FHIT andp53 gene abnormalities in bronchioloalveolar carcinomas. Correlations with clinicopathological data and K-ras mutations

Abstract

Bronchioloalveolar carcinoma (BAC) is a particular type of adenocarcinoma of the lung which accounts for up to 9 per cent of pulmonary malignancies. The aetiology and pathogenesis of this unique neoplastic disease are still unclear. Three histological subtypes of BAC have been recognized: mucinous, non‐mucinous, and sclerosing. Of these, mucinous and sclerosing BAC have a worse prognosis than non‐mucinous tumours. The different morphological patterns and clinical outcomes of the subtypes of BAC suggest differences in their biological behaviour. Previous reports have shown that the mucinous form of BAC is characterized by constant mutations at codon 12 of the K‐ras gene, whereas the other two histotypes show a frequency of K‐ras mutations which is not different from that observed in conventional lung adenocarcinomas. The present study of a series of 51 BACs, previously investigated for K‐ras gene mutations, has evaluated the status of two other genes, p53 and FHIT, known to be frequently altered in non‐small cell lung cancer. Loss of heterozygosity at microsatellite‐containing loci located within the FHIT gene was observed in 22 (43 per cent) BACs. The distribution of FHIT gene abnormalities was not statistically different in the three histological subtypes. p53 mutations were present in 13 (32 per cent) non‐mucinous/sclerosing BACs, while no mutations were seen in mucinous tumours (P‐0·039). Correlations with clinicopathological parameters showed that p53 mutations in BACs are associated with more aggressive tumours. No correlations were observed between FHIT or K‐ras gene abnormalities and clinicopathological data. In conclusion, these results indicate that FHIT alterations are frequently involved in BAC tumourigenesis and that genetic changes in the p53 and K‐ras genes can distinguish between different histotypes of BAC. © 1998 John Wiley & Sons, Ltd.

Loss of FHIT protein expression is related to high proliferation, low apoptosis and worse prognosis in non-small-cell lung cancer

“…The reported frequency of LOH at FHIT gene in NSCLC is between 20 and 70% of cases. 5,11,[17][18][19][20][21][22][23][24] Our results are similar to the highest frequency, with LOH in one or more microsatellites in 67.8% of 96 informative tumors. The differences between all series probably could be explained by the different markers used and the method of detection and evaluation of LOH.…”

“…3 Frequent allelic losses and homozygous deletions, [3][4][5][6][7][8][9][10][11][12][13][14][15][16] as well as the loss of heterozygosity (LOH) in microsatellites located at FHIT gene 5,11,12,[17][18][19][20][21][22][23][24] have been described at the FHIT locus in several human solid tumors arising from epithelial cells, including lung cancer.…”

Frequent allelic deletion at the FHIT locus associated with p53 overexpression in squamous cell carcinoma subtype of Taiwanese non-small-cell lung cancers

“…In agreement with previous studies (Burke et al, 1998;Marchetti et al, 1998;Tomizawa et al, 1998;Geradts et al, 2000), allelic deletion of the FHIT locus did not correlate with sex, age, staging, lymph node metastasis and survival. Thus, our results are consistent with the role of FHIT abnormalities at a relatively early stage of pulmonary neoplasia, rather than in the metastatic progression of invasive lung cancers.…”

“…It was previously indicated that the genetic changes at the FHIT locus may be correlated with p53 mutations (Burke et al, 1998;Marchetti et al, 1998;Chang et al, 2003), while other investigators found no statistically significant correlation between FHIT and p53 abnormalities in NSCLCs (Nelson et al, 1998;Geradts et al, 2000). By examining the FHIT/ p53 profiles, we noticed that the nine cases with synergistic effect of LOH at FHIT locus and p53 overexpression included six squamous cell carcinomas and three adenocarcinomas.…”

“…It has been proposed that the FHIT gene is specifically targeted by carcinogens in cigarette smoke, and a number of reports described an increased frequency of FHIT abnormalities at the DNA or protein level in smokers (Sozzi et al, , 1998Marchetti et al, 1998;Nelson et al, 1998;Tomizawa et al, 1998). Our series of 58 NSCLC patients included 24 smokers and 34 nonsmokers.…”