Search Results (231)

Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. Risk factors for EC include metabolic alterations (obesity, metabolic syndrome, insulin resistance), hormonal imbalance, age at menopause, reproductive factors, and inherited conditions, such as Lynch syndrome. For the inherited forms, several genes had been implicated in EC occurrence and development, such as POLE, MLH1, TP53, PTEN, PIK3CA, PIK3R1, CTNNB1, ARID1A, PPP2R1A, and FBXW7, all mutated at high frequency in EC patients. However, gene function impairment is not necessarily caused by mutations in the coding sequence of these and other genes. Gene function alteration may also occur through post-transcriptional control of messenger RNA translation, frequently caused by microRNA action, but transcriptional impairment also has a profound impact. Here, we review how chromatin modifications change the expression of genes whose impaired function is directly related to EC etiopathogenesis. Chromatin modification plays a central role in EC. The modification of chromatin structure alters the accessibility of genes to transcription factors and other regulatory proteins, thus altering the intracellular protein amount. Thus, DNA structural alterations may impair gene function as profoundly as mutations in the coding sequences. Hence, its central importance is in the diagnostic and prognostic evaluation of EC patients, with the caveat that chromatin alteration is often difficult to identify and needs investigations that are specific and not broadly used in common clinical practice. The different phases of the healthy endometrium menstrual cycle are characterized by differential gene expression, which, in turn, is also regulated through epigenetic mechanisms involving DNA methylation, histone post-translational modifications, and non-coding RNA action. From a medicolegal and policy-making perspective, the implications of using epigenetics in cancer care are briefly explored as well. Epigenetics in endometrial cancer is not only a topic of biomedical interest but also a crossroads between science, ethics, law, and public health, requiring integrated approaches and careful regulation. Full article

Microsatellite instability (MSI) is a clinically important biomarker for predicting responses to immune checkpoint inhibitors and identifying individuals with Lynch syndrome. Although MSI detection has been incorporated into Illumina’s next-generation tumor sequencing workflows, interpretation of the results remains challenging due to the absence of standardized thresholds and reporting criteria. In this retrospective study, we assessed the performance of MSI detection using Illumina’s targeted NGS panels—TruSight Tumor 170 and TruSight Oncology 500. The NGS-based MSI results were compared to those obtained by the reference method, MSI-PCR, across multiple tumor types in a real-world cohort of 331 cancer patients. The NGS method demonstrated high concordance overall (AUC = 0.922), though sensitivity was lower in colorectal cancers (AUC = 0.867) due to broader score variability and overlapping distributions. Our findings support the clinical utility of Illumina’s NGS-derived MSI scores for identifying MSI-H tumors, with a recommended MSI score cut-off value of ≥13.8%. Additionally, a borderline group was introduced, defined by an MSI score ranging from ≥8.7% to <13.8%. Within this range, the integration of TMB into the MSI classification workflow significantly improves diagnostic accuracy. For samples that remain inconclusive, orthogonal confirmation using MSI-PCR is advised to ensure accurate MSI classification. Full article

Background: Lynch syndrome (LS) is an autosomal dominant disease caused by germline pathogenic variants in one of the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene. LS patients harboring genetic variants in one of the MMR genes display a heterogeneous phenotype in terms of cancer penetrance (lifetime cancer risk) and expressivity (malignancies in gastrointestinal or other specific organs). Methods: DNA samples from the index cases of Family 1 and Family 2 were analyzed using a next-generation sequencing (NGS) multigene panel comprising 25 genes involved in major hereditary cancer predisposition syndromes. This NGS analysis revealed a variant of uncertain significance (VUS) in the PMS2 gene (NM_000535.7: c.184G>A; p.Gly62Arg) of both index cases, which was validated by Sanger sequencing. The structural and functional impact of this VUS was evaluated in silico using twelve different prediction tools and by immunohistochemical analysis of MMR proteins. Results: Based on the personal and family history of the two families, tumor pathology, and protein in silico analysis, the novel PMS2 gene variant described in this study may be associated with hereditary LS. Considering the low penetrance of PMS2 gene variants in LS-associated tumors and the intrafamilial variability of the associated clinical phenotypes, the multidisciplinary approach proposed in this study could significantly support the evaluation of suspected LS cases carrying PMS2 variants. Full article

