8.6 Loss of Heterozygosity

Loss of Heterozygosity is the genetic event in which a cell that initially carried two different alleles at a particular chromosomal locus loses one of these alleles, converting a heterozygous state into an effectively homozygous or hemizygous one, and serving as a common mechanism by which the second, remaining functional copy of a tumor suppressor gene is inactivated during cancer development.

The Basic Genetic Event

From Heterozygosity to Homozygosity or Hemizygosity

A cell is heterozygous at a given locus when it carries two distinct alleles, one inherited from each parent. Loss of heterozygosity occurs when the genetic information from one of these alleles is lost or replaced, leaving the cell with only the sequence and characteristics of the remaining allele at that locus.

Relevance to Tumor Suppressor Genes

When the allele retained after loss of heterozygosity is a previously inactivated tumor suppressor allele, and the allele lost was the remaining functional copy, the cell is left entirely without functional tumor suppressor protein, completing the biallelic inactivation required for full loss of that gene's protective activity.

Mechanisms Producing Loss of Heterozygosity

Chromosomal Deletion

A physical deletion of the chromosomal segment carrying the normal allele directly eliminates that copy, leaving only the previously mutated allele, or in some cases no allele at all, at the affected locus.

Mitotic Recombination

Recombination occurring between homologous chromosomes during mitosis can result in one daughter cell inheriting two copies of the chromosome arm carrying the mutant allele, replacing the normal allele with a second copy of the mutant one, while the sister daughter cell inherits two normal copies.

Chromosome Loss and Reduplication

Loss of an entire chromosome carrying the normal allele, sometimes followed by duplication of the remaining chromosome carrying the mutant allele to restore normal chromosome number, produces a cell homozygous for the mutant allele through whole-chromosome-level events rather than a localized deletion.

Gene Conversion

A smaller-scale process in which the sequence of the normal allele is directly replaced by the sequence of the mutant allele through a localized recombination-based repair mechanism can also produce loss of heterozygosity restricted to a limited genomic region.

Detection of Loss of Heterozygosity

Comparison of Allelic Markers

Loss of heterozygosity is typically detected by comparing genetic markers at a given locus between normal tissue and tumor tissue from the same individual, identifying loci where the tumor has become homozygous or hemizygous at a position where the normal tissue remains heterozygous.

Mapping Tumor Suppressor Gene Locations

Because loss of heterozygosity frequently occurs at the specific chromosomal location of a tumor suppressor gene relevant to a given tumor type, patterns of loss of heterozygosity across many tumor samples have historically served as an important tool for mapping the genomic locations of previously unidentified tumor suppressor genes.

Significance in Cancer Development

Loss of heterozygosity represents one of the principal mechanisms by which the second hit required for complete tumor suppressor gene inactivation is achieved, and its frequent occurrence at specific recurrent chromosomal locations across many cancer types underscores its central role in the multistep process by which tumor suppressor function is eliminated during carcinogenesis.