Loss of Heterozygosity (LOH) is a genetic event where a cell loses one of its two copies of a gene or a segment of a chromosome. LOH is a common occurrence in cancer development and plays a significant role in inactivating genes that normally prevent uncontrolled cell growth. Understanding LOH mechanisms and implications is important for cancer research and the development of targeted therapies.
Understanding Our Genetic Blueprint
Our genetic blueprint is contained within DNA, organized into structures called chromosomes. Humans have two copies of each chromosome, one inherited from each parent. Each chromosome carries many genes, which are segments of DNA that provide instructions for building and operating our bodies.
For most genes, we inherit two versions, or alleles, one from our mother and one from our father. If these two alleles are different, an individual is considered heterozygous for that gene. If the two alleles are identical, the individual is homozygous.
Among these genes are “tumor suppressor genes,” which act as brakes on cell division, regulating cell growth and preventing tumor formation. These genes help repair DNA errors or initiate programmed cell death if a cell is beyond repair. For these genes to function correctly, both inherited copies need to be working properly.
How Loss of Heterozygosity Drives Cancer
The link between LOH and cancer development is explained by Knudson’s “two-hit hypothesis,” proposed in 1971. This hypothesis suggests that for most tumor suppressor genes, both alleles must be inactivated for cancer to develop. In individuals with an inherited predisposition to cancer, one non-functional copy of a tumor suppressor gene is already present in every cell from birth.
LOH represents the “second hit” in this scenario, where the remaining functional copy of the tumor suppressor gene is lost or inactivated in a somatic cell. This loss of the second functional allele leads to the absence of the gene’s normal function, removing the natural brakes on cell division. For instance, in retinoblastoma, a childhood eye cancer, the first mutation in the RB1 gene is inherited, and LOH of the second, healthy copy drives tumor formation.
With both copies of the tumor suppressor gene inactivated, cells can grow and divide without proper control, contributing to tumor development. This mechanism is observed in numerous cancer types, where LOH leads to the inactivation of tumor suppressor genes like TP53, BRCA, and WT1. The consequence is unchecked cellular proliferation, a hallmark of cancer.
The Many Ways Loss of Heterozygosity Occurs
Loss of Heterozygosity can occur through several cellular mechanisms, each leading to the absence of a functional allele. One common mechanism is the deletion of a chromosomal region that contains the functional allele. This physically removes the gene copy, leaving only the non-functional one.
Another way LOH can happen is through mitotic recombination, a process where homologous chromosomes exchange genetic material during cell division. If this exchange leads to a cell having two copies of the same mutated allele, heterozygosity is lost, making the cell homozygous for the mutated allele without an additional mutation.
Gene conversion is a distinct mechanism where a segment of DNA on one chromosome is replaced by a copy of the corresponding segment from the homologous chromosome. If the “donor” chromosome carries a non-functional allele, the “recipient” chromosome can acquire this non-functional sequence, resulting in LOH. Lastly, the loss of an entire chromosome, followed by the duplication of the remaining chromosome carrying the non-functional allele, can also lead to LOH, maintaining the total chromosome number but eliminating heterozygosity.
Why Detecting Loss of Heterozygosity Matters
Detecting Loss of Heterozygosity holds clinical importance. LOH can serve as a biomarker for cancer diagnosis and prognosis, as specific patterns are linked to different cancer types and can help predict disease outcomes. For example, LOH at certain genetic locations has been correlated with a higher risk of cancer progression or poorer survival rates.
Understanding LOH can also inform cancer treatment strategies, guiding decisions for targeted therapies that are more effective in tumors exhibiting specific LOH patterns. Identifying genes inactivated due to LOH can reveal potential targets for new treatments. Detecting LOH can also help identify individuals at higher risk for inherited cancer syndromes, such as those with germline mutations in tumor suppressor genes like BRCA1, where LOH can signify an increased cancer risk.