Familial Cancer最新文献

The CHEK2 gene confers a moderate risk for breast cancer, but existing knowledge is largely based on the European founder variant, 1100delC. This study aimed to characterize the distinct phenotypes associated with unique CHEK2 variants in Brazilian families. In this cross-sectional study, 1055 patients meeting criteria for Hereditary Breast and Ovarian Cancer syndrome underwent germline multigene panel testing. Pathogenic/likely pathogenic variants (PVs) were found in 141 patients (13.4%), of whom 13 (9.2%) had a CHEK2 PVs. Subsequent family cascade testing brought the total number of individuals studied to 57. Three distinct CHEK2 PVs were identified: c.846 + 1G > C, c.349 A > G, and c.593-1G > T. While breast cancer was the most frequent tumor, specific PVs correlated with different cancer spectra. The c.349 A > G variant showed an enrichment for papillary thyroid cancer. In contrast, the c.846 + 1G > C variant was associated with melanoma, prostate, and testicular cancer, in addition to breast, colon, and kidney cancers. These findings suggest that different CHEK2 PVs may confer distinct cancer risks. Investigating these variants across diverse populations is crucial for refining phenotype characterization and improving genetic counseling as access to genetic testing expands.

Li-Fraumeni Syndrome (LFS) is an autosomal dominant condition associated with germline pathogenic variants in the tumor suppressor gene TP53. Carriers have a higher risk of developing multiple primary tumors and a broad spectrum of cancers. The main tumors include premenopausal breast cancer, sarcomas, adrenocortical carcinoma and central nervous system tumors. Melanoma is a recognized but uncommon manifestation of LFS, with few reports in the literature linking the syndrome to this malignancy. The main objective of this study is to evaluate the occurrence of melanoma in patients carrying the germline pathogenic variant in the TP53 gene, registered in the Brazilian Li-Fraumeni Syndrome Study (BLISS) database from 2018 to 2023. From our database, six out of 512 patients developed melanoma, with melanoma representing the sole clinical manifestation of LFS in half of these patients. Of the 512 patients with LFS, 417 were carriers of the R337H variant, and among them, three patients developed melanoma. Three melanomas were detected during routine surveillance with total-body photography and digital dermoscopy. This study shows that melanoma is one of the manifestations of LFS, highlighting the importance of its screening within the Toronto protocol. It is essential for healthcare professionals who manage patients with LFS to recognize this risk in order to enable early diagnosis and identification of precursor lesions.

NF2-Schwannomatosis (NF2-SWN) is a disease characterized by multiple tumors of the central and peripheral nervous system. Surgery remains an important treatment option, sometimes performed on an urgent basis, but usually planned within the context of complex multi-tumour burden and morbidity. It is difficult to provide a comprehensive generic decision tree because each patient has a unique disease burden, but we will detail in this review the therapeutic indications for each tumor type, vestibular schwannomas, meningiomas, spinal schwannomas and meningiomas, spinal ependymomas and peripheral schwannomas. The experience of the multidisciplinary team impact outcomes in this rare disease and centralized care has been shown to improve the disease course.

While the physical manifestations of NF2-related schwannomatosis (NF2-SWN) have been well documented, there are a limited number of qualitative studies on health-related quality of life in NF2-SWN. The present study sought to explore the cumulative impact of symptoms, treatments, and healthcare on the quality of life of individuals with NF2-SWN. We interviewed 16 adolescent and adult patients with NF2-SWN enrolled in the INTUITT-NF2 clinical trial and 10 clinicians with NF2-SWN expertise from the United States, United Kingdom, and Australia. Analysis of patient and clinician interviews yielded five overall themes: (1) impacts on daily living, (2) impacts on life roles, (3) impacts on relationships and social integration, (4) impacts on psychological and emotional wellbeing, and (5) burden of treatment and healthcare. Multiple symptom areas contributed to impairments in quality of life across each theme. These findings reveal that quality of life in NF2-SWN is shaped not only by individual symptoms, but by their complex, cumulative impact-highlighting the urgent need for disease-specific tools and holistic care approaches that reflect the lived realities of patients across the lifespan.

Pancreatic cancer is a highly aggressive malignancy, with 10%-20% of cases linked to inherited genetic risk factors. Pathogenic variants (PVs) in the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene have been associated with pancreatic cancer among Caucasians. However, data from South Asians are lacking. We investigated the prevalence of CDKN2A germline variants in 200 consecutively and prospectively enrolled, unselected pancreatic cancer patients from Pakistan. Comprehensive variant detection was performed using high-resolution melting analyses followed by DNA sequencing. Novel variants were investigated for pathogenicity using in-silico tools, and potentially functional variants were screened in 200 healthy controls. Five unique CDKN2A variants were identified, including one novel synonymous variant c.285G > T (p.Val95Val), one missense variant c.442G > A (p.Ala148Thr), one intronic variant (c.150 + 32A > T), and two variants (c.*29G > C and c.*69C > T) in the 3' untranslated region. No PVs in CDKN2A were detected. All variants were classified as benign, except the novel synonymous variant (p.Val95Val), which was categorized as a variant of uncertain significance (VUS) based on in-silico protein function prediction scores (Revel 0.38; PhyloP 2.88). This variant was identified in a 61-year-old male patient of Punjabi ethnicity with Grade 2 periampullary ductal adenocarcinoma with lymphovascular invasion and was absent in 200 healthy controls. Our study showed that CDKN2A PVs are very rare among unselected Pakistani pancreatic cancer patients, suggesting a negligible contribution to inherited pancreatic cancer risk in this population.

The 2024 Biennal Meeting of the International Society for Gastrointestinal Hereditary Tumors (InSiGHT) was held in Barcelona from June 19th to 22nd. The meeting featured a diverse program, including lectures, abstract presentations, flash talks, debates and poster presentations. Over 400 attendants from various countries participated. The primary focus of the program was on Lynch syndrome and polyposis syndromes. Other conditions addressed included constitutional mismatch repair deficiency (CMMRD), hereditary pancreatic cancer, hereditary gastric cancer, early-onset colorectal cancer, and familial colorectal cancer. This personal report summarizes a selection of lectures and debates, highlighting the progress made in the understanding of each hereditary cancer syndrome and its related conditions.

Genetic testing advancements have improved detection of hereditary polyposis syndromes. Many individuals with unexplained adenomatous polyposis previously underwent limited genetic testing and may benefit from updated testing to identify underlying hereditary polyposis syndromes. We aimed to evaluate the yield of updated testing in adenomatous polyposis cases with previously negative germline genetic testing. Individuals with adenomatous polyposis with uninformative genetic testing prior to 2016 and subsequent updated multi-gene panel testing were analyzed. The updated multi-gene panel testing included the currently recommended 12 polyposis-associated genes. Twenty-one individuals met study criteria. Updated genetic testing identified pathogenic variants (PV) in 6/21 (29%) with four (19%) of the PVs associated with a polyposis phenotype (APC [× 2], AXIN2, and biallelic PMS2) and two (10%) were associated with other cancer predisposition syndromes (ATM and RAD51C). Although APC was included in the initial testing for the two patients found to have APC PVs, the previously completed deletion/duplication analysis did not include the 5' untranslated region. Updated genetic testing in individuals with unexplained polyposis had a very high yield and identified previously undetected PVs. Updated testing enabled more accurate diagnoses and personalized surveillance recommendations as well as identification of at-risk relatives. Given the improved diagnostic yield, it is crucial to consider genetic testing for individuals with unexplained polyposis who have previously undergone limited testing, due to small gene lists and/or outdated technology, ensuring alignment with current standards.