Background: The national guidelines, informed by evidence from the National Institutes of Health (NIH), define the criteria for genetic testing of BRCA1/2 and other genes associated with Hereditary Breast and Ovarian Cancer (HBOC) and Lynch Syndrome (LS). When a germline pathogenic variant (PV) is identified in an index case, clinical recommendations advise informing at-risk relatives about the availability of predictive genetic testing, as early identification of carriers allows for timely implementation of preventive measures. Methods: This retrospective observational study examined data collected between 2017 and 2024 at the Medical Genetics Unit of the “Renato Dulbecco” University Hospital in Catanzaro, Italy. The analysis focused on trends in the identification of individuals carrying PVs in cancer predisposition genes (CPGs) and the subsequent uptake of cascade genetic testing (CGT) among their family members. Results: Over the study period, from 116 probands were performed 257 CGTs on 251 relatives. A notable reduction of approximately ten years in median age was observed, 39% were found to carry familial mutation and were referred to personalized cancer prevention programs. Among these, 62% accessed Oncological Genetic Counselling (CGO) within one year of the proband’s diagnosis, suggesting effective communication and outreach. Conclusions: The findings highlight the critical role of effective CGO and intrafamilial communication in hereditary cancer prevention. The identification of PVs, followed by timely CGTs and implementation of preventive strategies, significantly contributes to early cancer risk management. Periodic monitoring of CGT uptake and outcome trends, as demonstrated in this study, is essential to refine and optimize genetic services and public health strategies. Full article

Cutaneous manifestations can serve as early and sometimes the first clinical indicators in various hereditary cancer predisposition syndromes. This review provides a comprehensive overview of the dermatological signs associated with these syndromes, aiming to facilitate their recognition in clinical practice. Hereditary Breast and Ovarian Cancer syndrome is notably linked to an increased risk of melanoma. BAP1 tumor predisposition syndrome is characterized by BAP1-inactivated melanocytic tumors. Muir–Torre syndrome, a variant of Lynch syndrome, presents with distinctive cutaneous neoplasms such as sebaceous carcinomas, sebaceous adenomas, and keratoacanthomas. PTEN hamartoma tumor syndrome commonly features hamartomatous growths, trichilemmomas, acral keratoses, oral papillomas, and genital lentiginosis. Gorlin syndrome is marked by basal cell carcinomas and palmoplantar pits, while Peutz–Jeghers syndrome is identified by mucocutaneous pigmentation. In familial adenomatous polyposis, the cutaneous findings include epidermoid cysts, fibromas, desmoid tumors, and lipomas. Additionally, we examined monogenic disorders associated with cancer risk and skin involvement, such as xeroderma pigmentosum, neurofibromatosis type 1, familial atypical multiple-mole melanoma syndrome, and Fanconi anemia. The early recognition of these dermatologic features is essential for a timely diagnosis and the implementation of appropriate surveillance strategies in individuals with hereditary cancer syndromes. Full article

