Germline pathogenic variants (GPVs) in the in ataxia-telangiectasia mutated (ATM) gene are present in approximately 0.35
Hereditary colorectal cancer syndromes, such as Lynch syndrome and familial adenomatous polyposis, arise from pathogenic/likely pathogenic (P/LP) germline variants in DNA mismatch repair or tumor suppressor genes. Traditional Sanger sequencing could cover only phenotype-driven genes and cannot detect copy number variants (CNVs). Next-generation sequencing (NGS) enables simultaneous multi-gene analysis and CNV detection. In this study, we compared the results of phenotype-driven Sanger sequencing with those of panel-based NGS in patients suspected of having hereditary colorectal cancer syndromes at a single institution. Patients tested for hereditary colorectal cancer syndromes between 2008 and 2018 (Sanger) and 2019–2022 (NGS) were retrospectively analyzed. The NGS assay targeted 171 cancer predisposition genes, and CNVs were inferred by read-depth analysis and confirmed with multiplex ligation-dependent probe amplification. Detected variants were classified per ACMG/AMP 2015 guidelines. Microsatellite instability (MSI) and mismatch repair (MMR) immunohistochemistry (IHC) results were compared with molecular findings. Among 423 patients (254 Sanger, 169 NGS), the detection rate of pathogenic or likely pathogenic variants was higher in NGS (55.0
Lynch Syndrome, the most common hereditary cancer syndrome affecting 1 in 279 Americans, relies on primary care providers to identify at-risk individuals and promote adherence to prevention strategies. However, adherence remains suboptimal. This review examines barriers and facilitators impacting adherence for individuals with Lynch Syndrome and their primary care providers. A systematic search of six electronic databases (Embase, PubMed, MEDLINE, Google Scholar, CINAHL, and Web of Science) was conducted for studies published between 2011 and 2024. Studies examining barriers or facilitators to cancer prevention among individuals with Lynch Syndrome or primary care providers were included. Methodological quality was assessed using the Joanna Briggs Institute criteria for qualitative studies. Four studies met the inclusion criteria (sample sizes 13–60). Key barriers included limited provider and patient knowledge of Lynch Syndrome, psychological distress related to cancer risk, uncertainty surrounding follow-up protocols, and competing lifestyle priorities. Facilitators included strong wellness motivation, family support, and coordinated care pathways that support surveillance and preventive care. Adherence to cancer prevention in Lynch Syndrome is influenced by psychosocial factors and provider knowledge gaps. Addressing these barriers through targeted education and coordinated care models may improve adherence to prevention in this high-risk population.
Use of polygenic risk scores (PRS) as a risk-stratification tool in cancer screening is an area of increasing interest. The BARCODE1 study is an observational prostate cancer screening study, investigating the use of PRS to risk-stratify people by risk of prostate cancer, with those identified as higher risk invited for prostate cancer screening. Participants of BARCODE1 were invited to take part in a psychosocial sub-study aiming to explore the effect of receiving a polygenic risk score on psychological health, family risk communication and impact on health behaviours. 1300 participants of the BARCODE1 study were invited to complete questionnaires before and after receiving the results of their PRS. A sub-group were invited to participate in one-to-one in-depth semi-structured interviews, conducted in-person, by telephone or video-call. Interviews were audio recorded and transcribed verbatim. Data were analysed using Reflexive Thematic Analysis and the results are reported here. Eighteen participants were interviewed and four themes identified; (a) mutual benefit, (b) emotional impact, (c) risk communication and (d) stoical attitudes to health. Participants reported minimal short-term impact on psychosocial health reported following receipt of a PRS. All participants communicated their genetic risk with their spouse/partner; however, some chose not to inform their children. Participants described themselves as having typical ‘male’ stoical responses to managing their health and that they did not feel the PRS results had an impact on their health behaviours. Providing an individualised PRS informing future risk of prostate cancer was well received. Overall, participants did not report being psychologically, socially or emotionally affected by receiving this genomic risk information. For those identified as being at higher risk it is important that there is access to healthcare professionals who are competent in discussing the meaning of the results. ClinicalTrials.gov NCT03857477, registered 26th Feb 2019.
