Loss of heterozygosity

diploid

population of 10 individuals, that bottlenecked down to three individuals repeatedly, resulted in all individuals homozygous.

Loss of heterozygosity (LOH) is a type of genetic abnormality in

(slight differences between the versions of the gene inherited from each parent) is no longer present.

In cancer

The loss of heterozygosity is a common occurrence in

or via other mechanisms, resulting in a loss of heterozygosity event, and leaving no tumor suppressor gene to protect the body. Loss of heterozygosity does not imply a homozygous state (which would require the presence of two identical alleles in the cell).

Knudson two-hit hypothesis of tumorigenesis

Main article:

Knudson hypothesis

• First Hit: The first hit is classically thought of as a point mutation, but generally arises due to epigenetic events which inactivate 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: While the second hit is commonly assumed to be a deletion that results in loss of the remaining functioning TSG allele, the original published mechanism of RB1 LOH was mitotic recombination/gene conversion/copy-neutral LOH, not deletion. There is a critical difference between deletion and CN-LOH, as the latter mechanism cannot be detected by comparative genomic hybridization (CGH)-based gene copy number counting, and requires allelic genotyping. Either way, LOH leaves only non-functioning alleles of the TSG, and the individual may go on to develop cancer.

Copy-neutral LOH

Copy-neutral LOH is thus called because no net change in the copy number occurs in the affected individual. Possible causes for copy-neutral LOH include acquired uniparental disomy (UPD) and 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.

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.

Retinoblastoma

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

]

Homologous recombination repair

In breast, ovarian, pancreatic and prostate cancers, a core enzyme employed in homologous recombination repair (HRR) of DNA damage is often defective due to LOH, that is genetic defects in both copies (in the diploid human genome) of the gene encoding an enzyme necessary for HRR.^[7] Such LOH in these different cancers was found for DNA repair genes BRCA1, BRCA2, BARD1, PALB2, FANCC, RAD51C and RAD51D.^[7] Reduced ability to accurately repair DNA damages by homologous recombination may lead to compensating inaccurate repair, increased mutation and progression to cancer.

Detection

Loss of heterozygosity can be identified in cancers by noting the presence of

virtual karyotyping

using SNP arrays.

In asexual organisms

It has been proposed that LOH may limit the longevity of asexual organisms.

meselson effect

.

See also

• Inbreeding depression
• Microsatellite instability
• Tumor suppressor gene
• Virtual Karyotype
• Knudson hypothesis
• Deletion (genetics)

References

1. ^ [Association of the autoimmune diseases scleroderma with an immunologic response to cancer,] Christine G. Joseph et al., Science, 343:152 (10 January 2014)
2. ^ Mao X, Young BD, Lu YJ. The application of single-nucleotide polymorphism microarrays in cancer research. Curr Genomics. 2007 Jun;8(4):219–28.
3. ^ Gondek LP, Tiu R, O'Keefe CL, Sekeres MA, Theil KS, Maciejewski JP. Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD, and MDS-derived AML. Blood. 2008 Feb 1;111(3):1534–42.
4. ^ Beroukhim R, Lin M, Park Y, Hao K, Zhao X, Garraway LA, et al. Inferring loss-of-heterozygosity from unpaired tumors using high-density oligonucleotide SNP arrays. PLoS Comput. Biol. 2006 May;2(5):e41.
5. ^ Ishikawa S, Komura D, Tsuji S, Nishimura K, Yamamoto S, Panda B, et al. Allelic dosage analysis with genotyping microarrays. Biochem Biophys Res Commun. 2005 Aug 12;333(4):1309–14.
6. ^ Lo KC, Bailey D, Burkhardt T, Gardina P, Turpaz Y, Cowell JK. Comprehensive analysis of loss of heterozygosity events in glioblastoma using the 100K SNP mapping arrays and comparison with copy number abnormalities defined by BAC array comparative genomic hybridization. Genes Chromosomes Cancer. 2008 Mar;47(3):221–37.
7. ^ ^{a b} Westphalen CB, Fine AD, André F, Ganesan S, Heinemann V, Rouleau E, Turnbull C, Garcia Palacios L, Lopez JA, Sokol ES, Mateo J. Pan-cancer Analysis of Homologous Recombination Repair-associated Gene Alterations and Genome-wide Loss-of-Heterozygosity Score. Clin Cancer Res. 2022 Apr 1;28(7):1412-1421. doi: 10.1158/1078-0432.CCR-21-2096. PMID: 34740923; PMCID: PMC8982267
8. ^ Tucker AE, Ackerman MA, Eads BD, Xu S, Lynch M. Population-genomic insights into the evolutionary origin and fate of obligately asexual Daphnia pulex. PNAS. 2013; 110:15740.
9. ^ Archetti M. Recombination and loss of complementation: A more than two-fold cost for parthenogenesis. J Evol Biol 2004; 17(5):1084–1097.

External links

Wikimedia Commons has media related to Loss of heterozygosity.

• "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