Concept that both a germline predisposition and a somatic event are required for the inactivation of tumor suppressor genes in cancer.
Applies to heritable cancer syndromes manifested by mutations in tumor suppressor genes with high penetrance.
The first hit is an inherited mutant allele in the germline and the simplest second hit is a somatic loss of the normal (wild-type) allele leaving a single copy of the mutant allele.
Most commonly the second hit is a combination of multiple and complex somatic changes.
With most sporadic cancers there are complex traits such that the germline predisposition is related to low penetrance genomic variants in oncogenes or tumor suppressor genes.
Two mutations in a tumor suppressor gene are required for tumorigenesis, regardless of whether the mutations are inherited or acquired.
In inherited cases, the first mutation, or hit, is found in the germline of a parent and is inherited, and only one somatic hit on the other (wild-type) allele of the same gene is required for tumorigenesis.
In acquiring disease, both mutations occur somatically, each affecting one of the two alleles of the tumor suppressor gene.
Bilateral tumors in paired organs are assumed to be hereditary, because a family history of cancer and earlier age at onset or often associated with such tumors.
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