Genetic testing for known familial pathogenic or likely pathogenic germline variants in cancer susceptibility genes is central to identifying relatives at heightened risk for cancer. However, current data suggest that uptake of this practice referred to as “cascade testing” remains suboptimal. Research demonstrates that healthcare providers can alleviate barriers to cascade testing by providing informational resources to facilitate patient-mediated sharing of their genetic test results with their at-risk relatives. We recruited 103 individuals with a pathogenic or likely pathogenic variant in BRCA1or BRCA2 (BRCA1/2). Participants were randomized to receive a family communication guide with or without a 2-minute video (BRCAShare) that describes the concept of a relative’s recent diagnosis of a harmful variant in BRCA1/2, meant to facilitate sharing of results with relatives. All participants were given surveys to assess reactions to and impact of BRCAShare across three domains: (1) participants’ sharing of genetic information and intent to share genetic information; (2) perceived susceptibility to and seriousness of BRCA1/2 cancer related risks, benefits, or barriers to intrafamilial sharing of results and cascade testing; (3) the impact of family dynamic on sharing of genetic information. The group given access to the BRCAShare video (guide + video) had significantly higher odds of reporting an intent to share and actual sharing with other family members compared to those who did not receive BRCAShare (guide only). Perceptions of cancer risk did not change significantly after viewing BRCAShare, however participants demonstrated strong understanding of risks and benefits of genetic testing at baseline. There was not a significant association between family dynamics and more intent to share. Our research suggests that this video message is a useful method for facilitating family sharing of BRCA1/2 results.
Abstract Background The GEN1 gene is involved in DNA damage repair, as are several prostate cancer susceptibility genes, and is now included in several NGS clinical testing panels. The aim of our study was to investigate the role of GEN1 mutations in the etiology of prostate cancer. Methods First, we sequenced GEN1 in 390 Polish men with familial prostate cancer and 300 population controls using exome sequencing to identify protein-truncating variants and to analyze their possible association with prostate cancer risk. In addition, we performed a large association study of a recurrent frameshift variant of GEN1 (c.1929_1932delAAAG) among 5,857 men with unselected prostate cancer and 3,956 controls. We compared the clinical characteristics of prostate tumors in carriers of c.1929_1932delAAAG and in non-carriers. We conducted loss of heterozygosity (LOH) analysis at the GEN1 locus in prostate cancers from two men with the c.1929_1932delAAAG variant. To analyze survival, patients were followed from diagnosis to death for an average of 101 months. Results We detected two frameshift variants (c.2515_2519delAAGTT (p. Lys839Glufs*2), c.1539delT (p. Asp514Ilefs*13)) by sequencing the GEN1 gene of 390 Polish patients with familial prostate cancer and 300 cancer-free controls. Neither variant was associated with increased prostate cancer risk: c.2515_2519delAAGTT was detected in 20.5% of 390 cases and in 17.1% of 300 controls (p = 0.28), c.1539delT was detected in one case (0.3%) and none of the controls (p = 1.00). The GEN1 variant, c.1929_1932delAAAG (p. Lys645Cysfs*29), was observed in 13 of 5,857 (0.22%) unselected cases and 8 of 3,956 (0.20%) controls (OR = 1.10, p = 0.84). Clinical characteristics of prostate tumors in 13 carriers of c.1929_1932delAAAG and 5,844 non-carriers were similar. All-cause survival was similar for variant carriers and non-carriers (age-adjusted HR = 0.68, p = 0.76). The wild-type GEN1 allele was not lost in two prostate tumors in men with the c.1929_1932delAAAG variant. Conclusions Our analysis suggests that GEN1 is not a prostate cancer susceptibility gene. The study has clinical implications for genetic counseling of men who tested positive for germline variants of GEN1 .
Abstract Aim Due to the expansion of knowledge about genetic predispositions to breast cancer, the International Hereditary Cancer Center in Szczecin has been solicited to update the Polish ministerial guidelines for the qualification of patients who should be offered prophylactic mastectomy. Methods This publication is a review of the scientific literature on the impact of TP53, PTEN, PALB2, CHEK2 pathogenic variants (PVs) predisposing to breast cancer. The number of prophylactic procedures was estimated in May 2024 based on the analysis of pedigree, clinical data and a telephone survey of unselected carriers of the Cancer Genetics Outpatient Clinics in Szczecin. Results The literature data justifies prophylactic mastectomy in all women who carry germline pathogenic variants in TP53, PTEN or PALB2. For CHEK2 carriers prophylactic mastectomy is only justified for women carrying a high-risk variant (i.e. carriers of protein-truncating variants with a positive breast cancer family history). We propose these changes will result in approximately 122 additional bilateral procedures and 25 unilateral procedures annually. conclusions Current, evidence based data supports extending the qualification criteria for prophylactic mastectomy among TP53, PTEN, PALB and CHEK2 PV carriers.
