While loss-of-heterozygosity (LOH) mutations have been repeatedly implicated in oncogenesis, the mechanisms for their production in cancers remain to be delineated. By examining both LOHs generating homozygous-major genotypes and LOHs generating homozygous-minor genotypes at single-nucleotide resolution using next generation sequencing on the AluScan platform for thirty solid-tumor and leukemia genomes, here we show: (a) massive occurrence of LOHs in the various cancers; (b) the mainly CNV-neutral and interstitial nature of the LOHs; and (c) a strong preference for the formation of the homozygous-major genotype. These LOH characteristics, confirmed by the whole-genome sequence reported for primary lung and lung-to-liver metastatic cancer, point to the formation of LOHs through repair of...[ Read more ]

While loss-of-heterozygosity (LOH) mutations have been repeatedly implicated in oncogenesis, the mechanisms for their production in cancers remain to be delineated. By examining both LOHs generating homozygous-major genotypes and LOHs generating homozygous-minor genotypes at single-nucleotide resolution using next generation sequencing on the AluScan platform for thirty solid-tumor and leukemia genomes, here we show: (a) massive occurrence of LOHs in the various cancers; (b) the mainly CNV-neutral and interstitial nature of the LOHs; and (c) a strong preference for the formation of the homozygous-major genotype. These LOH characteristics, confirmed by the whole-genome sequence reported for primary lung and lung-to-liver metastatic cancer, point to the formation of LOHs through repair of double-strand breaks by interhomolog recombination as the consequence of a defective DNA-damage response, thereby providing a unified mechanism for generating the mutations required for oncogenesis as well as the progression of cancer cells. A large number of tumor suppressor genes and other cancer related genes identified based on the Tumor Suppressor Gene (TSGene) and Network of Cancer Genes (NCG) databases, in the AluScan sequence reads of the 30 cancer genomes, and two whole genome sequencing data which underwent LOH and GOH mutations. The mainly interstitial character of the cancer LOHs was evident from the well-spaced LOH occurrences in the copy neutral LOH regions as well as the distribution of LOH fragment lengths showing a substantial fraction of fragments that were ≤ 1 Mb in size. To calculate LOH fragment length; we used heterozygous loci as marker and caluculated distance between two heterozygous loci which had at least one LOH mutation. The interstitial nature of the major fraction of copy-neutral LOHs observed supports gene conversion event by repair of double strand breaks (DSB) through interhomolog recombination. Gene conversion is an important mechanism in the production of cancer LOHs. In conclusion, analysis of cancer LOHs and GOHs in the present study has revealed evidence for the occurrence of LOHs and tag-along GOHs in cancers brought about by repair of DSBs through interhomolog recombination under conditions of relaxed cell cycle checkpoints due to a defective DNA-damge repair (DDR). On this basis, cancer may be regarded foremost as a disease of the DNA-damage response, where the mutator phenotype arising from DDR derangement provides a unified mechanism for generating interhomolog recombination-induced mutations to drive the initiation, development and aggressiveness of the neoplastic state from its oncogenic beginning to its terminal stages of unconstrained growth and proliferation. This thesis work has taken LOH study at micro level upto single base LOH analysis which was called as interstitial LOH. In all earlier LOH studies, LOH event was considered as deletion of big fragment but no study was performed at micro level. Micro level interstitial LOH analysis concludes that LOHs and GOHs are equally aboundant in cancer genome,

In previous cancer genomic variant studies, LOH event mutation was considered as much lower in number and less promident compare to GOHs mutations. The reason behind this approach was that the formation of the homozygous-major genotype for LOH event mutation was ignored.