loss of heterozygosity
Summary
Loss of heterozygosity (LOH) refers to the loss of one functional allele of a gene in a cell that was previously heterozygous, leaving only the mutated or non-functional allele. This is a key mechanism in tumor suppressor gene inactivation, consistent with Knudson's 'two-hit hypothesis' of carcinogenesis. LOH is commonly detected in hereditary and sporadic cancers.
Detail
In Knudson's two-hit hypothesis, both alleles of a tumor suppressor gene (e.g., RB1, TP53, APC, BRCA1/2) must be inactivated for loss of function and subsequent tumorigenesis. In hereditary cancer syndromes, an individual inherits one defective allele (first hit, germline mutation) present in all cells, making them heterozygous at that locus. A second somatic hit—commonly via loss of heterozygosity—inactivates the remaining normal allele, resulting in complete loss of tumor suppressor function and promoting neoplastic transformation. LOH can occur through several mechanisms: mitotic nondisjunction with loss of the normal chromosome, mitotic recombination, gene conversion, deletion of the chromosomal region containing the wild-type allele, or whole chromosome loss. This differs from sporadic cancers, where both hits are somatic and occur within a single cell lineage, making hereditary cancers present earlier and often bilaterally (e.g., bilateral retinoblastoma) compared to sporadic unilateral cases. LOH is detected in the lab using polymorphic markers (like microsatellites or SNPs) to compare tumor DNA with normal tissue DNA from the same patient; if a heterozygous marker in normal tissue becomes homozygous (or hemizygous) in tumor tissue, LOH is present at that locus. Clinically, LOH analysis helps identify tumor suppressor gene loci involved in carcinogenesis and has been studied in cancers like retinoblastoma, Wilms tumor, colorectal cancer (APC, DCC, TP53), and breast/ovarian cancer (BRCA1/2). LOH is an important concept for understanding autosomal dominant cancer predisposition syndromes, which are dominant at the organismal level due to inheritance pattern but recessive at the cellular level since both alleles must be lost for cancer to develop.
Sources
- Robbins and Cotran Pathologic Basis of Disease
- First Aid for the USMLE Step 1
- Molecular Biology of the Cell (Alberts et al.)
- Kumar, Abbas, Aster - Robbins Basic Pathology
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