Cancer 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. We 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. In 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%) had a high decisional conflict score (greater than 37.5) related to the RRSO decision. Higher education (β = 11.40, 95% C.I: 0.59, 22.20; p = 0.039), non-white race (β = 11.12, 95% C.I: 0.66, 21.57; p = 0.037), and having children (β = 22.89, 95% C.I: 10.07, 35.71; p < 0.001) were significantly associated with higher decisional conflict. Lower decisional conflict was significantly associated with genetic testing more than 3 years prior (β = -13.14, 95% C.I: -23.27, -2.99; p = 0.012). Many women with a BRCA PV who have not elected for RRSO are experiencing high levels of decisional conflict related to the decision regarding RRSO. Interventions that target decisional conflict are needed to increase the uptake of RRSO which will result in a reduction of the risk of ovarian cancer in women with BRCA1 or BRCA2 PV.

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.

BackgroundNeurofibromatosis 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.MethodsThis 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.ResultsA total of 60 patients with NF1 were included; 55.2% of them were females. CALMs were the most common cardinal criteria, affecting 80% of the patients. Among NF1 patients, 12 had PN (20%). Only four patients received Selumetinib therapy. Genetic testing was performed in 39 patients, revealing pathogenic NF1 variants in 29 (74.4%). Pain medications were used by eight patients (13.3%). NF-1-related pain negatively impacted patients’ attention (24%), outdoor activities (24%), and social interactions with friends (20%). Among NF1 patients, 28 (46.7%) required hospitalization, twelve ER visits were conducted by seven (11.7%) NF1 patients, and outpatient services were utilized by nearly all NF1 patients (96.7%), with 1076 outpatient visits. The overall financial burden was high, with NF1 patients incurring $64.5 million, PN patients $13.5 million, and PN patients treated with Selumetinib $3.7 million.ConclusionThis study highlights the clinical and healthcare challenges of NF1 and PN in Saudi Arabia, emphasizing the need for a multidisciplinary approach that combines medical, psychological, and financial support. The limited access to Selumetinib represents a gap. Increasing treatment accessibility and financial support are key to improving the outcomes and QoL.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13053-025-00325-8.

BackgroundColorectal 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% are hereditary, linked to germline pathogenic variants (PVs) in mismatch repair genes (MLH1, MSH2, MSH6, PMS2) and other susceptibility genes (APC, EPCAM). In Pakistan, small-range PVs in MLH1 and MSH2 account for 34.5% of hereditary nonpolyposis colorectal cancer (HNPCC)/suspected-HNPCC and 1.1% of non-HNPCC cases. However, the contribution of large genomic rearrangements (LGRs) in MLH1, MSH2, MSH6, and the 3′ end of EPCAM remains uncharacterized.MethodsWe comprehensively screened 199 Pakistani CRC patients (HNPCC/suspected-HNPCC:18 and non-HNPCC:181), previously tested negative for small-range PVs in MMR genes. LGRs in MLH1, MSH2, MSH6, and the 3′ end of EPCAM were analyzed using multiplex ligation-dependent probe amplification (MLPA). Deletion breakpoints were characterized using long-range polymerase chain reaction (PCR) and Sanger sequencing.ResultsFive distinct MSH2 deletions (5′ upstream, exons 1–3, exons 1–6, exon 7, and exon 11) were identified in 11.1% (2/18) of HNPCC/suspected-HNPCC and 3.3% (6/181) of non-HNPCC cases. A recurrent 5′ upstream deletion was identified in four unrelated patients, including one suspected-HNPCC and three non-HNPCC cases. Other deletions were identified in patients with variable family histories of cancer. No LGRs were detected in MLH1, MSH6, or the 3′ end of EPCAM. Notably, 87.5% of patients with MSH2 LGRs belonged to Punjabi ethnicity.ConclusionsOur findings demonstrate that MSH2 LGRs occur at a notable frequency among Pakistani CRC patients, with a recurrent 5′ upstream deletion representing a potential Punjabi founder variant. Inclusion of this deletion into targeted genetic testing panels may enhance diagnostic yield and improve risk stratification for CRC in Pakistan.

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.

BackgroundLynch syndrome is due to error in DNA mismatch repair (MMR) genes caused by germline pathogenic variants. For some families highly suspicious of Lynch syndrome, the diagnosis may not be confirmed.Case presentationWe present a family where Lynch syndrome has been suspected for 20 years. Although haplotyping and tumor analyses suggested Lynch syndrome, newer sequencing methods such as whole-genome sequencing and long-read sequencing, were needed to detect the underlying genetic cause of their cancer predisposition. We identified a > 3kbp retrotransposon (RT) insertion in MSH6 to be the causative germline variant. Further, we reviewed the literature for RT events in Lynch syndrome families and found a total of 40 RT cases, making up about 0.5% of Lynch cases. Two-third of the RTs were shorter ALU-elements (< 500 bp).ConclusionsAlthough RTs insertions do not seem to be a common cause of Lynch syndrome, the number might be underestimated because of the difficulties in detecting these variants with well-established methods like Sanger sequencing and NGS target sequencing.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13053-025-00324-9.

BackgroundHereditary colorectal cancer (CRC) predisposition syndromes account for 5–10% of all diagnosed CRC cases. Lynch syndrome (LS), Familial Adenomatous Polyposis (FAP), and MUTYH-associated polyposis (MAP) are well-characterized hereditary syndromes known to contribute to colorectal cancer predisposition. However, other inherited genetic factors beyond these established conditions remain underexplored. Recent advancements in next-generation sequencing (NGS) have facilitated the identification of germline pathogenic variants (gPV) in cancer predisposition genes, enhancing diagnostic and management strategies for hereditary CRC syndromes. Using this technology, this study aimed to investigate the genetic causes of CRC in 23 Turkish patients belonging to 23 different families.MethodsPatients with a personal or familial history of colorectal cancer (CRC) or polyposis were selected from a cohort of 54 individuals examined between 2019 and 2022. Genetic testing was performed using the TruSight® Cancer and Qiaseq panels on the Illumina NextSeq next-generation sequencing (NGS) platform.ResultsA total of 23 variants were identified, including 10 pathogenic or likely pathogenic variants, 5 of which were novel. These germline pathogenic/likely pathogenic variants were detected in the key genes MLH1, MSH6, PMS2, and APC, which are associated with LS and FAP. Variants were also found in other genes, including FANCC, CHEK2, ATM, and MUC16. Additionally, 13 variants of uncertain significance (VUS) were identified, 5 of which were novel. These VUS were detected in the genes MUTYH (linked to MAP), ATR, XRCC3, PALB2, ATM, SYNE1, RAD51D, NF1, ABRAXAS1, ERBB2, FGFR, and CHEK2, necessitating further investigation to determine their potential role in CRC predisposition.ConclusionThese findings highlight the utility of NGS in identifying germline variants linked to hereditary CRC syndromes and emphasize the need for functional studies to assess the pathogenicity of VUS.