Background: Hereditary cancer syndromes such as BRCA1/2 and Lynch syndrome significantly increase the lifetime risk of ovarian, fallopian tube, and endometrial cancers. Risk-reducing salpingo-oophorectomy (RRSO) and hysterectomy are standard preventive strategies. Vaginal natural orifice transluminal endoscopic surgery (vNOTES) has recently emerged as a minimally invasive, scarless alternative that may enhance patient acceptance while maintaining oncologic safety. Objective: This narrative review aims to synthesize the current evidence regarding the role of vNOTES in risk-reducing gynecologic surgery for women with hereditary cancer syndromes, focusing on surgical feasibility, technical considerations, oncologic safety, and patient-reported outcomes. Methods: A structured literature search was conducted in PubMed and Web of Science for studies published between January 2000 and April 2025, using terms related to vNOTES, prophylactic gynecologic surgery, BRCA mutations, and Lynch syndrome. Inclusion criteria focused on studies reporting outcomes of vNOTES in risk-reducing or oncologic contexts. A total of eight studies were included for qualitative synthesis. Results: vNOTES has demonstrated technical feasibility and favorable surgical outcomes in risk-reducing procedures such as RRSO and hysterectomy in BRCA and Lynch syndrome carriers. Comparative studies report lower postoperative pain, faster recovery, and high patient satisfaction, with oncologic standards maintained through specimen containment, peritoneal inspection, and adherence to the SEE-FIM protocol. Limitations include the learning curve and restricted access to the upper abdomen, which may necessitate hybrid approaches in selected cases. Conclusions: vNOTES offers a promising, patient-centered surgical approach for hereditary cancer prevention, combining oncologic safety with enhanced recovery and cosmetic benefits. Further research is needed to standardize protocols, evaluate long-term outcomes, and define its role within broader personalized cancer prevention strategies. Full article

Multigene panel testing for hereditary breast and ovarian cancer is becoming a standard in medical care. Recent studies highlight the importance of pathogenic variants in genes with moderate or low penetrance. 255 consecutive breast cancer cases who met the criteria for genetic testing were approached by next-generation sequencing. From 104 pathogenic mutations identified, 21 were in moderate-risk genes, three in low-risk genes and eight in the group with insufficient evidence genes. The most frequent PVs in moderate-risk genes were in the CHEK2 gene—Checkpoint kinase 2 gene (13 cases), the ATM gene—Ataxia-telangiectasia Mutated gene (six cases), BARD1—BRCA1-associated ring domain 1 gene (one case) and RAD 51C–radiation sensitive 51 Paralog C—(one case) genes. Among the low-risk genes, we identified only three pathogenic mutations (two in MSH1 gene—melanocyte-stimulating hormone gene—and one in MLH1 gene—MutL homolog 1 gene). Reporting on low-risk mutations and those with insufficient evidence regarding breast cancer risk is valuable to enable a more comprehensive view of genetic factors influencing disease development and improve screening protocols, tailor diagnostic strategies, and individualize treatment plans. This approach also enhances our understanding of BC risk in various populations, potentially leading to new insights into genetic contributions to cancer and the refinement of risk models for patient care. Full article

The integrity of the genome is maintained by mismatch repair (MMR) proteins that recognize and repair base mismatches and insertion/deletion errors generated during DNA replication and recombination. A defective MMR system results in genome-wide instability and the progressive accumulation of mutations. Tumors exhibiting deficient MMR (dMMR) and/or high levels of microsatellite instability (termed “microsatellite instability high”, or MSI-H) have been shown to possess fundamental differences in clinical, pathological, and molecular characteristics, distinguishing them from their “microsatellite stable” (MSS) counterparts. Molecularly, they are defined by a high mutational burden, genetic instability, and a distinctive immune profile. Their distinct genetic and immunological profiles have made dMMR/MSI-H tumors particularly amenable to treatment with immune checkpoint inhibitors (ICIs). The ongoing development of biomarker-driven therapies and the evaluation of novel combinations of immune-based therapies, with or without the use of conventional cytotoxic treatment regimens, continue to refine treatment strategies with the goals of maximizing therapeutic efficacy and survival outcomes in this distinct patient population. Moreover, the resultant knowledge of the mechanisms by which these features are suspected to render these tumors more responsive, overall, to immunotherapy may provide information regarding the potential optimization of this therapeutic approach in tumors with proficient MMR (pMMR)/MSS tumors. Full article

