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 primary tumors of the upper aerodigestive tract and this is a chief cause of death. Genomic instability reflecting the propensity and the susceptibility of the genome to acquire multiple alterations is considered a driving force behind multiple carcinogenesis and the alterations of the length of single repetitive genomic sequences or microsatellite instability (MI), implicating impaired DNA repair mechanisms, and could be a sensitive marker for assessing genomic instability in multiple HNC. To investigate whether a genetic defect(s) involving the mismatch repair system constitutes a risk factor in patients with multiple head and neck cancer, we examined replication errors (RER) at 10 microsatellite loci in 21 primary and 5 second primary cancers in 21 patients with multiple malignancies of the upper aerodigestive tract, in comparison with match-paired primary HNC from patients without multiple malignancies. A RER+ phenotype (alterations at > or =2 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 multiple primary cancers but only in 11 tumors from 40 (27.5%) HNC patients with single cancer (P=0.001). A RER+ phenotype was also associated with a positive familial cancer history (P=0.046). Our results suggest that a genetic instability may play an important role in the pathogenesis of multiple primary cancers and that testing for MI in a primary HNC may be useful in detecting patients with high risk for developing multiple malignancies of the upper aerodigestive tract.

Prediction of recurrence by microsatellite analysis in head and neck cancer.

We examined the possibility of using microsatellite alterations as markers to detect clonal tumor-derived cell populations in histopathologically negative surgical margins and cervical lymph nodes from head and neck cancer (HNC) patients. We used polymerase chain reaction (PCR)-based microsatellite analysis DNA to analyze primary tumors, paired surgical margins, and cervical lymph nodes from 41 HNC patients. Samples were scored for alterations as defined by the presence of new alleles (shifts) or loss of heterozygosity (LOH) at each of 10 markers. We identified 25 (61%) patients with primary HNC who appeared to have had a complete resection on the basis of the histopathological assessment and who were informative regarding microsatellite alterations in tumor tissue. In 11 of these 25 (44%) cases, PCR analysis of surgical margins showed the same microsatellite alterations as in the primary tumors. In 7 of these 11 patients, the carcinoma recurred locally, as compared with 1 out of 14 patients with negative margins (log rank test, P = 0.0049). Conversely, we were unable to detect clonal neoplastic cells in histopathologically negative lymph nodes examined by molecular analysis. Cox regression analysis showed that molecular positive margins were an independent prognostic factor (P = 0.04) for recurrence. This study demonstrates that microsatellite analysis may be a valuable tool for evaluating the risk of local recurrence.