HOMOZYGOUS DELETIONS OF METHYLTHIOADENOSINE PHOSPHORYLASE (MTAP) ARE MORE FREQUENT THAN P16(INK4A) (CDKN2) HOMOZYGOUS DELETIONS IN PRIMARY NONSMALL CELL LUNG CANCERS (NSCLC)

Homozygous deletions of the tumor suppressor gene p16(INK4A) and defic iency of methylthioadenosine phosphorylase (MTAP), both located on chr omosome 9p21, have been independently reported in non-small cell lung cancer (NSCLC). To determine the frequency of co-deletion of these two genes, we investigated 50 samples of primary NSCLC using a quantitati ve PCR-ELISA. All specimens were fixed in formalin, paraffin embedded and stored until assayed. Histologic subtypes included 25 adenocarcino mas (50%), 21 squamous cell carcinomas (42%) and four large cell carci nomas (8%). Homozygous deletions of MTAP exon 8 could be detected in 1 9 of 50 NSCLC samples (38%). Adenocarcinoma (11 of 25, 44%) showed a h igher deletion frequency than squamous cell carcinoma (six of 21, 29%) . In contrast, homozygous p16(INK4A) deletions were detected in only n ine of 50 (18%) samples using specific primers for p16(INK4A) exon 1 a lpha. No difference between the histological subtypes and p16(INK4A) d eletion frequency was observed. We further investigated the ten sample s with MTAP deletions but intact p16(INK4A) exon 1 alpha with primers specific for p16(INK4A) exon 3, the exon nearest to MTAP exon 8. Inter estingly, none of the ten samples had deletion of the p16(INK4A) exon 3 coding region. Fine mapping analysis performed in ten samples showed a frequent breakpoint between MTAP exon 4 and exon 5. In addition, p1 6 protein expression could not be detected in five out of six samples with intact p16 but deleted MTAP locus. These data show a high frequen cy of homozygous MTAP deletions in NSCLC which is associated with dete ctable co-deletion of p16(INK4A) only half of the cases. This result s uggests the existence either of another tumor suppressor gene telomeri c of p16(INK4A) or of deletions involving 3'-untranslated (3'-UTR) reg ulatory regions of p16(INK4A) that can interfere with its expression o r function.