Loss of heterozygosity
Loss of heterozygosity (LOH). Most diploid cells, for example human somatic cells, contain two copies of the genome, one from each parent (chromosome pair); each copy contains approximately 3 billion bases (Adenine (A), Guanine (G), Cytosine (C) or Thymine (T)). For the majority of positions in the genome the base present is consistent between individuals, however a small percentage may contain different bases (usually one of two for instance ‘A’ or ‘G’) and these positions are called ‘single nucleotide polymorphisms’ or ‘SNPs’. When the genomic copies derived from each parent have different bases for these polymorphic regions (SNPs) the region is said to be heterozygous. The majority of the genome within somatic cells of individuals are heterozygous. However, one parental copy of a region can sometimes be lost, resulting in the region lacking differences at these polymorphic loci (SNPs) and therefore showing loss of heterozygosity (LOH). Loss of heterozygosity due to loss of one parental copy in a region is also called hemizygosity in that region.
It is a common occurrence in cancer, where it indicates the absence of a functional tumor suppressor gene in the lost region. However, many people remain healthy with such a loss, because there still is one functional gene left on the other chromosome of the chromosome pair. However, the remaining copy of the tumor suppressor gene can be inactivated by a point mutation, leaving no tumor suppressor gene to protect the body. Loss of heterozygosity does not imply a reversal to the homozygous state.
Knudson two-hit hypothesis of tumorigenesis
- First Hit: The first hit is classically thought of as a point mutation that inactivates one copy of a tumor suppressor gene (TSG), such as Rb1. In hereditary cancer syndromes, individuals are born with the first hit. The individual does not develop cancer at this point because the remaining TSG allele on the other locus is still functioning normally.
- Second Hit: The second hit is classically thought of a deletion that results in loss of the remaining functioning TSG allele. This leaves only non-functioning alleles of the TSG, and the individual goes on to develop cancer.
Copy-neutral LOH is thus called because no net change in the copy number occurs in the affected individual. Other names for copy-neutral LOH are acquired uniparental disomy (UPD) or gene conversion. In UPD, a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent due to errors in meiosis I or meiosis II. This acquired homozygosity could lead to development of cancer if the individual inherited a non-functional allele of a tumor suppressor gene.
In tumor cells copy-neutral LOH can be biologically equivalent to the second hit in the Knudson hypothesis. Acquired UPD is quite common in both hematologic and solid tumors, and is reported to constitute 20 to 80% of the LOH seen in human tumors. Determination of virtual karyotypes using SNP-based arrays can provide genome-wide copy number and LOH status, including detection of copy-neutral LOH. Copy-neutral LOH cannot be detected by arrayCGH, FISH, or conventional cytogenetics. SNP-based arrays are preferred for virtual karyotyping of tumors and can be performed on fresh or paraffin-embedded tissues.
The classical example of such a loss of protecting genes is hereditary retinoblastoma, in which one parent's contribution of the tumor suppressor Rb1 is flawed. Although most cells will have a functional second copy, chance loss of heterozygosity events in individual cells almost invariably lead to the development of this retinal cancer in the young child.
Breast Cancer and BRCA1/2
The genes BRCA1 and BRCA2 show loss of heterozygosity in samplings of tumors from patients who have germline mutations. BRCA1/2 are genes that produce proteins which regulate the DNA repair pathway by binding to Rad51.
Loss of heterozygosity can be identified in cancers by noting the presence of heterozygosity at a genetic locus in an organism's germline DNA, and the absence of heterozygosity at that locus in the cancer cells. This is often done using polymorphic markers, such as microsatellites or single-nucleotide polymorphisms, for which the two parents contributed different alleles. Genome-wide LOH status of fresh or paraffin embedded tissue samples can be assessed by virtual karyotyping using SNP arrays.
- Microsatellite instability
- Tumor suppressor gene
- Virtual Karyotype
- Knudson hypothesis
- Deletion (genetics)
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- "Long-term study of the clinical significance of loss of heterozygosity in childhood acute lymphoblastic leukemia" – Leukemia
- "Loss of heterozygosity identifies genetic changes in chronic myeloid disorders, including myeloproliferative disorders, myelodysplastic syndromes and chronic myelomonocytic leukemia" – Modern Pathology
- "Mapping loss of heterozygosity in normal human breast cells from BRCA1/2 carriers" – BJC
- "Loss of Heterozygosity Studies on Chromosome 12q in Disseminated Superficial Actinic Porokeratosis: Lessons to be Learned" – Journal of Investigative Dermatology