4/29/16 BMS 525, Spring, HW#31 Spencer Thomas

Structural Variation in the Human Genome and its role in Disease.Structural variation of the genome can arise at the level of SNPs, CNVs,

macroscale chromatin structure, and even genome wide disruptions. One fairly well characterized structural variation in cancer is broadly classified as chromosomal instability (CIN) which is characterized by widespread microsatellite aberrations as well as indels in genes, creating CNV for oncogenes and tumor suppressor genes. In the case of sporadically acquired cancers, including some colorectal cancer and the most common breast carcinoma (invasive ductal carcinoma (IDC)), loss of regulatory DNA repair pathways and genomic maintenance systems results in a so-called mutator phenotype that is associated with lack of DNA repair competence and, in general, cellular maintenance pathways. These mutator phenotype facilitate acquisition of SNPs and CNVS that alter WT alleles, and can promote microsatellite instability (MIN).

MIN is associated with mutations in numerous other genes, which contribute to progression of colon and IDC, occurring in ~15% of colon cancers and results from dysfunction of the mismatch repair (MMR) system mutagenesis or DNMT hypermethylation of certain promoters (MLH1). These inherited (A)n or (CA)n thus promote tumorigenesis through generating mutations in target genes that possess coding microsatellite repeats in important mitogen and apoptosis-regulating pathways, such as the TGF-ß pathway (TGFBR2) and intrinsic-apoptotic pathways (BAX). Incidentally, these microsatellites cause replication slippage which even upon recognition, will not result in cellular senescence and potentiating cellular genomic aberrations, aka MIN. Although, dysregulation of cell maintenance pathways contributes to the overall chromosomal instability (CIN), the accumulation of microsatellite repeats results in local and widespread topographical changes in the chromosomes. Macroscopically, the folding and general arrangement of chromosomes harboring mutations may further affect the spatial regulation and chromosomal organization at the 10 nm, 30 nm, and 300 nm level.

Although MIN causes alterations at the transcriptional level, perturbation of replication and origin selection. Accumulation of microsatellites results in physical blockade of replication and origins by gaining macrosatellite rich loops, but disruption of DDR checkpoints and mitosis checkpoints has also been observed with the mutations and amplifications been observed in key genes

Additionally, these MIN and at the holistic level can result in inadvertent activation of homologous repair pathways as well as retrotransposons. One key translocation documented in subsets in both CRC and IDC is when highly active promoters (IgG) translocate to sites of proto-oncogenes (RAF/MEK/ERK/MAPK), which facilitates proliferation and general CIN. Similarly, alterations in the MMR and DDR pathways in association with MIN facilitated unequal crossovers between palindromic oriented repeats on homologous chromosomes can result in reciprocal duplications concomitant to deletions. Mispairing between inverted near-palindromic repeats can result in inversion of intervening sequences that may result in the production of new genes or, more importantly, key inadvertent intra-chromosomal loops, which is a catalyst for chromosomal wide CIN. Consequently, these duplications, inversions, and deletions frequently mediate polymorphic sequence rearrangement via non-allelic homologous recombination, and disperse changes in copy numbers.

4/29/16 BMS 525, Spring, HW#31 Spencer Thomas