Microsatellite instability as biomarker for risk of multiple primary malignancies of the upper aerodigestive tract

Head and neck cancer (HNC) patients are at high risk of developing second p rimary tumors of the upper aerodigestive tract and this is a chief cause of death. Genomic instability reflecting the propensity and the susceptibilit y of the genome to acquire multiple alterations is considered a driving for ce behind multiple carcinogenesis and the alterations of the length of sing le repetitive genomic sequences or microsatellite instability (MI), implica ting impaired DNA repair mechanisms, and could be a sensitive marker for as sessing genomic instability in multiple HNC. To investigate whether a genet ic defect(s) involving the mismatch repair system constitutes a risk factor in patients with multiple head and neck cancer, we examined replication er rors (RER) at 10 microsatellite loci in 21 primary and 5 second primary can cers in 21 patients with multiple malignancies of the upper aerodigestive t ract, in comparison with match-paired primary HNC from patients without mul tiple malignancies. A RER+ phenotype (alterations at greater than or equal to2 loci) was observed at 10 microsatellite alterations on chromosomes 2, 3 , 11, 17 in at least one tumor from 15 out of 21 (71.5%) patients with mult iple primary cancers but only in 11 tumors from 40 (27.5%) HNC patients wit h single cancer (P=0.001). A RER+ phenotype was also associated with a posi tive familial cancer history (P=0.046). Our results suggest that a genetic instability may play an important role in the pathogenesis of multiple prim ary cancers and that testing for MI in a primary HNC may be useful in detec ting patients with high risk for developing multiple malignancies of the up per aerodigestive tract.