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Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours that originate from the interstitial cells of Cajal. GISTs are mainly driven by gain-of-function mutations in receptor tyrosine kinase or platelet-derived growth factor receptor alpha. Surgical resection is the only curative treatment for localized tumours and all currently approved medical GIST treatments are based on orally available tyrosine kinase inhibitors. Recent discoveries in the molecular and clinical features of GISTs have greatly impacted GIST management. Due to the provincially rather than nationally administered Canadian healthcare system, there have been inconsistencies in the treatment of GISTs across the country. Therefore, guidance on the latest knowledge, clinical management and treatment of GIST is needed to standardize the approach to GIST management nationwide. To establish pan-Canadian guidance, provide up-to-date data and harmonize the clinical practice of GIST management in high- and low-throughput centres across Canada; a panel of 20 physicians with extensive clinical experience in GIST management reviewed relevant literature. This included radiologists, pathologists, interventional radiologists, surgeons and medical oncologists across Canada. The structured literature focused on seven key domains: molecular profiling, radiological techniques/reporting, targeted localized therapy, intricacies of systemic treatments, emerging tests, multidisciplinary care and patient advocacy. This literature review, along with clinical expertise and opinion, was used to develop this concise and clinically relevant consensus paper to harmonize the knowledge and clinical practice on GIST management across Canada. The content presented here will help guide healthcare providers, especially in Canada, in terms of approaching and managing GIST. [ABSTRACT FROM AUTHOR]

A multi-disciplinary symposium on early-age onset cancer (EAOC) was held in October 2023 to explore challenges experienced by this rapidly growing population. A major outcome of the symposium was recognition of the remarkable similarities of EAOC patients' journeys across cancer sites. Prevention and early detection of cancer are hindered by a lack of awareness among patients and family doctors that cancer can and does occur in younger persons. Distinct characteristics of the disease—such as a later stage at diagnosis and more aggressive tumor biology—require more potent treatments, which result in profound physical and psychosocial consequences that are unique to this age group. EAOC patient empowerment emerged as another key theme of the symposium. The development of a greater number of specialized clinics was called for, and patient support groups were recognized for the vital role they play in empowering patients and their families. Leading-edge medical advancements hold tremendous hope across the spectrum of EAOC care. New technologies based on genomic profiling, immunotherapy and microbiome alteration contribute to the development of highly effective, personalized approaches to treatment. All symposium participants expressed their commitment to speak with one resounding voice to advocate for equitable access to leading care practices for EAOC patients; thus, a fourth symposium is planned for November 2024. [ABSTRACT FROM AUTHOR]

The E3 ubiquitin ligase Mule is often overexpressed in human colorectal cancers, but its role in gut tumorigenesis is unknown. Here, we show in vivo that Mule controls murine intestinal stem and progenitor cell proliferation by modulating Wnt signaling via c-Myc. Mule also regulates protein levels of the receptor tyrosine kinase EphB3 by targeting it for proteasomal and lysosomal degradation. In the intestine, EphB/ephrinB interactions position cells along the crypt-villus axis and compartmentalize incipient colorectal tumors. Our study thus unveils an important new avenue by which Mule acts as an intestinal tumor suppressor by regulation of the intestinal stem cell niche.