Risk-reducing mastectomy (RRM) for germline pathogenic variant (GPVs) carriers were historically performed as total mastectomy (TM) or skin-sparing mastectomy (SSM), although nipple-sparing mastectomy (NSM) has recently emerged as an oncologically safe RRM option. This retrospective cohort study included all female patients with confirmed BRCA1, BRCA2, PALB2, or other high-penetrance GPVs at two academic institutions in Canada between 2003 and 2024. Temporal trends in NSM uptake were assessed using the Mantel-Haenszel test for trend and multivariable logistic regression. After exclusions, 559 GPV carriers including 319 (57
Abstract Background Patients with von Hippel-Lindau-associated central nervous system hemangioblastoma (VHL-CNS-Hb) have a large economic burden, but there is limited real-world evidence describing their clinical burden in the United States (US). This study compared treatment patterns and monitoring procedures between patients with VHL-CNS-Hb and matched controls in the US. Methods Patients with VHL-CNS-Hb and matched controls were identified from Optum’s de-identified Clinformatics® Data Mart Database. The index date was the date of first CNS-Hb diagnosis (VHL-CNS-Hb cohort) or the date of a random medical claim within the patient’s claims (control cohort). Treatment patterns were assessed in the VHL-CNS-Hb cohort using unadjusted incidence rates. Pain management drug use, disease monitoring procedures, and visits to medical specialists were compared between cohorts using unadjusted and adjusted generalized linear models. Clinical trial number: not applicable. Results The most common treatment observed in the VHL-CNS-Hb cohort (N = 220) was targeted therapy for renal cell carcinoma (2.34 treatment events per 10 person-years). Pain management drug use, monitoring, and specialist visits peaked during the first/second year post-index. Compared to controls (N = 1100), VHL-CNS-Hb patients had higher rates of pain management drug use (adjusted incidence rate ratio [IRR]: 1.96), monitoring procedures (adjusted IRR: 3.93), and specialist visits (adjusted IRRs: 2.49–25.44; all P ≤ 0.001). Conclusions Patients with VHL-CNS-Hb had a substantial, long-term clinical burden that included treatment for multiple VHL manifestations—reflecting the multi-organ nature of the disease—frequent pain management drug use, and high levels of healthcare use for disease monitoring and specialist visits.
Abstract Background Hereditary breast and ovarian cancer (HBOC) confers a markedly increased lifetime risk of breast and ovarian cancers. As no effective surveillance method for early detection of ovarian cancer has been established, risk-reducing salpingo-oophorectomy (RRSO) is recommended for patients with HBOC to prevent disease onset. We evaluated the clinical characteristics of patients with HBOC and the surgical outcomes of RRSO performed at our institution. Methods We retrospectively reviewed women diagnosed with HBOC at our institution between 2018 and 2024. For analyses of surgical outcomes, male patients, patients with prior bilateral adnexectomy, and patients diagnosed with HBOC who did not undergo RRSO were excluded. Clinical data including patient characteristics, surgical procedures, genetic testing, and pathological findings were assessed. Results A total of 283 women were diagnosed with HBOC, and 43 (15.1%) underwent testing based on the results of affected relatives. After excluding 39 patients with prior bilateral adnexectomy, and 105 who did not undergo RRSO, 139 patients were included in the surgical analysis. The uptake rate of RRSO among female patients with HBOC was 57%. The median age at surgery was 50 years (range, 35–75). Pathogenic BRCA1 variants were identified in 48 patients (34.5%), BRCA2 variants in 90 (64.7%), and both BRCA1 and BRCA2 variants in 1 (0.7%). A history of malignancy was observed in 121 patients (breast cancer, n = 121; pancreatic cancer, n = 1; ovarian cancer, n = 1; others, n = 3). Laparoscopic RRSO was performed in 138 cases, with one additional hysterectomy performed laparoscopically and one via laparotomy. No perioperative complications were observed. All 6 cases before April 2020 were performed outside insurance coverage; after insurance coverage was initiated in April 2020, 16 were non-covered and 117 were covered by insurance. Pathological examination revealed occult high-grade serous carcinoma in 4 patients (2.9%) and serous tubal intraepithelial carcinoma in 5 patients (3.6%). To date, no cases of primary peritoneal carcinoma following RRSO have been identified. Conclusions RRSO was performed safely at our institution, with the detection rate of intraepithelial and invasive carcinoma comparable to previous reports. Although no cases of primary peritoneal carcinoma have been observed postoperatively to date, the residual risk remains, indicating the need for continued long-term surveillance.
