Pediatric duodenal cancer and biallelic mismatch repair gene mutations

Gastrointestinal malignancies are extremely rare in the pediatric population, and duodenal cancers represent an even more unusual entity. Intestinal cancers in young adults and children have been observed to be associated with functional deficiencies of the mismatch repair (MMR) system causing a cancer-predisposition syndrome. We report the case of a 16-year-old female with duodenal adenocarcinoma and past history of medulloblastoma found to have a novel germline bialleleic truncating mutation (c.[949C>T]+[949C>T]) of the PMS2 gene. Pediatr Blood Cancer 2009;53:116–120. © 2009 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62997/1/21957_ftp.pd

Colorectal Tumour Microsatellite Instability Test Results: Perspectives from Patients

<p>Abstract</p> <p>Purpose</p> <p>To determine which individuals with colorectal cancer (CRC) were interested in knowing the results of their tumour microsatellite instability (MSI) and immunohistochemistry (IHC) testing. We were also interested in the patients' reasons for choosing to learn their results and in the impact of those results on overall self-assessed quality of life.</p> <p>Patients and Methods</p> <p>CRCs from 414 individuals were assayed for MSI and IHC for DNA mismatch repair gene products (<it>MLH1</it>, <it>MSH2</it>, <it>MSH6</it>). Individuals were invited to learn their MSI/IHC results. They randomly received either brief or extended educational materials about the testing and a pretest survey to learn reasons for their interest and to assess their pretest quality of life.</p> <p>Results</p> <p>Of the 414 individuals, 307 (74%) chose to learn their results. There was no significant difference in interest in knowing test results according to gender, age, educational level, or family history of colon cancer. The level of detail in the information piece received by the patients did not influence their desire to know their test results. Self-assessed quality of life was not altered by receiving results and was not correlated with the test outcome.</p> <p>Conclusions</p> <p>Individuals with colorectal cancer had a high level of interest in learning their individual MSI/IHC test results and did not seem deterred by the inherent complexity or ambiguity of this information. Regardless of test outcome, results did not significantly affect self-assessed quality of life. Further studies are needed to assess comprehension of results and behavioural changes resulting from the learning of MSI/IHC results.</p

Colorectal cancer and self-reported tooth agenesis

BACKGROUND: Germline mutations in APC and AXIN2 are both associated with colon neoplasia as well as anomalous dental development. We tested the hypothesis that congenitally missing teeth may occur more commonly in individuals diagnosed with colorectal cancer than in individuals without this diagnosis. METHODS: Via a survey conducted on 1636 individuals with colorectal cancer (CRC) and 2788 individuals with no colorectal cancer from the Colon Cancer Family Registry, self-reported information on congenitally missing teeth was collected. The frequency of missing teeth between cases and controls was compared using Pearson’s chi-squared test or Fisher’s exact test. RESULTS: 4.8% of cases and 5.7% of controls reported having at least one missing tooth (p = 0.20). When we stratified by recruitment site, gender, and mutation status where available, frequency of missing teeth was not statistically significantly different between cases and controls. CONCLUSIONS: This study did not provide support for there being a general predisposition to missing teeth among a large cohort of CRC patients. The study neither addresses nor excludes the possibility, however, that individuals presenting with notable hypodontia/oligodontia might still have an increased risk for colorectal neoplasia

Mutational landscape of candidate genes in familial prostate cancer

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108266/1/pros22849-sm-0001-SupTab-S1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/108266/2/pros22849.pd

Genome-Wide Transcriptional Profiling Reveals MicroRNA-Correlated Genes and Biological Processes in Human Lymphoblastoid Cell Lines

Expression level of many genes shows abundant natural variation in human populations. The variations in gene expression are believed to contribute to phenotypic differences. Emerging evidence has shown that microRNAs (miRNAs) are one of the key regulators of gene expression. However, past studies have focused on the miRNA target genes and used loss- or gain-of-function approach that may not reflect natural association between miRNA and mRNAs.To examine miRNA regulatory effect on global gene expression under endogenous condition, we performed pair-wise correlation coefficient analysis on expression levels of 366 miRNAs and 14,174 messenger RNAs (mRNAs) in 90 immortalized lymphoblastoid cell lines, and observed significant correlations between the two species of RNA transcripts. We identified a total of 7,207 significantly correlated miRNA-mRNA pairs (false discovery rate q<0.01). Of those, 4,085 pairs showed positive correlations while 3,122 pairs showed negative correlations. Gene ontology analyses on the miRNA-correlated genes revealed significant enrichments in several biological processes related to cell cycle, cell communication and signal transduction. Individually, each of three miRNAs (miR-331, -98 and -33b) demonstrated significant correlation with the genes in cell cycle-related biological processes, which is consistent with important role of miRNAs in cell cycle regulation.This study demonstrates feasibility of using naturally expressed transcript profiles to identify endogenous correlation between miRNA and miRNA. By applying this genome-wide approach, we have identified thousands of miRNA-correlated genes and revealed potential role of miRNAs in several important cellular functions. The study results along with accompanying data sets will provide a wealth of high-throughput data to further evaluate the miRNA-regulated genes and eventually in phenotypic variations of human populations

Mutations in the Human naked cuticle Homolog NKD1 Found in Colorectal Cancer Alter Wnt/Dvl/β-Catenin Signaling

BACKGROUND:Mutation of Wnt signal antagonists Apc or Axin activates beta-catenin signaling in many cancers including the majority of human colorectal adenocarcinomas. The phenotype of apc or axin mutation in the fruit fly Drosophila melanogaster is strikingly similar to that caused by mutation in the segment-polarity gene, naked cuticle (nkd). Nkd inhibits Wnt signaling by binding to the Dishevelled (Dsh/Dvl) family of scaffold proteins that link Wnt receptor activation to beta-catenin accumulation and TCF-dependent transcription, but human NKD genes have yet to be directly implicated in cancer. METHODOLOGY/PRINCIPAL FINDINGS:We identify for the first time mutations in NKD1--one of two human nkd homologs--in a subset of DNA mismatch repair-deficient colorectal tumors that are not known to harbor mutations in other Wnt-pathway genes. The mutant Nkd1 proteins are defective at inhibiting Wnt signaling; in addition, the mutant Nkd1 proteins stabilize beta-catenin and promote cell proliferation, in part due to a reduced ability of each mutant Nkd1 protein to bind and destabilize Dvl proteins. CONCLUSIONS/SIGNIFICANCE:Our data raise the hypothesis that specific NKD1 mutations promote Wnt-dependent tumorigenesis in a subset of DNA mismatch-repair-deficient colorectal adenocarcinomas and possibly other Wnt-signal driven human cancers

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

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

Prognostic Significance of Defective Mismatch Repair and BRAF V600E in Patients with Colon Cancer

Colon tumors with defective DNA mismatch repair (dMMR) have a well characterized phenotype and accounts for ~15–20% of sporadic colon cancer (CC) as well as those colon cancer patients with Lynch Syndrome. Although the presence of dMMR appears to be a favorable prognostic marker, data suggests that these patients do not respond as well to adjuvant chemotherapy