Loss of Heterozygosity


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.

Keywords: loss of heterozygosity; polymorphism; chromosome instability; tumour suppressor gene; cancer genomics

Figure 1. Mechanisms of LOH (loss of heterozygosity) formation. Most of the causes of LOH shown here lead to loss of chromosomal material (loss LOH), but some can lead to copy number neutral LOH (neutral LOH). Note that although not shown here, a reduplication of the retained chromosome can occur at any time including before the LOH event and can lead to neutral LOH for any of the loss LOH mechanisms. Blue and red chromosomes are homologous, and other colours represent DNA (deoxyribonucleic acid) from other chromosomes.
Figure 2. Common methods of LOH detection. Microsatellite analysis by PCR (polymerase chain reaction) was one of the earliest methods of detection. Shown are a heterozygous locus (Het) with both alleles retained in the tumour, a heterozygous locus with the larger allele lost (LOH) in the tumour (with some remaining signal from contaminating normal DNA, arrowhead) and a homozygous (Hom) and therefore uninformative locus. N, normal DNA; T, tumour DNA. SNP (single nucleotide polymorphism) arrays measure the overall copy number (red dots and blue line), the genotype at each locus (green bars, heterozygous; pink bars, homozygous) and the allele‐specific copy number (red and green lines). Areas of loss LOH (CNL‐LOH), neutral LOH (CNN‐LOH) and allelic imbalance are indicated. In a next‐generation sequencing approach, reads from exome data are binned together along the chromosome and the depth‐of‐coverage (DCC) ratio is calculated. The top panel shows the overall copy number, and the bottom panel shows the B‐allele frequency (number of reads supporting the ‘B’ allele divided by the total number of reads for an SNP). Areas of loss and LOH (CNL‐LOH) are shown in red.
Figure 3. Functional consequences of LOH. Chromosomes shown in blue and protein (or RNA, ribonucleic acid) products in red or purple (different colours indicate products of different genes). White areas in products indicate change in function, from somewhat to highly deleterious. Arrows indicate LOH event, leading to either copy number loss LOH (single chromosome) or copy number neutral LOH (two chromosomes). X: pathogenic mutation. A, B: different alleles, either somatic or germline.


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Further Reading

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Gorringe, Kylie L(Sep 2016) Loss of Heterozygosity. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026643]