Background and Objectives: Lynch syndrome (LS), an autosomal dominant condition arising from germline mutations in mismatch repair (MMR) genes, is a major cause of hereditary early-onset colorectal cancer (CRC). Although patients diagnosed before age 50 represent a critical subgroup where Lynch syndrome might be more prevalent, data on the precise frequency, clinical outcomes, and molecular correlates remain heterogeneous across studies. This systematic review was conducted to (1) estimate the prevalence of MMR deficiency (dMMR) and confirmed LS in patients diagnosed with CRC before the age of 50, and (2) examine immunohistochemistry (IHC) mismatch repair testing patterns and associated molecular findings (BRAF mutations, MLH1 promoter hypermethylation, somatic MMR gene alterations). Methods: Following a predefined search strategy in PubMed, Scopus, and Web of Science, five relevant studies were identified (n = 5). Each study comprised patients younger than 50 who underwent IHC-based tumor screening. Data extraction covered demographic details, number of patients tested, proportion with abnormal IHC, frequency of somatic or germline MMR gene mutations, and method of classification into sporadic dMMR vs. LS. Quality assessment was performed using recommended scales for observational studies. Results: Among 5 studies totaling 960 early-onset CRC patients, the frequency of dMMR CRC ranged from 8.4% to 19.1%. The confirmed prevalence of LS among all young-onset CRC was between 5.0% and 5.9% in three studies but reached 8.9% in another and 5.1% in yet another. Across all studies, the presence of right-sided tumors and histopathological features such as tumor-infiltrating lymphocytes were more common in dMMR cancers. Incorporation of MLH1-promoter hypermethylation and/or BRAF V600E mutation testing aided discrimination of sporadic dMMR CRC from germline LS cases. Conclusions: The prevalence of LS in CRC patients younger than 50 is clinically significant, at approximately 5–9%. Routine IHC-based MMR screening is both feasible and effective for detecting LS in early-onset CRC. Further research is needed to standardize universal testing protocols, delineate the role of additional molecular assays, and ensure comprehensive genetic counseling for at-risk individuals. Full article

Background and Objectives: Despite the well-established role of the BRCA and mismatch repair (MMR) genes in DNA damage repair pathways, a substantial proportion of familial cancer cases still lack pathogenic variants in those genes. Next Generation Sequencing (NGS) panels have emerged as a powerful tool to identify hereditary cancer at-risk individuals and subsequently provide them with accurate management. Materials and Methods: Families harbouring PVs in RAD50, RAD51C, RAD51D, and BRIP1 were identified by analysing a cancer-predisposing genes panel using Ion S5 system technology. A retrospective cohort of 155 families tested only for the BRCAs of MMR genes were reanalysed, prompted by an increase in familial cases or new cancer diagnoses among index cases. Results: We identified 40 families through molecular reanalysis (33 with Hereditary Breast and Ovarian Cancer (HBOC) and 7 with Lynch Syndrome (LS)), with positive test results among 155 families lacking BRCA or MMR mutations. The most frequently mutated genes after ATM and CHEK2 were BRIP1, RAD51D, and RAD51C with 16, 13, and 9 positive families, respectively. The phenotype–genotype correlations not only revealed ovarian and HER-negative breast cancer predispositions but also other cancer types, particularly lung and gastric, and individuals with a second or third distinct cancer episode. Conclusions: Broader ranges of malignancies, including gastric, lung, and bladder, have been identified among BRIP1, RAD51D, and RAD51C positive families. The results generated using NGS provide a comprehensive genetic landscape in each patient that could explain the diversity of phenotypes shown in PV families that, combined with non-genetic factors, might enable accurate surveillance and personalized treatments. NGS reanalysis doubled our diagnostic yield and was a good strategy to identify hereditary cancer families that would otherwise be overlooked. Full article