* Context.--Data regarding the clinical impact of subspecialist pathology review of appendiceal neoplasms are limited. Objective.--To determine whether pathology review by gastrointestinal pathologists at a tertiary-care referral center resulted in significant changes in the diagnosis and clinical management of appendiceal neoplastic lesions. Design.--We conducted a retrospective review of all patients with an initial diagnosis of appendiceal neoplasm referred to a tertiary-care referral center in Ontario, Canada, from 2010-2016. The discordance rate between original and review pathology reports, the nature of discordances, and the impact of any discordance on patient management were recorded. Results.--A total of 145 patients with appendiceal lesions were identified (low-grade mucinous appendiceal neoplasm [n = 79], invasive mucinous adenocarcinoma [n = 12], 'colorectal type' adenocarcinoma [n = 12], goblet cell carcinoid and adenocarcinomas ex goblet cell carcinoid [n = 24], and other lesions/neoplasms [n = 20]). One or more changes in diagnoses were found in 36 of 145 cases (24.8%), with changes within the same category of interpretation (n = 10), stage (n = 7), grade (n = 6), and categoric interpretation (n = 5) being the most common. In 10 of 36 patients (28%), the diagnostic change led to a significant change in management, including recommendation for additional surveillance, systemic chemotherapy, additional surgery, or discontinuation of surveillance. Conclusions.--Subspecialist pathology review of appendiceal neoplastic lesions led to a change in diagnosis in 36 of 145 cases (24.8%), of which nearly 30% (10 of 36 cases) led to a change in clinical management. The overall rate of clinically significant discordances was 7% (10 of 145). Our findings suggest that subspecialist pathology review of appendiceal neoplasms referred to specialized centers is justified. (Arch Pathol Lab Med. 2020;144:764-768; doi: 10.5858/arpa.2019-0214-OA), A large proportion of appendiceal neoplasms are first identified during pathologic review of appendectomies performed for presumed benign causes. The most common include well-differentiated neuroendocrine tumors ('carcinoids'), mucinous tumors, goblet [...]

A locus on human chromosome 11q23 tagged by marker rs3802842 was associated with colorectal cancer (CRC) in a genome-wide association study; this finding has been replicated in case-control studies worldwide. In order to identify biologic factors at this locus that are related to the etiopathology of CRC, we used microarray-based target selection methods, coupled to next-generation sequencing, to study 103 kb at the 11q23 locus. We genotyped 369 putative variants from 1,030 patients with CRC (cases) and 1,061 individuals without CRC (controls) from the Ontario Familial Colorectal Cancer Registry. Two previously uncharacterized genes, COLCA1 and COLCA2, were found to be co-regulated genes that are transcribed from opposite strands. Expression levels of COLCA1 and COLCA2 transcripts correlate with rs3802842 genotypes. In colon tissues, COLCA1 co-localizes with crystalloid granules of eosinophils and granular organelles of mast cells, neutrophils, macrophages, dendritic cells and differentiated myeloid-derived cell lines. COLCA2 is present in the cytoplasm of normal epithelial, immune and other cell lineages, as well as tumor cells. Tissue microarray analysis demonstrates the association of rs3802842 with lymphocyte density in the lamina propria (p = 0.014) and levels of COLCA1 in the lamina propria (p = 0.00016) and COLCA2 (tumor cells, p = 0.0041 and lamina propria, p = 6 × 10(-5)). In conclusion, genetic, expression and immunohistochemical data implicate COLCA1 and COLCA2 in the pathogenesis of colon cancer. Histologic analyses indicate the involvement of immune pathways.

Genome-based testing in oncology is a rapidly expanding area of health care that is the basis of the emerging area of precision medicine. The efficient and considered adoption of novel genomic medicine testing is hampered in Canada by the fragmented nature of health care oversight as well as by lack of clear and transparent processes to support rapid evaluation, assessment, and implementation of genomic tests. This article provides an overview of some key barriers and proposes approaches to addressing these challenges as a potential pathway to developing a national approach to genomic medicine in oncology. [ABSTRACT FROM AUTHOR]

Background Genetic testing for hereditary cancer susceptibility has advanced over time due to the discovery of new risk genes, improved technology and decreased cost. In the province of Ontario, testing eligibility criteria were initially developed to include hereditary breast, ovarian and colorectal cancer syndromes. The rapid evolution of genetic technologies has facilitated the ability to interrogate a large number of genes concurrently. This, coupled with new knowledge about risk genes, necessitated a coordinated approach to expanding the scope of genes and indications tested and synchronisation of access and test utilisation across the province as required in a publicly funded universal healthcare system. Methods Ontario Health--Cancer Care Ontario convened expert working groups to develop a standardised and comprehensive cancer gene list for adults and accompanying hereditary cancer testing (HCT) criteria using an evidence-based framework and broad laboratory and clinical genetics engagement. Results A standardised 76-cancer-gene panel, organised into 13 larger disease site panels and 25 single/small gene panels, was developed and endorsed by the working groups. Provincial genetic testing eligibility criteria were updated to align with the new panels and to guide clinical decision-making. In the first year following the implementation of these changes, 10 564 HCT panels were performed with an overall mutation detection rate of 12.2%. Conclusion Using an evidence framework and broad clinical engagement to develop and endorse an updated guidance document, cancer genetic testing for adults in Ontario is now standardised and coordinated across the province. [ABSTRACT FROM AUTHOR]

