACT FROM AUTHOR]

The article focuses on the challenges U.S. healthcare providers face in obtaining ethical informed consent for hereditary cancer genetic testing, highlighting disparities between community clinicians and genetic counselors in adequately covering essential elements of informed consent. It discusses barriers such as lack of education and time constraints emphasizing the need for tailored patient education and the involvement of specialized genetic counselors to ensure comprehensive understanding.

Introduction: Renal cell carcinoma is one of the ten more common malignant tumors worldwide, with a high incidence and mortality rate. Kidney cancer frequently presents at an advanced stage, and it is almost invariably fatal. Much progress has been made in identifying molecular targets for therapy in the hope of improving survival rates, but still, we have no good markers for early detection or progression of the disease. Von Hippel Lindau syndrome (VHL) is an autosomal dominant cancer hereditary syndrome in which affected individuals are at risk of developing bilateral and multifocal renal cell carcinomas (RCC) as well as other tumors. These patients provide an ideal platform to investigate the potential of urinary exosomal miRNA biomarkers in the early development of ccRCC, as these patients are regularly imaged and tumors are actively monitored until the tumor reaches 3 cm before surgical excision. This allows for pre- and post-surgical urine collection and comparison to excised tumor tissues. Studying different biomarkers in urine can provide comprehensive molecular profiling available to patients and physicians and can be a great source of additional tumor genetic information. Methods: Pre- and postoperative urine samples were obtained from a cohort of VHL patients undergoing surveillance and surgical excision of ccRCCs, and exosomes were extracted. MicroRNA-Seq analysis was performed on miRNA extracted from both urine-derived exosomes and FFPE material from excised ccRCCs. Results: MicroRNA-Seq analysis highlighted a significant difference in the urinary exosome-derived miRNA expression profiles between VHL patients and normal control individuals. This included decreased expression of the miR-320 family, such as miR-320a, known to be decreased in sporadic ccRCC and suppressed by the HIF1α transcription factor activated by the loss of the VHL gene. MiR-542-5p represented a potential marker of VHL-associated ccRCC that was lowly expressed in normal control urinary exosomes, significantly increased in the preoperative urinary exosomes of tumor-bearing VHL patients, and subsequently reduced to normal levels of expression after tumor excision. In concordance with this, the expression of miR-542-5p was increased in the VHL-associated ccRCC in comparison to the normal kidney. Conclusions: This study shows the potential for miRNA profiling of exosomes from readily available biofluids to both distinguish VHL patient urine from normal control urine microRNAs and to provide biomarkers for the presence of VHL syndrome-associated ccRCC. Further validation studies are necessary to demonstrate the utility of urinary exosome-derived miRNAs as biomarkers in kidney cancer. [ABSTRACT FROM AUTHOR]