Substratification of mismatch repair deficient endometrial cancers based on mechanism of MMR loss can provide prognostic and predictive refinement.

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.

The Vital Role of Family Physicians in the Screening and Early Detection of Lynch Syndrome: A Case Report

Localised upper tract urothelial carcinoma (UTUC) presents a diagnostic challenge due to its biological heterogeneity and anatomical complexity. Early detection and precise risk stratification are crucial for improved prognosis. The combination of histology, urine cytology, and biopsy plays a central role in preoperative diagnosis. Histopathological analysis allows for the determination of tumour grade, with the distinction between low-grade and high-grade tumours being particularly important. Urine cytology demonstrates high specificity for high-grade tumours, but limited sensitivity for low-grade lesions. Molecular markers such as FGFR3 and TP53 mutations, as well as microsatellite instability (MSI) in Lynch syndrome, can contribute to risk stratification and assessment of tumour behaviour. Endoscopic resection represents an effective organ-preserving therapy, particularly for non-invasive tumours. Despite higher recurrence rates compared with radical nephroureterectomy (RNU), it can be a valuable option for patients with chronic renal insufficiency given its organ-sparing approach. However, close follow-up is essential to detect recurrences early.

Multiple cancers occur in the same individual, such as hereditary breast and ovarian cancer (HBOC) syndrome and Lynch syndrome. Here, we report a patient with HBOC syndrome who developed four different cancer types (pancreatic cancer, right lung adenocarcinoma, prostate cancer, and left lung adenocarcinoma) within a relatively short period of 6.5years. In HBOC syndrome, the lung adenocarcinoma is rare, and the tumors were initially suspected to be lung metastases from pancreatic cancer, respectively. The pathological analysis results in each of the three lesions were inconsistent. A whole-exome analysis was performed on all three tumors using next-generation sequencing (NGS). The results showed that many of the deletion mutations found in pancreatic cancer were not present in other lung tumors. Homologous recombination is required for the repair of deletion mutations, but this function is impaired in HBOC syndrome. Deletions occurring in the primary tumor are irreversible and should be inherited in metastatic lesions. Therefore, we hypothesized that these three cancers arose independently, that each lung tumor was a primary tumor rather than a metastasis of pancreatic cancer, and that their resection would be curative. This assumption was reasonable, as no new lesions were observed in a 10-year follow-up study since the onset of pancreatic cancer. Tracking genetic traits using NGS helps understand the origins and progression of malignant tumors.

Lynch Syndrome (LS) is a hereditary cancer predisposition syndrome caused by germline pathogenic/likely pathogenic variants in mismatch repair (MMR) genes. While LS is not traditionally thought to increase childhood cancer risk, some studies have shown an increased prevalence of germline MMR variants in the pediatric oncology population. Herein, we discuss 55 individuals with pediatric cancer and LS. Of these, MSH2 was the most common germline change (36%). Of those tested for loss of heterozygosity (LOH) or microsatellite instability (MSI), the majority had LOH present (78%) and were MSI high (71%), suggesting the contribution of LS to oncogenesis in these individuals.

Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer, is a genetic condition that increases the risk of developing colorectal cancer (CRC) and other cancers due to defective DNA mismatch repair (dMMR). This article reports a case of a patient who developed lung adenocarcinoma followed by CRC. The detection of dMMR by immunohistochemistry in both the metastatic lesion and CRC led to retrospective testing, which revealed a concomitant loss of MLH1 and PMS2 in the primary lung cancer. Germline testing subsequently confirmed a diagnosis of LS associated with an MLH1 mutation, with significant familial clustering observed. The patient responded effectively to anti-PD-1 immunotherapy. This case highlights that lung adenocarcinoma can be a manifestation of LS and underscores the critical importance of retrospective MMR testing in establishing the diagnosis. Furthermore, it demonstrates the efficacy of immune checkpoint inhibitions in advanced dMMR tumors.

Lynch syndrome is the result of pathogenic variants in mismatch repair genes that increase the risk of cancer, including adrenocortical carcinoma. Little is known, however, about the clinical characteristics of patients with Lynch syndrome-associated adrenocortical carcinoma. In order to understand the clinical characteristics and prevalence of Lynch syndrome-associated adrenocortical carcinoma, we conducted a retrospective chart review of patients with adrenocortical carcinoma and germline genetic testing results, indicating pathogenic variants in mismatch repair genes consistent with Lynch syndrome at a single academic tertiary-care institution. In total, 21 patients with Lynch syndrome-associated adrenocortical carcinoma were identified from 2003 to 2024. Three patients met Amsterdam I criteria, and 12 patients met Amsterdam II criteria (including adrenocortical carcinoma as a Lynch syndrome-associated cancer). More than 90% of patients with available histopathology had high-grade tumors, suggesting a more aggressive nature. The prevalence of Lynch syndrome-associated adrenocortical carcinoma is estimated at 2.6%. This study further demonstrates that adrenocortical carcinoma is a Lynch syndrome-associated cancer and may be associated with a high-grade disease. Furthermore, our findings suggest that further research should be pursued to investigate the potential utility of immunotherapy for adrenocortical carcinoma, especially in the presence of microsatellite instability.