Background: We investigated the prevalence of Lynch syndrome as a hereditary cause of colon cancer in the young Jamaican colorectal cancer (CRC) population. Methods: We identified patients aged 40 years or younger in whom primary CRC was diagnosed at the University Hospital of the West Indies from January 2004 to December 2008. We reviewed the medical records and hematoxylin and eosin (H&E)-stained histopathology slides. Tumour blocks were tested for microsatellite instability (MSI). Patients with MSI-high phenotype (MSI-H) tumours had genetic counselling, after which genomic DNA was extracted from peripheral blood to test for MLH1 and MSH2 germline mutations. Patients also had pedigree mapping. Results: There were 2 5 patients with CRC aged 40 years or younger with no history of hereditary colon cancer syndrome. The patients' mean age was 33 (range 21-40) years. Histopathologic review confirmed CRC in all patients; 8 of 25 (32%) showed morphologic features suggestive of MSI. We detected MSI-H in 5 of 23 (22%) tumour blocks tested. Review with H&E staining correctly identified 80% of cases positive for MSI-H. The false-positive rate and positive predictive value on H&E review was 50%. The negative predictive value of histomorphologic H&E review was 94%. Three patients were available for and had mutational analysis of DNA mismatch repair genes; 2 were positive for mutations in keeping with Lynch syndrome and 1 had MLH1 alterations of uncertain significance. All 3 met the Amsterdam criteria for hereditary nonpolyposis CRC. Conclusion: Thirteen percent of the population had mutations in keeping with Lynch syndrome. This prevalence is similar to that reported for white populations. Contexte : Nous avons analyse la prevalence du syndrome de Lynch comme cause hereditaire du cancer du colon dans la population jamaicaine jeune touchee par le cancer colorectal (CCR). Methodes : Nous avons recense les patients de 40 ans et moins chez qui on avait diagnostique un CCR a l'Hopital universitaire West Indies entre janvier 2004 et decembre 2008. Nous avons passe en revue les dossiers medicaux et les coupes histologiques apres coloration a l'hematoxyline-eosine (H-E). Puis nous avons analyse l'instabilite microsatellitaire (IMS) des blocs tumoraux. Les patients presentant des tumeurs a phenotype IMS eleve (IMS-E) ont eu une consultation en genetique, apres quoi on a extrait l'ADN de leur genome a partir d'un specimen de sang peripherique pour un depistage des mutations affectant les lignees germinales MLH1 et MLH2. On a aussi dresse la cartographie du genome des patients. Resultats : On a denombre 25 patients atteints de CCR ages de 40 ans ou moins sans antecedents de syndrome hereditaire de cancer du colon. L'age moyen des patients etait de 33 ans (de 21 a 40 ans). L'analyse histologique a confirme la presence de CCR chez tous les patients; 8 patients sur 25 (32 %) manifestaient des caracteristiques morphologiques d'IMS. Nous avons decele une IMS-E dans 5 blocs tumoraux sur les 23 (22 %) testes. Un controle par coloration H-E a correctement confirme 80 % des cas d'IMS-E averes. Le taux de faux-positifs et la valeur predictive positive de la coloration H-E ont ete de 50 %. La valeur predictive negative du controle histologique H-E a ete de 94 %. Trois patients etaient disponibles et ont subi une analyse mutationnelle des genes de reparation du mesappariement de l'ADN; 2 se sont reveles positifs a l'egard de mutations concordant avec le syndrome de Lynch et un presentait des alterations du MLH1 de portee incertaine. Les 3 patients repondaient aux criteres d'Amsterdam de CCR non polyposique hereditaire. Conclusion : Treize pour cent de la population presentaient des mutations concordant avec un syndrome de Lynch. Cette prevalence ressemble a celle que l'on observe dans les populations de race blanche., Colorectal cancer (CRC) is the third most commonly diagnosed cancer in men and women and is the fourth leading cause of cancer deaths in Jamaica. (1,2) These proportions are comparable [...]