Abstract

Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome types I and II, and the related subtypes Turcot and Muir-Torre syndrome, have all been associated with inheritance of germ line mutations in the DNA mismatch repair (MMR) genes. Fifty individuals have recently been identified with an early onset of a different spectrum of cancers associated with inheritance of two MMR mutations--resulting either in a constitutive loss of MMR function, or greatly impaired MMR function. In contrast to Lynch I and II individuals, individuals with inheritance of homozygous or compound heterozygous mutations in the MMR genes that result in a complete lack of protein, present with hematological and brain malignancies in the first decade of life. Biallelic mutations with compromised but residual protein function present with a broader spectrum of cancers (brain, hematological or gastrointestinal) in the second to fourth decades of life. We propose that inheritance of two MMR mutations in an individual and the unique tumor spectrum that occurs with an early onset should be defined separately from Lynch syndrome I and II, or the subtypes Turcot and Muir-Torre. We suggest Lynch III as an appropriate name for identifying individuals with constitutively compromised MMR associated with biallelic mutations.