Background The National Comprehensive Cancer Network recommends microsatellite instability (MSI)/mismatch repair (MMR) testing to guide genetic counseling referrals for Lynch syndrome (LS) in patients with colorectal cancer. Studies show poor adherence with genetic counseling referral guidelines. Colon and rectal cancers are frequently treated as one entity despite molecular, epidemiologic, and biologic differences. Methods We investigated facility- and patient-level adherence with genetics testing/referral guidelines for LS and other germline mutations among rectal cancer patients at one institution. This is a retrospective review of patients with rectal cancer at a tertiary hospital from 2018 to 2023, excluding years 2020 to 2022 to minimize confounding factors associated with COVID-19. Indications for genetic testing/referrals were based on the Collaborative Group of the Americas on Inherited Colorectal Cancer guidelines. Results We sampled 177 patients, aged 27 to 96 years. A total of 149 (84.2%) underwent MMR/MSI testing; 47 (26.6%) were eligible for genetics referral. Nineteen (40.4%) were referred to genetics, and 14 (73.7%) underwent counseling/testing. One patient was diagnosed with LS, two with MUTYH-associated polyposis, and one with BRCA2. Conclusion This study demonstrates poor facility-level adherence with MSI/MMR testing recommendations and poor patient-level compliance with genetic referrals in rectal cancer. When recommendations were met, patients with germline mutations benefited from adjustments to their disease management.

Assessing quality of life in individuals with hereditary cancer risk: Results from phases 1-3a of the EORTC QLQ-HCR30 questionnaire.

Exome Sequencing Identifies Variants in MLH1 and ERBB2 as Potential Cancer-Predisposing Factors in Familial Early-Onset Colorectal Cancer.

Background Lynch syndrome (LS) is defined by having a pathogenic constitutional variant affecting one of the four mismatch repair (MMR) genes: MSH2, MLH1, MSH6 or PMS2 . In 2017, National Institute for Health and Care Excellence guidelines recommended screening all newly diagnosed colorectal cancer (CRC) patients for possible LS. We assessed referral pathways to molecular pathology and onwards to clinical genetics from our regional services covering the 1.9 million population of Northern Ireland, following implementation of this guidance, and resultant diagnostic rates of LS. Methods CRCs diagnosed between November 2019 and February 2022, and referred for molecular testing, were identified for this audit. Samples which were microsatellite instability-high (MSI-H) and BRAF WT were subsequently referred to the Clinical Genetics service for constitutional MMR gene testing. Results A total of 1949 CRCs were tested for MSI status corresponding to 97.6% of the population. Of these, 239 (12.3%) were classified as MSI-H and 113 of these 239 tumours (47.2%) were BRAF wild type, prompting referral for germline testing. 102 of the 113 cases (90.3%, or 5.8% of the total) were referred to clinical genetics, revealing 24 patients with constitutional variants. This equates to 1.2% of the total cohort of 1949 patients initially screened by MSI testing. Predictive testing yielded a further 33 family relatives with LS. Conclusions To the best of our knowledge, we are the first region in the UK to demonstrate universal MSI testing for CRC that has captured over 95% of the CRC population, with 90% onward referral rate to clinical genetics for constitutional testing yielding comprehensive detection of LS at the population level, for this patient group presenting with CRC.

Gene-specific cancer risks in female Lynch syndrome carriers: A copula-based meta-analysis.

Pitfalls in MLH1 promoter methylation assessment, including POLEmut/MLH1meth endometrial adenocarcinoma.

Gynecologic manifestations often serve as key diagnostic clues associated with a broad spectrum of hereditary syndromes. The authors summarize the spectrum of gynecologic abnormalities observed with these syndromes, emphasizing their implications for radiologic practice. Hereditary cancer predisposition syndromes such as Lynch syndrome, BRCA and BRCA2 mutations, and Cowden syndrome are associated with distinct gynecologic features, including increased risks of cancers and structural anomalies, which can be effectively assessed with imaging. The authors synthesize current knowledge on the imaging characteristics of gynecologic abnormalities linked to these syndromes and highlight the diagnostic challenges in image interpretation. Current syndrome-specific imaging recommendations, including screening and surveillance guidelines, are also summarized herein. The authors emphasize the importance of integrating radiologic findings with clinical context, with the aim enhancing awareness and expertise in the detection and characterization of gynecologic manifestations associated with hereditary syndromes, thereby contributing to optimal patient management. ©RSNA, 2025.

Pathogenic germline variants among patients with ovarian cancer by self-reported ancestry: A commercial laboratory collaborative research registry study.