Lynch syndrome (LS)—also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC)—is caused by pathogenic germline mutations in DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, and PMS2. Although it accounts for only 1–5% of all colorectal cancers (CRCs), LS presents with a particularly high lifetime cancer risk and often occurs at younger ages. Identifying LS in patients under 60 years old is crucial for targeted surveillance and early interventions. Variations in clinical presentation and prognosis may exist based on the specific gene mutated, yet these patterns are not fully elucidated. This review aims to synthesize data on clinical outcomes among LS patients under 60, with an emphasis on how different MMR gene mutation patterns might influence prognosis, survival, and treatment decisions. Five population-based studies examining CRC patients younger than 60 years were included according to predefined eligibility criteria. Two independent reviewers screened and extracted data focusing on MMR deficiency detection methods (microsatellite instability [MSI] and/or immunohistochemistry [IHC]), rates of confirmed germline mutations, frequency of BRAF testing, and clinical endpoints such as stage distribution, survival outcomes, and recurrence. Risk of bias was assessed using standardized tools appropriate to each study design. The synthesis focused on comparing outcomes among individuals with MLH1, MSH2, MSH6, and PMS2 mutations, as well as delineating the proportion of patients with sporadic MSI under 60 years of age. Across the five studies, MSI positivity in CRC patients under 60 years ranged from 7.5% to 13%. The frequency of confirmed germline MMR mutations varied between 0.8% and 5.2% in specific cohorts, aligning with LS prevalence estimates of 1–5%. Different mutation patterns correlated with some variation in clinical presentation. Cases with MSH2 and MLH1 mutations more frequently exhibited synchronous or metachronous tumors, while MSH6 and PMS2 mutations displayed more heterogeneous IHC patterns. Where survival data were provided, LS patients under 60 years had better overall survival compared to MMR-proficient individuals, though some studies also noted a potential lack of benefit from standard 5-fluorouracil adjuvant therapy in MMR-deficient tumors. Screening by MSI or by IHC—supplemented with BRAF mutation testing to exclude sporadic MSI—facilitates early detection of LS in CRC patients under 60 and highlights notable differences between mutation types. Although overall outcomes for LS patients can be favorable, especially for stage II disease, the precise impact of each specific mutated gene on clinical course remains heterogeneous. Future large-scale prospective studies are needed to clarify optimal screening protocols and individualized treatment strategies for LS patients under 60. Full article

Background: Hereditary colorectal cancer syndromes, including familial adenomatous polyposis (FAP), Lynch syndrome (LS), and Peutz–Jeghers syndrome (PJS), are associated with an increased risk of small bowel cancer (SBC). Due to the low incidence and non-specific presentation of SBC, effective surveillance strategies are essential for early detection and management. This review aims to evaluate and compare current endoscopic techniques for small bowel surveillance in these patients. Methods: A comprehensive review was conducted using peer-reviewed studies sourced from PubMed. Various endoscopic modalities, including capsule endoscopy (CE), device-assisted enteroscopy (DAE), and intraoperative enteroscopy (IOE), were assessed for their diagnostic yield, safety, and clinical utility. Surveillance recommendations of the different syndromes were also examined. Results: CE offers high sensitivity but lacks histological sampling capability. DAE, including double-balloon enteroscopy (DBE) and single-balloon enteroscopy (SBE), enables direct visualization, biopsy, and therapeutic interventions, albeit with greater procedural complexity. In FAP, duodenal surveillance follows the Spigelman classification to stratify cancer risk, while jejunal and ileal polyps remain less studied. LS patients have an increased SBC risk, warranting tailored endoscopic approaches. In PJS, surveillance aims to mitigate intussusception risks and allow early malignancy detection. Conclusions: Optimized surveillance strategies in hereditary colorectal cancer syndromes require a multimodal approach, integrating advanced endoscopic techniques with genetic risk stratification. Centralized care in tertiary centers improves outcomes by ensuring standardized surveillance protocols and enhancing early cancer detection. Artificial intelligence (AI) applied to CE and DAE is shaping promising prospects for the future surveillance of small bowel polyps by enhancing diagnostic accuracy and reducing the duration of the diagnostic process. Further research should investigate AI-assisted imaging and molecular biomarkers to optimize screening strategies. Full article

