CaRMS at 50: Making the match for medical education

Entry into postgraduate medical training in Canada is facilitated through a national application and matching system which establishes matches between applicants and training programs based on each party’s stated preferences. Health human resource planning in Canada involves many factors, influences, and decisions. The complexity of the system is due, in part, to the fact that much of the decision making is dispersed among provincial, territorial, regional, and federal jurisdictions, making a collaborative national approach a challenge. The national postgraduate application and matching system is one of the few aspects of the health human resources continuum that is truly pan-Canadian. This article examines the evolution of the application and matching system over the past half century, the values that underpin it, and CaRMS' role in the process

Exome sequencing identifies nonsegregating nonsense ATM and PALB2 variants in familial pancreatic cancer.

We sequenced 11 germline exomes from five families with familial pancreatic cancer (FPC). One proband had a germline nonsense variant in ATM with somatic loss of the variant allele. Another proband had a nonsense variant in PALB2 with somatic loss of the variant allele. Both variants were absent in a relative with FPC. These findings question the causal mechanisms of ATM and PALB2 in these families and highlight challenges in identifying the causes of familial cancer syndromes using exome sequencing

ID1 and ID3 Regulate the Self-Renewal Capacity of Human Colon Cancer-Initiating Cells through p21

SummaryThere is increasing evidence that some cancers are hierarchically organized, sustained by a relatively rare population of cancer-initiating cells (C-ICs). Although the capacity to initiate tumors upon serial transplantation is a hallmark of all C-ICs, little is known about the genes that control this process. Here, we establish that ID1 and ID3 function together to govern colon cancer-initiating cell (CC-IC) self-renewal through cell-cycle restriction driven by the cell-cycle inhibitor p21. Regulation of p21 by ID1 and ID3 is a central mechanism preventing the accumulation of excess DNA damage and subsequent functional exhaustion of CC-ICs. Additionally, silencing of ID1 and ID3 increases sensitivity of CC-ICs to the chemotherapeutic agent oxaliplatin, linking tumor initiation function with chemotherapy resistance

Randomized Controlled Trial of the Use of an Educational Cancer Website to Increase Cancer Patient’s Participation into a Research Study

[[abstract]]The present randomized controlled trial was conducted to determine if providing access to an educational colorectal cancer Website for patients with colorectal cancer might increase their subsequent participation in a population-based cancer study. A total of 384 potential participants recruited from colorectal cancer cases identified from the Ontario Cancer Registry and the Mount Sinai Hospital in Toronto, Ontario, Canada were randomly divided into two groups. The control group was mailed an invitation package containing a brochure describing a population-based cancer registry (the Ontario Familial Colorectal Cancer Registry, OFCCR), a family history questionnaire, and a colorectal cancer educational pamphlet. The intervention group was mailed the information for access to a colorectal cancer educational Website in addition to the materials sent to the control group. Results indicated that providing access information to an educational Website about colorectal cancer did not increase the participation of colorectal cancer patients in a population-based cancer study. The participation for the intervention group (66%) was not significantly different (p=0.38) from the control group (62%). The additional provision of a Website with colorectal cancer information to patients appears not to be an effective strategy to improve subsequent participation in a population-based cancer study

Identification of genes expressed by immune cells of the colon that are regulated by colorectal cancer-associated variants.

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

Cholecystectomy and the risk of colorectal cancer by tumor mismatch repair deficiency status

Gallbladder diseases and cholecystectomy may play a role in the development of colorectal cancer (CRC). Our aim was to investigate the association between cholecystectomy and CRC risk overall and by sex, family history, anatomical location, and tumor mismatch repair (MMR) status

Colorectal cancer linkage on chromosomes 4q21, 8q13, 12q24, and 15q22

A substantial proportion of familial colorectal cancer (CRC) is not a consequence of known susceptibility loci, such as mismatch repair (MMR) genes, supporting the existence of additional loci. To identify novel CRC loci, we conducted a genome-wide linkage scan in 356 white families with no evidence of defective MMR (i.e., no loss of tumor expression of MMR proteins, no microsatellite instability (MSI)-high tumors, or no evidence of linkage to MMR genes). Families were ascertained via the Colon Cancer Family Registry multi-site NCI-supported consortium (Colon CFR), the City of Hope Comprehensive Cancer Center, and Memorial University of Newfoundland. A total of 1,612 individuals (average 5.0 per family including 2.2 affected) were genotyped using genome-wide single nucleotide polymorphism linkage arrays; parametric and non-parametric linkage analysis used MERLIN in a priori-defined family groups. Five lod scores greater than 3.0 were observed assuming heterogeneity. The greatest were among families with mean age of diagnosis less than 50 years at 4q21.1 (dominant HLOD = 4.51, α = 0.84, 145.40 cM, rs10518142) and among all families at 12q24.32 (dominant HLOD = 3.60, α = 0.48, 285.15 cM, rs952093). Among families with four or more affected individuals and among clinic-based families, a common peak was observed at 15q22.31 (101.40 cM, rs1477798; dominant HLOD = 3.07, α = 0.29; dominant HLOD = 3.03, α = 0.32, respectively). Analysis of families with only two affected individuals yielded a peak at 8q13.2 (recessive HLOD = 3.02, α = 0.51, 132.52 cM, rs1319036). These previously unreported linkage peaks demonstrate the continued utility of family-based data in complex traits and suggest that new CRC risk alleles remain to be elucidated. © 2012 Cicek et al