p53 genetic abnormalities and myc activation in human lung carcinoma

Abstract

p53 mutations and myc gene amplification and expression were studied in 119 lung carcinomas of all histological types. A mutant p53 immunophenotype was previously found in 47% of these tumors by immunohistochemical analysis. Seven cases exhibited p53 genomic rearrangements on Southern blots. Elevated levels of p53 transcript were found in 12 carcinomas (10%) and decreased levels in 27 carcinomas (23%) on Northern blots. In most of the cases, low levels of transcript were associated with negative immunostaining, whereas elevated levels of mRNA were related to positive immunostaining (mutant immunophenotype). p53 RT/PCR analysis in 10 tumors with absence of transcript on Northern blots revealed only weak or absent expression of normal and/or altered size transcripts. These abnormal transcripts showed deletions, insertions or splicing abnormalities. Taken together, p53 abnormalities were found in 66% of lung carcinomas [52% of neuroendocrine (NE) carcinomas and 75% of NSCLC]. c-myc was found to be activated in 24% (10/42) of these NE and in 48% (33/69) of these NSCLC carcinomas using Southern- and Northern-blot techniques. In addition, L- and N-myc genes were also activated in 26% (10/42) of NE carcinomas. No correlation was found between p53 mutations and myc activation in SCLC or in NSCLC, but their association was significantly more frequent in NSCLC than in SCLC. These results indicate that the p53-positive immunophenotype uncovers the occurrence of p53 point mutations in lung cancer and that p53 and c-myc gene alterations are important but represent independent occurrences in the development of lung tumors.

p53 protein is absent from the serum of patients with lung cancer

“…The accumulation of mutations leading to increased rates of cell division, the ability to invade locally and to metastasise, and the general escape from cellular social controls governing cell behaviour provide the molecular basis for neoplasia. Alterations to the p53 gene are the most frequent genetic changes revealed so far in human cancer and occur in 43-75% of non-small-cell lung cancers (NSCLC) (Marchetti et al, 1993;Mitsudomi et al, 1993a;Gazzeri et al, 1994) and 32-70% of small-cell lung cancers (SCLC) (Miller et al, 1992;Lohmann et al, 1993;Ryberg et al, 1994), demonstrating its importance in the pathogenesis of these malignancies. (Bartek et al, 1991), and more recently, in lung tumours (Pappot et al, 1996).…”

“…Overexpression of mutant p53 may identify more aggressive tumours and hence patients with unfavourable prognoses. p53 mutation (Miller et al, 1992;Gazzeri et al, 1994;Ryberg et al, 1994) and protein accumulation (Caamano et al, 1991;Brambilla et al, 1993) also frequently occur in primary lung carcinoma, which is the leading cause of cancer mortality in North America (Boring et al, 1993). Prognosis for these patients is largely dependent on the stage of the tumour presenting at clinical diagnosis, although other factors, including p53 overexpression in tumour tissue, have also been reported to predict reduced patient survival (Quinlan et al, 1992;Mitsudomi et al, 1993a).…”

Distinct pattern of E2F1 expression in human lung tumours: E2F1 is upregulated in small cell lung carcinoma

“…Relationships between E2F1, p53, pRb and hp14 ARF status in lung carcinoma Status of p53, pRb and hp14 ARF had been previously analysed in this series of tumours (Brambilla et al, 1993;Gazzeri et al, 1994Gazzeri et al, , 1998aGouyer et al, 1998). In these tumours, pRb function was inactivated, either by loss-of-function mutations or p16 INK4a loss and/or cyclin D1 overexpression in 29/36 (80%) NE tumours and 18/22 (82%) NSCLC respectively.…”

“…There was no inverse nor direct correlation linking E2F1 and hp14 ARF or p53 expression in any histological tumour class. However, we noticed that overexpression of E2F1 was frequently associated with inactivation of hp14 ARF [as detected by negative immunostaining (Gazzeri et al, 1998b)] (20/ 36, 69%) and/or of p53 [as indicated by p53-positive immunoreactivity (Gazzeri et al, 1994)] (18/36, 50%) in NE lung tumours (Table 2).…”

“…Pathways involving p53 and pRb tumour suppressor genes are frequently deregulated during lung tumorigenesis. p53 is inactivated in 70% of human lung tumours either by missense (Chiba et al, 1990;Brambilla et al, 1993) or null mutations (Gazzeri et al, 1994). pRb pathway is di erentially disrupted in NSCLC and high grade NE tumours.…”