HOMOZYGOUS DELETIONS AT CHROMOSOME 9P21 AND MUTATION ANALYSIS OF P16 AND P15 IN MICRODISSECTED PRIMARY NON-SMALL-CELL LUNG CANCERS

Loss of heterozygosity on chromosome 9p has been detected in many prim ary human tumors and cell lines, suggesting that this chromosomal arm harbors one or more tumor suppressor genes, The recently cloned pld an d p15 genes, mapped to 9p21, are likely candidates for such tumor supp ressors. To map the deletion at chromosome 9p21 in non-small cell lung tumors, we analyzed DNA from 25 tumors and matching normal DNAs at si x microsatellite markers that flank the region occupied by the pld and p15 genes, Loss of heterozygosity of at least one microsatellite mark er on chromosome 9p21 was detected in 13 (52%) of 25 tumors, including one tumor that exhibited homozygous deletion of both human IFN alpha and D9S171. Six tumors analyzed by a comparative multiplex PCR techniq ue showed homozygous deletions of the sequence tag site marker c5.1 (w ithin p16). Screening for mutations in p16 and p15 revealed one tumor with a non-sense mutation in exon 2 of p16, but no mutations were dete cted in p15 in any of the tumors. Thus, in these analyses approximatel y one-half of the non-small cell lung tumors had loss of heterozygosit y at chromosome 9p21, and of these tumors, one-half had homozygous del etions of the region that includes p16. This appears to confirm the im portance of a locus in this region critical to growth control in lung. The apparent lack of other mutations in p16 and p15 in the tumors wit h loss of heterozygosity leaves open the possibility of an unidentifie d gene in this region that may function as a tumor suppressor.