Loss of Heterozygosity

Abstract

Abstract Loss of heterozygosity (LOH) is a genetic event frequently observed in many cancer types. The loss of one allele of a genetic locus can have multiple possible functional effects including haploinsufficiency, loss of gene expression and being the second ‘hit’ that unmasks a recessive tumour suppressor gene. LOH can be caused by mitotic errors, chromothripsis, gene conversion and inappropriate repair of DNA (deoxyribonucleic acid) breaks. The methods for detecting LOH are evolving from single locus assays such as microsatellite analysis, to accurate and sensitive genome‐wide assays including single‐nucleotide polymorphism arrays and massively parallel DNA sequencing. LOH is an important tool to aid in the discovery of novel tumour suppressor genes and now is gaining importance as a biomarker for clinical decision making in certain contexts. Key Concepts Loss of heterozygosity is a common genetic event in cancer whereby one allele is lost, leading to part of the genome appearing homozygous in the tumour where heterozygous in matching normal DNA. Allelic imbalance is different from LOH: both alleles are still present but are in different numbers of copies. Regions of LOH can be copy number neutral or show copy number loss. Whole‐chromosome LOH can be caused by mitotic nondisjunction. Defects in homologous recombination repair lead to increased levels of LOH in cancer. The two‐hit hypothesis describes the inactivation of both copies of a recessive tumour suppressor gene in cancer; LOH can be one such hit. Haplo‐insufficiency is where a gene cannot perform its function normally when present as only one copy and is a likely reason for selection of some LOH events.