Loss of heterozygosity (LOH) is a type of genetic abnormality in diploid organisms in which one copy of an entire gene and its surrounding chromosomal region are lost. [1] Since diploid cells have two copies of their genes, one from each parent, a single copy of the lost gene still remains when this happens, but any heterozygosity (slight differences between the versions of the gene inherited from each parent) is no longer present.
The loss of heterozygosity is a common occurrence in cancer development. Originally, a heterozygous state is required and indicates the absence of a functional tumor suppressor gene copy in the region of interest. 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. The remaining copy of the tumor suppressor gene can be inactivated by a point mutation 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).
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. [2] 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. [3] [4] [5] [6] 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.
The genes BRCA1 and BRCA2 show loss of heterozygosity in samplings of tumors from patients who have germline mutations.[ citation needed ]BRCA1/2 are genes that produce proteins which regulate the DNA repair pathway by binding to Rad51.[ citation needed ]
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.
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.
It has been proposed that LOH may limit the longevity of asexual organisms. [8] [9] The minor allele in heterozygous areas of the genome is likely to have mild fitness consequences compared to de-novo mutations because selection has had time to remove deleterious alleles. When allelic gene conversion removes the major allele at these sites organisms are likely to experience a mild decline in fitness. Because LOH is much more common than de-novo mutation, and because the fitness consequences are closer to neutrality, this process should drive Muller's ratchet more quickly than de-novo mutations. While this process has received little experimental investigation, it is known that major signature of asexuality in metazoan genomes appears to be genome wide LOH, a sort of anti-meselson effect.
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or reduction in its function. In combination with other genetic mutations, this could allow the cell to grow abnormally. The loss of function for these genes may be even more significant in the development of human cancers, compared to the activation of oncogenes.
A genetic screen or mutagenesis screen is an experimental technique used to identify and select individuals who possess a phenotype of interest in a mutagenized population. Hence a genetic screen is a type of phenotypic screen. Genetic screens can provide important information on gene function as well as the molecular events that underlie a biological process or pathway. While genome projects have identified an extensive inventory of genes in many different organisms, genetic screens can provide valuable insight as to how those genes function.
BRCA2 and BRCA2 are human genes and their protein products, respectively. The official symbol and the official name are maintained by the HUGO Gene Nomenclature Committee. One alternative symbol, FANCD1, recognizes its association with the FANC protein complex. Orthologs, styled Brca2 and Brca2, are common in other vertebrate species. BRCA2 is a human tumor suppressor gene, found in all humans; its protein, also called by the synonym breast cancer type 2 susceptibility protein, is responsible for repairing DNA.
Genetics, a discipline of biology, is the science of heredity and variation in living organisms.
The Knudson hypothesis, also known as the two-hit hypothesis, is the hypothesis that most tumor suppressor genes require both alleles to be inactivated, either through mutations or through epigenetic silencing, to cause a phenotypic change. It was first formulated by Alfred G. Knudson in 1971 and led indirectly to the identification of tumor suppressor genes. Knudson won the 1998 Albert Lasker Clinical Medical Research Award for this work.
RecLOH is a term in genetics that is an abbreviation for "Recombinant Loss of Heterozygosity".
In molecular biology, SNP array is a type of DNA microarray which is used to detect polymorphisms within a population. A single nucleotide polymorphism (SNP), a variation at a single site in DNA, is the most frequent type of variation in the genome. Around 335 million SNPs have been identified in the human genome, 15 million of which are present at frequencies of 1% or higher across different populations worldwide.
Malignant rhabdoid tumour (MRT) is a very aggressive form of tumour originally described as a variant of Wilms' tumour, which is primarily a kidney tumour that occurs mainly in children.
Oncogenomics is a sub-field of genomics that characterizes cancer-associated genes. It focuses on genomic, epigenomic and transcript alterations in cancer.
The following outline is provided as an overview of and topical guide to genetics:
DNA repair and recombination protein RAD54-like is a protein that in humans is encoded by the RAD54L gene.
Integrator complex subunit 6 is a protein that in humans is encoded by the INTS6 gene.
Virtual karyotype is the digital information reflecting a karyotype, resulting from the analysis of short sequences of DNA from specific loci all over the genome, which are isolated and enumerated. It detects genomic copy number variations at a higher resolution for level than conventional karyotyping or chromosome-based comparative genomic hybridization (CGH). The main methods used for creating virtual karyotypes are array-comparative genomic hybridization and SNP arrays.
Chromothripsis is a mutational process by which up to thousands of clustered chromosomal rearrangements occur in a single event in localised and confined genomic regions in one or a few chromosomes, and is known to be involved in both cancer and congenital diseases. It occurs through one massive genomic rearrangement during a single catastrophic event in the cell's history. It is believed that for the cell to be able to withstand such a destructive event, the occurrence of such an event must be the upper limit of what a cell can tolerate and survive. The chromothripsis phenomenon opposes the conventional theory that cancer is the gradual acquisition of genomic rearrangements and somatic mutations over time.
Genome instability refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy.
Disease gene identification is a process by which scientists identify the mutant genotypes responsible for an inherited genetic disorder. Mutations in these genes can include single nucleotide substitutions, single nucleotide additions/deletions, deletion of the entire gene, and other genetic abnormalities.
Chromosomal instability (CIN) is a type of genomic instability in which chromosomes are unstable, such that either whole chromosomes or parts of chromosomes are duplicated or deleted. More specifically, CIN refers to the increase in rate of addition or loss of entire chromosomes or sections of them. The unequal distribution of DNA to daughter cells upon mitosis results in a failure to maintain euploidy leading to aneuploidy. In other words, the daughter cells do not have the same number of chromosomes as the cell they originated from. Chromosomal instability is the most common form of genetic instability and cause of aneuploidy.
GTP-binding protein Di-Ras3 (DIRAS3) also known as aplysia ras homology member I (ARHI) is a protein that in humans is encoded by the DIRAS3 gene.
PyClone is a software that implements a Hierarchical Bayes statistical model to estimate cellular frequency patterns of mutations in a population of cancer cells using observed alternate allele frequencies, copy number, and loss of heterozygosity (LOH) information. PyClone outputs clusters of variants based on calculated cellular frequencies of mutations.
HRDetect is a whole-genome sequencing (WGS)-based classifier designed to predict BRCA1 and BRCA2 deficiency based on six mutational signatures. Additionally, the classifier is able to identify similarities in mutational profiles of tumors to that of tumors with BRCA1 and BRCA2 defects, also known as BRCAness. This classifier can be applied to assess the implementation of PARP inhibitors in patients with BRCA1/BRCA2 deficiency. The final output is a probability of BRCA1/2 mutation.