Background/Objectives: Endometrial cancer (EC) is a common malignancy in developed countries, with incidence closely linked to lifestyle factors and genetic predispositions, notably Lynch syndrome. Traditional biopsy methods for diagnosis and monitoring are invasive. This study aims to develop and validate a non-invasive diagnostic method for EC using liquid biopsy, specifically examining circulating tumor DNA (ctDNA) for its potential in early detection and disease monitoring. Methods: A cohort of 63 patients with EC or atypical endometrial hyperplasia (AEH) was recruited from the Gynecological Unit of the Azienda Ospedaliera Universitaria Federico II. Plasma samples were processed to extract ctDNA, which was sequenced and analyzed for mutations. Matched tumor tissue and germline DNA were also examined to confirm mutation concordance and assess potential genetic predispositions. Results: Pathogenic mutations were identified in plasma ctDNA in 59 out of 63 cases (93%), with a 65% concordance between plasma ctDNA mutations and those found in solid tumor samples. Key mutations in genes such as PTEN, PIK3R1, and KMT2C were significantly associated with a higher tumor grade and advanced stage disease, such as myometrial infiltration. Conclusions: Liquid biopsy shows promise as a minimally invasive diagnostic and monitoring tool for EC, offering real-time insights into tumor biology. The high mutation concordance between the plasma ctDNA and tumor tissue underscores the potential of a liquid biopsy in managing EC, particularly for patients at risk of recurrence. Further longitudinal studies are needed to establish ctDNA as a standard tool in EC diagnosis and monitoring. Full article

Gastrointestinal cancers, especially colorectal cancer, represent a major health care issue. According to the data, the incidence of these cancers exceeds 50/100,000, mainly in high-income countries. Risk factors for the disease include genetic factors (i.e., Lynch syndrome) and lifestyle factors, e.g., overweight and obesity, smoking tobacco products, low-fiber diet, and low physical activity. When diagnosed early, gastrointestinal cancers can, in most cases, be effectively treated. This review focuses on the presentation of research in the area of screening and its results. It provides insights into current trends in research on methods of early cancer detection and improving screening reporting. Differing levels of screening reporting are one of the main challenges faced by researchers in this field. Research on this issue should be conducted in parallel with research on methods of early diagnosis. Finally, the development of diagnostic methods and communication with patients are important elements of public health. Full article

Background: The efficacy of germline testing in colorectal cancer has been proven; however, germline testing in individuals with sebaceous neoplasms is less well defined. This review aims to summarize the literature on sebaceous neoplasms to date, describing the somatic tumor profiles, tumor screening methods, and personal and family history that are suspicious of a germline mutation. Sebaceous neoplasms can be attributed to a variety of etiologies, including UV exposure, immunodeficiency, germline mutations, or multifactorial influences associated with aging. Sebaceous tumors with abnormal microsatellite instability and mismatch repair deficiency are indicative of a germline mutation in 20–50% of cases, which is similar to rates found in colorectal tumors. Personal and familial history can also be suggestive of a germline etiology in these patients and should be assessed routinely, as approximately 30% of individuals with sebaceous neoplasms carry a germline mutation. We outline a strategy for the identification of individuals at risk for germline mutations, recommendations for the management of mutation carriers, and treatment options for individuals with sebaceous neoplasms. Conclusions: Sebaceous tumors are most often sporadic; however, evaluations of a germline etiology are prudent to effectively identify those at risk of additional malignancies as well as at-risk family members. Referral to genetic counseling and germline genetic testing for individuals at risk can significantly impact cancer treatment and screening in patients and their families. Full article