ALLELIC DELETION ANALYSIS OF THE FHIT GENE PREDICTS POOR SURVIVAL IN NONSMALL CELL LUNG-CANCER

The fragile histidine triad (FHIT) gene at chromosome 3p14.2 is a cand idate tumor suppressor gene linked to cancers of the lung, breast, col on, pancreas, and head and neck. Reports of frequent allelic deletion and abnormal transcripts in primary lung tumors plus recent evidence t hat it is targeted by tobacco smoke carcinogens suggest that it plays an important role in lung carcinogenesis. Non-small cell lung carcinom a still maintains a poor 5-year survival rate with the stage of diseas e at presentation as a major determinant of prognosis. We examined for allelic deletion at the FHIT locus in a series of 106 non-small cell lung carcinomas for which a full clinical, epidemiological, and 5-year survival profile was available. We found an allelic deletion frequenc y of 38% at one or two intragenic microsatellites, Allelic deletion of FHIT was related to tumor histology with 4 of 20 adenocarcinomas (20% ) displaying loss of heterozygosity (LOH) compared with 12 of 22 (55%) nonadenocarcinomas (P = 0.03), We found that 63% of tumors with LOH o f FHIT also had p53 missense mutations whereas only 26% with LOH had w ild type p53 negative sequence (P = 0.02), We also found a significant trend toward poorer survival in patients with LOH of at least one loc us of the FHIT gene (log rank, P = 0.01). This survival correlation is independent of tumor stage, size, histological subtype, degree of dif ferentiation, and p53 mutation status. Our data support the hypothesis that the loss of the FHIT contributes to the molecular pathogenesis o f human lung cancer and is an indicator of poor prognosis.