There is extensive evidence that aspirin prevents cancer, but the mechanism of action is uncertain. Once-daily low-dose aspirin (75-100 mg) completely and permanently inactivates the cyclooxygenase (COX) activity of prostaglandin G/H synthase-1 (COX-1) in platelets, suppressing thromboxane (TX)A2-dependent platelet activation. In this article, we review the mechanistic links between platelet activation, inflammation, cancer development, and progression and summarize recent clinical trial results and associated biomarker studies. We hypothesize that persistently enhanced platelet activation has 2 distinct tumorigenic consequences mediated by the release of TXA2: (1) at sites of gastrointestinal mucosal lesions, it promotes a local inflammatory response with COX-2 induction and enhanced prostaglandin E2 biosynthesis, contributing to early events in carcinogenesis; (2) it inhibits T-cell immunity to cancer by the activation of TXA2 receptors in lymphocytes, promoting cancer progression and metastasis dissemination. Supporting these hypotheses, abnormal and persistent platelet activation has been demonstrated in patients recently diagnosed with cancer and in those with adenomatous colonic polyps. To date, most clinical trials evaluating aspirin have focused on either primary cancer prevention, metastasis prevention (adjuvant treatment), or cardiovascular prevention. For an individual, benefits may accrue from one (or all) of these areas, and they collectively need to be balanced against bleeding risk. Collating large clinical datasets for meta-analysis alongside mechanistic studies will inform the interpretation of clinical trials, with the aim of identifying individuals most likely to benefit from aspirin. SIGNIFICANCE STATEMENT: We reviewed the experimental and clinical evidence supporting a previously unrecognized role of platelet activation in both the early stage of colorectal carcinogenesis and in cancer progression and metastasis. The findings support the use of low-dose aspirin in cancer prevention and treatment. Data from large randomized clinical trials support the use of aspirin for the prevention of Lynch syndrome cancers and in the adjuvant setting for patients with colorectal cancer whose tumors have a mutation in the phosphatidylinositol 3-kinase pathway genes. Although thromboxane A2-dependent platelet activation is the most thoroughly investigated mechanism and the established drug target of the antiplatelet effect of low-dose aspirin, it seems biologically plausible that other pathways of platelet activation, such as the ADP-P2Y12 pathway, may play a similar and possibly complementary role.

Germline MLH1 c.-42 C > T is a likely pathogenic variant predisposing to a reduced-penetrance/modified Lynch syndrome phenotype featuring MLH1-methylated cancers

MSAI-Path: Predicting Microsatellite Instability From Routine Histology Slides Without Reinventing the Wheel.

Background: Colorectal cancer (CRC) represents a rapidly escalating public health challenge in the Kingdom of Saudi Arabia (KSA), where it is the second most common cancer overall and the leading cancer among men.(1,2) Methods: A Systematic review of current evidence for colorectal cancer in Saudi Arabia, its financial impact, and the human resources required to support care of such burden. A comprehensive literature search was conducted across PubMed/MEDLINE, Embase, Scopus, Web of Science, and Google Scholar, as well as gray literature sources, including Saudi National Cancer Registry reports and documents from the Saudi Ministry of Health. The search identified 27 records from database searching and 21 records from the registry and other sources. After the removal of 8 duplicates, 40 records were screened at the title and abstract level. Full texts of CRC articles were assessed for eligibility, of which 10 were excluded (non-Saudi populations, insufficient CRC-specific data, or non-original research), leaving 30 studies included in the final qualitative synthesis. A PRISMA-style flow was used to summarize the study selection process. Results: In 2020, the incidence and mortality rate of CRC in Saudi Arabia were 14.6% and 1.48% among all cancers, respectively [1]. National guidelines in Saudi Arabia recommend CRC screening for all individuals above 45 years using colonoscopy, flexible sigmoidoscopy, or fecal occult blood test. The incidence of cancer increased (1990-2016) approximately 10-fold for colon Cancer [2], A dangerous combination of genetic vulnerability and modern lifestyle pressures fuels this epidemic. Approximately 11.6% of young Saudi CRC patients have confirmed Lynch Syndrome(3). And 83% of all Saudi CRC patients carry the GSTM1 null genotype, this genetic trait leaves them highly sensitive to environmental carcinogens [4]. These genetic risks collide with modifiable factors, including sedentary habits and poor knowledge of high-fiber diets [5,2,4], leading to metabolic weaknesses like widespread Vitamin D deficiency [6]. The high overall one-, three-, and five-year survival rates were 83, 65, and 52.0% [7]. is fundamentally driven by failures in early detection. Screening rates are extremely low [8,9] primarily because physicians fail to recommend testing [8,10] and the public wrongly believes screening is unnecessary unless they feel sick [9,10,11]. Conclusion: To control Colorectal cancer demands immediate risk-stratification, genetic testing for all early-onset cases, and aggressive, physician-led efforts to increase public engagement with non-invasive screening options. The increasing incidence of CRC in Saudi Arabia, along with rising treatment costs, underscores the necessity for early detection and efficient healthcare resource allocation. Managing the projected increase in CRC cases over the next five years requires a strategic assessment of workforce needs, including ensuring sufficient numbers of oncologists, nurses, and allied health professionals, alongside effective training and recruitment strategies.