Loss of heterozygosity: what is it good for?

• DOI: 10.1186/s12920-015-0123-z
• Publication Date: 2015-07-31T15:45:50Z
• Authors: Georgina L. Ryland; Maria A. Doyle; David Goode; Samantha E. Boyle; David Y.H. Choong; Simone M. Rowley; Jason Li; ; David DL Bowtell; Richard W. Tothill; Ian G. Campbell; Kylie L. Gorringe
• Keywords: Haploinsufficiency; Penetrance; Human genetics

Loss of heterozygosity (LOH) is a common genetic event in cancer development, and known to be involved the somatic loss wild-type alleles many inherited syndromes. The wider involvement LOH assumed relate unmasking somatically mutated tumour suppressor gene through wild type allele. We analysed 86 ovarian carcinomas for mutations 980 genes selected on basis their location regions LOH. identified 36 significantly genes, but these could only partly account quanta samples. Using our own TCGA data we then evaluated five possible models explain selection non-random accumulation genomes: 1. Classic two-hit hypothesis: high frequency biallelic inactivation genes. 2. Epigenetic methylation 3. Multiple alternate-gene inactivation: low disruption. 4. Haplo-insufficiency: Single copy 5. Modified reduction homozygosity penetrance germline predisposition alleles. determined that while high-frequency under model 1 rare, (particularly copy-number neutral LOH) are enriched deleterious increased promoter methylation, likely contain under-expressed suggestive haploinsufficiency. Reduction SNPs may also play minor role. It depends its effect multiple Selection number better fit classic whereas attributed multi-gene mapping alone unlikely successful identifying novel genes; combined approach more effective.