SOMATIC MICROSATELLITE MUTATIONS AS MOLECULAR TUMOR CLOCKS

Microsatellite (MS) mutations can potentially unravel the past of muta tor phenotype tumors, with greater genetic diversity expected in older regions. Rapid clonal expansions of xenografts were characterized by relatively homogenous MS alleles, whereas greater diversity was observ ed in a colorectal cancer with the greatest variation in its adjacent adenoma. A subcutaneous lung cancer metastasis demonstrated diversity consistent with its one-month clinical duration and evidence of active mitosis during dormancy. The genetic legacy inherent to multistep tum origenesis provides direct estimates of tumor ages, with up to thousan ds of cell divisions and high death rates necessary to yield the obser ved diversities. MS molecular tumor clocks have the unique potential t o systematically reconstruct the early and occult evolution of individ ual human mutator phenotype tumors.