Abstract Background Breast cancer is the most common cancer among women worldwide. While lifestyle factors contribute to rising incidence, 5–14% of cases result from pathogenic variants in core susceptibility genes such as BRCA1, which also increases ovarian cancer risk and, in men, prostate cancer risk. BRCA1 variants are typically autosomal dominant, making family history a key criterion for genetic testing under guidelines like HBOC or NCCN. Although usually inherited, de novo BRCA1 pathogenic variants occur rarely; only twelve cases have been reported. We present a young woman with breast cancer without a significant family history, and a pathogenic de novo BRCA1 variant. Case presentation We report a 37-year-old woman with HER2-positive, ER/PR-positive invasive breast cancer without relevant family history. After imaging-confirmed T1cN0M0 disease, she received neoadjuvant Her2-targeted chemotherapy, breast-conserving surgery, postneoadjuvant trastuzumab emtansine, radiotherapy, and ongoing endocrine therapy. Genetic testing by Next Generation Sequencing revealed a BRCA1 frameshift variant (NM_007294.4:c.1335_1336del, p.(Arg446Serfs*9)) which was classified as pathogenic per ENIGMA/ACMG guidelines. Absent from population databases and previously reported in cancer cases, it disrupts protein function. Cascade testing showed neither parent carried the variant; microsatellite analysis confirmed parentage, indicating a de novo pathogenic variant. Conclusion A rare de novo BRCA1 variant was identified in a young breast cancer patient. Such variants are likely underdiagnosed due to historical testing limitations and reliance on family history. This case highlights the importance of genetic testing and inclusion in hereditary cancer prevention programs, even without a family history.
Multiple endocrine neoplasia type 1 (MEN1), or Wermer’s syndrome, is a rare autosomal dominant genetic disorder caused by MEN1 mutations, which rarely result in thymic tumors. However, effective therapies or standard treatments are still lacking for patients with MEN1-associated tumors. Some patients with MEN1-associated tumors, such as parathyroid carcinoma and insulinoma, have both germline and somatic MEN1 mutations, consistent with Knudson’s two-hit hypothesis. However, this hypothesis has seldom been reported in connection with MEN1-associated thymic tumors. Herein, we observed a family carrying the MEN1 p.L105Sfs*14 mutation in which two males were diagnosed with MEN1-associated thymic neuroendocrine tumors (NETs). The proband was diagnosed with a left adrenal cortical adenoma and underwent surgery at 49 years of age. After two years, he underwent another surgery for thymic NET. The proband’s son underwent robot-assisted resection at the age of 29 years. Whole exome sequencing (WES) and 425 cancer-related gene panel sequencing revealed that they both had the same germline MEN1 p.L105Sfs*14 mutation and that the son carried the somatic MEN1 p.Q96* mutation. We present a case of two novel MEN1 variants (p.L105Sfs*14 and p.Q96*) in thymic NET. These mutations have not been previously reported in patients with MEN1-associated thymic NET; they resulted in the production of a truncated menin protein. The two-hit of MEN1 germline and somatic mutations occurred in the thymic tumor of the proband’s son. This may partially be the reason for early tumor onset and is consistent with the “two-hit hypothesis”.
BackgroundCancer family syndromes can predispose to malignancies of different sites, including brain and spinal tumours. Germline mutations associated with a high risk of cancer can also be found in patients with metastatic tumours of the brain. We present a few such cases, underscoring the importance of DNA germline testing in all primary and metastatic brain tumours.Case presentationsWe report four cases illustrating the role of DNA testing in intervention decisions in families of patients with both primary and secondary brain tumours. In this article, we included a case of Li-Fraumeni, Lynch, and von Hippel-Lindau syndromes, as well as a metastatic widespread example of BRCA1-related ovarian cancer.ConclusionsIn all primary and metastatic brain tumours, genetic testing for germline mutations of high-risk cancers should be considered.
