1.8.9 Loss of Heterozygosity Definition

Loss of Heterozygosity Definition is the description of an event in which a cell that originally carried two distinguishably different copies of a given chromosomal region, one inherited from each parent, comes to retain only a single version of that region, whether because one copy has been physically deleted, because one entire chromosome has been lost, or because a segment of one chromosome has been replaced by a duplicate of the corresponding segment from the other chromosome. Loss of heterozygosity is of particular significance in cancer cell biology when it affects a region containing a tumor suppressor gene whose remaining, retained copy carries a prior inactivating alteration, since the loss eliminates the last source of that gene's normal, protective function.

Conceptual Basis of Loss of Heterozygosity

Heterozygosity as the Starting Condition

Loss of heterozygosity presumes an initial condition in which a cell's two copies of a chromosomal region are distinguishable from one another, typically because they carry different sequence variants inherited separately from each parent, a condition referred to as heterozygosity. It is the loss of this distinguishable difference, through elimination of one of the two versions, that defines the event.

Mechanistic Focus on the Chromosomal Region Rather Than a Single Gene

While loss of heterozygosity is most often discussed in relation to its consequence for a specific tumor suppressor gene located within the affected region, the underlying event itself typically involves a broader stretch of chromosomal material, meaning that loss of heterozygosity at a given tumor suppressor locus frequently affects numerous additional genes located nearby on the same chromosome segment.

Mechanisms Producing Loss of Heterozygosity

Physical Deletion of One Copy

Loss of heterozygosity can arise from a physical deletion that removes the chromosomal segment carrying one of the two versions of a given region, leaving only the remaining, structurally intact version present within the cell.

Loss of an Entire Chromosome

Loss of heterozygosity can arise from loss of an entire chromosome during cell division, a more extensive event that eliminates one full copy of every gene located on that chromosome, including the specific region of interest.

Mitotic Recombination Resulting in Duplication of One Parental Copy

Loss of heterozygosity can arise through a process in which a segment of one chromosome is exchanged with the corresponding segment of its homologous partner during cell division, resulting in a cell that retains two copies of the region, but with both copies now derived from what was originally only one of the two parental versions.

Consequences of Loss of Heterozygosity for Tumor Suppressor Genes

Completion of Biallelic Inactivation

When loss of heterozygosity affects a chromosomal region in which one copy of a tumor suppressor gene already carries an inactivating mutation, the loss of the remaining, previously functional copy completes biallelic inactivation of that gene, eliminating any remaining source of its normal protective function.

A Common Second Hit in the Two Hit Model

Loss of heterozygosity is frequently observed as the specific mechanism completing the second hit required by the two hit model of tumor suppressor inactivation, since a broad chromosomal loss affecting the remaining functional copy represents a statistically more probable route to completing inactivation than acquisition of a second independent point mutation.

Detection of Loss of Heterozygosity

Comparison of Marker Signals Between Tumor and Normal Tissue

Loss of heterozygosity is identified by comparing signals at heterozygous marker positions between a tumor sample and a corresponding normal tissue sample from the same individual, with loss of one of the two signals present in the normal tissue, but absent in the tumor tissue, indicating that loss of heterozygosity has occurred at that position within the tumor cells.

Significance of Loss of Heterozygosity Within Cancer Cell Biology

A Recurrent Marker of Tumor Suppressor Gene Inactivation

Because loss of heterozygosity recurrently affects chromosomal regions containing known tumor suppressor genes across many cancer types, its detection serves as a valuable indicator for identifying which tumor suppressor genes have likely undergone complete inactivation within a given tumor.