p53 null mutations undetected by immunohistochemical staining predict a poor outcome with early-stage non-small cell lung carcinomas

The importance of p53 mutations in the pathogenesis of human lung carcinoma is well established, but it is still controversial whether the presence of p53 mutations or overexpression of p53 protein adversely affects an indivi dual patient's chances of survival. The controversy may be partially due to the methodological differences in examination for p53 alterations: gene an alysis or immunohistochemical staining. Furthermore, recent studies have su ggested that different types of mutations of the p53 tumor suppressor gene confer different biological properties. To clarify the relationship between immunohistochemical staining and prognosis, we investigated mutations usin g single-strand conformation polymorphism followed by sequencing for exons 4-8 and 10 in 144 surgically treated non-small cell lung carcinoma patients with intensive clinical follow-up. Of 144 cases, 107 adenocarcinomas were examined fur immunohistochemical staining with RSP53 antibody, p53 gene mut ations were observed in 65 tumors (45%), including 44 missense and 21 null mutations, the latter comprising 7 nonsense mutations, 8 deletions, 2 inser tions, and 4 splicing junction mutations. Presence of p53 mutations was an independent prognostic factor with a statistical trend (P = 0.14) in stage I patients but not in all cases. When examined by mutational pattern, null mutation was a significant indicator of poor outcome by multivariate analys is (P = 0.03) in stage I patients, whereas cases with missense mutations an d without mutations did not differ (P = 0.76). Forty (37%) tumors demonstra ted overexpression of the p53 protein but without any survival difference. Most tumors (76%) with missense mutations were immunopositive, but those wi th null mutations with one exception (93%) were not, and the concordance be tween the mutations and immunohistochemical staining was rather low at 65%. These data suggest that the type of p53 mutation is important for predicti on of outcome in early-stage non-small cell lung carcinoma patients, wherea s immunohistochemical staining for abnormal p53 gene products is nonpredict ive. Furthermore, null mutations causing loss of function of the gene produ ct may play more important roles than missense mutations in humor progressi on.