To identify predictors of decisional conflict among women with a BRCA pathogenic variant (PV) who were eligible for risk reducing salpingo-oophorectomy (RRSO) who had not made a decision to have surgery at least one year after receiving genetic test results. Women with a BRCA1 or BRCA2 PV between the ages of 35 and 70 years old, who had not elected for RRSO at least 12 months after receipt of genetic test results, were administered self-report questionnaires investigating demographic variables, decisional conflict (Decisional Conflict Scale), cancer-related distress (Impact of Event Scale) and cancer risk perception. Decisional conflict scores were generated and a multivariable linear regression was conducted to identify variables associated with decisional conflict. A sample of 107 women completed questionnaires. Overall, 44 participants (41
Hereditary cancer syndromes are genetic conditions that increase an individual's risk for multiple cancer types, often due to mutations that affect critical cellular processes such as DNA repair and cell cycle regulation. Skin cancers, including malignant melanoma (MM), basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and related precancerous lesions may be underrecognized in some hereditary cancer syndromes, as suggested by underlying biological mechanisms and their underreporting in studies. In this narrative review, we examine the skin cancer risks associated with the most prevalent hereditary cancer syndromes, including Li-Fraumeni syndrome (LFS), Lynch syndrome (LS), hereditary breast and ovarian cancer syndrome (HBOC), ATM-associated hereditary cancer syndrome, CHEK2-associated hereditary cancer syndrome, BRIP1-associated cancer predisposition, and hereditary leiomyomatosis and renal cell carcinoma (HLRCC). This review consolidates existing evidence and suggests that mixed cancer syndromes, especially LFS, LS, and HBOC but also pathogenic ATM and CHEK2 variants may predispose individuals to skin cancers, warranting tailored screening and preventive measures. On the basis of emerging evidence, we recommend dermatologic evaluation and individualized UV protection strategies for patients with reviewed hereditary cancer syndromes to reduce skin cancer risk and enhance early detection.
Neurofibromatosis type 1 (NF1; 613113) is a hereditary neurocutaneous disorder that causes tumors in the nervous system, significantly impacting the quality of life (QoL). It is characterized by diverse clinical manifestations, including café-au-lait macules (CALMs), axillary or inguinal freckling, Lisch nodules, skeletal abnormalities, and various types of neurofibromas. Plexiform neurofibromas (PN), a common complication of NF1, are often inoperable and prone to recurrence. The study aimed to describe the clinical characteristics and healthcare burden of NF1, including those with PN and those receiving Selumetinib therapy, in Saudi Arabia. This retrospective observational study was conducted at the National Guard Health Affairs King Abdulaziz Medical City in Saudi Arabia. Patient medical records were retrospectively reviewed from January 2016 to January 2024. We included all patients diagnosed with NF1 who fulfilled the National Institutes of Health (NIH) diagnostic criteria in 2021 or had a confirmed pathogenic NF1 variant on genetic testing. A total of 60 patients with NF1 were included; 55.2
Colorectal cancer (CRC) is the fourth most common cancer in Pakistan and poses significant public health challenges. While the majority of CRC cases are sporadic, 5–10
Multiple polyposis syndromes include Familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome (PJS), Juvenile polyposis syndrome (JPS), PTEN hamartoma tumor syndrome (PHTS), MUTYH-associated polyposis (MAP), NTHL1-associated polyposis (NAP), Polymerase proofreading-associated polyposis (PPAP), and MBD4-associated polyposis. Common to these syndromes is the presence of polyps in the large intestine and very high risk of developing colorectal cancer (CRC), which can reach up to 100% in the case of FAP. The development of FAP is associated with pathogenic variants of the APC gene. However, pathogenic variants are not always detected in patients with FAP, which poses a significant clinical challenge for both patients and their families, who may be at increased risk for developing the disease. A second strong predisposition to CRC is MAP, characterized by biallelic pathogenic variants in the MUTYH gene, with a phenotype similar to FAP. This mini review focuses on potential approaches to improve the diagnosis of patients in whom pathogenic variants in the APC and MUTYH genes are not detected by routine testing.
