Microsatellite Instability and its Significance to Hereditary and Sporadic Cancer

Up to one million people within the United States may have Lynch syndrome (LS), but only 10% have been diagnosed. Early identification of these individuals is critical because they are predisposed to the development of colorectal and several other cancers at a relatively young age. Individuals with LS carry a germline mutation in one of four DNA mismatch repair genes, which leads to hypermutability in simple repetitive DNA sequences. This hallmark molecular phenotype called microsatellite instability (MSI) is now widely used to screen individuals needing germline sequencing to confirm diagnosis of LS. Standardized markers for MSI testing and other improvements in methodology have greatly improved the accuracy and cost-effectiveness of MSI testing. The current trend toward universal MSI screening of all colorectal and endometrial cancers will save lives by identifying LS prior to the development of deadly cancer. New technologies for MSI detection, such as next generation sequencing, open the possibility of a single test for LS that determines both tumor MSI status and germline mutations. Moreover, MSI detection is poised to take on an even greater role in prediction of responses to the new immunotherapies targeted at MSI-positive tumors

Regulated Expression of Chromobox Homolog 5 Revealed in Tumors of ApcMin/+ ROSA11 Gene Trap Mice

The gene-trap lacZ reporter insertion, ROSA11, in the Cbx5 mouse gene illuminates the regulatory complexity of this locus in ApcMin/+ mice. The insertion site of the β-Geo gene-trap element lies in the 24-kb intron proximal to the coding region of Cbx5. Transcript analysis indicates that two promoters for Cbx5 flank this insertion site. Heterozygotes for the insertion express lacZ widely in fetal tissues but show limited expression in adult tissues. In the intestine, strong expression is limited to proliferative zones of crypts and tumors. Homozygotes for ROSA11, found at a lower than Mendelian frequency, express reduced levels of the coding region transcript in normal tissues, using a downstream promoter. Analysis via real-time polymerase chain reaction indicates that the upstream promoter is the dominant promoter in normal epithelium and tumors. Bioinformatic analysis of the Cbx5 locus indicates that WNT and its target transcription factor MYC can establish a feedback loop that may play a role in regulating the self-renewal of the normal intestinal epithelium and its tumors

Biometrics DOI: 10.1111/j.1541-0420.2006.00522.x A Statistical Test of the Hypothesis that Polyclonal Intestinal Tumors Arise by Random Collision of Initiated Clones

Summary. The random collision hypothesis is a mathematical idealization of intestinal tumor formation that can account for the polyclonal origin of tumors without requiring a mechanistic description of clonal interaction. Using data from recent polyclonality studies in mice, we develop a statistical procedure to test the random collision hypothesis. Elements from stochastic geometry and approximations due to Armitage (1949, Biometrika 36, 257–266) support a statistical model of tumor count data. Bayesian analysis yields the posterior distribution of the number of heterotypic tumors, from which p-values are computed to test random collision

Identification of Mom7, a Novel Modifier of ApcMin/+ on Mouse Chromosome 18

The ApcMin mouse model of colorectal cancer provides a discrete, quantitative measurement of tumor multiplicity, allowing for robust quantitative trait locus analysis. This advantage has previously been used to uncover polymorphic modifiers of the Min phenotype: Mom1, which is partly explained by Pla2g2a; Mom2, a spontaneous mutant modifier; and Mom3, which was discovered in an outbred cross. Here, we describe the localization of a novel modifier, Mom7, to the pericentromeric region of chromosome 18. Mom7 was mapped in crosses involving four inbred strains: C57BL/6J (B6), BTBR/Pas (BTBR), AKR/J (AKR), and A/J. There are at least two distinct alleles of Mom7: the recessive, enhancing BTBR, AKR, and A/J alleles and the dominant, suppressive B6 allele. Homozygosity for the enhancing alleles increases tumor number by approximately threefold in the small intestine on both inbred and F1 backgrounds. Congenic line analysis has narrowed the Mom7 region to within 7.4 Mb of the centromere, 28 Mb proximal to Apc. Analysis of SNP data from various genotyping projects suggests that the region could be as small as 4.4 Mb and that there may be five or more alleles of Mom7 segregating among the many strains of inbred mice. This has implications for experiments involving ApcMin and comparisons between different or mixed genetic backgrounds