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.

Among the major regulators of the G 1 restriction point are cyclin D1 and the retinoblastoma gene product (RB). In non-small cell lung cancer (NSCLC), the cyclin D1 gene is amplified/over-expressed in almost 50% of cases, and RB is inactivated in 6-32% of cases. It is of interest to evaluate concurrently the alterations of both genes on the same series of NSCLCs, to investigate whether cyclin D1 and RB alterations are alternative pathways leading to inactivation of the G 1 restriction point or if they can occur in the same tumor, possibly exerting an additive effect on cancer progression. We investigated a series of 57 NSCLCs, analyzing cyclin D1 and RB at the gene and protein levels by Southern blot, Northern blot and immunohistochemistry. The cyclin D1 gene was amplified in 18 cases. cyclin D1 immunoreactivity was seen in 25 tumors. Amplification and expression were significantly associated. RB immunohistochemical expression was absent in 9 of 42 informative cases. RB mRNA expression was low to absent in 9 of 45 informative cases. cyclin D1 amplification was associated with normal RB mRNA, and cyclin D1 over-expression was associated with normal RB immunoreactivity, supporting the hypothesis that alterations of cyclin D1 and RB are alternative mechanisms by which tumor cells may escape the G 1 restriction point. A concurrent alteration of RB and cyclin D1 was seen in a small subset of NSCLCs. Abnormalities of cyclin D1 and/or RB at the gene and/or expression level were present in more than 90% of cases, stressing that cyclin D1 and/or RB alterations represent an important step in lung tumorigenesis. Int. J. Cancer 75:187-192, 1998. Wiley-Liss, Inc.The control of mammalian cell proliferation occurs largely during the G 1 phase of the cell cycle (Pardee, 1989). This control mechanism, known as the restriction point or R-point, consists of a multimolecular system composed of cyclins D, cyclin-dependent kinases (cdk), cdk inhibitors and the retinoblastoma protein (RB) . Alterations of this pathway may represent an obligatory step in tumorigenesis; it is important to evaluate the abnormalities of not only the single genes involved in the pathway, but also the functional alterations of the whole multicomponent mechanism Lukas et al., 1995).Among the major regulators of the G 1 restriction point are cyclin D1 and RB. cyclin D1, by complexing with the cyclin-dependent kinases cdk4 and cdk6, promotes cell proliferation by phosphorylating RB and inactivating its growth-restraining properties (Hatekayama et al., 1994). The interplay of cyclin D1, cdk and cdk inhibitors operates upstream to the RB, and most data support the hypothesis that both the G 1 -accelerating function of cyclin D1/cdk and the growth suppression by cdk inhibitors strictly require the presence of a functional RB . The cyclin D1 gene is amplified/rearranged and/or over-expressed in several types of human neoplasms (Bartkova et al., 1995), and the RB gene is the archetypal tumor suppressor that is inactivated by mutations, deletions or sequestrations of...

Findings at Lipiodol-CT enable a reliable diagnosis of intrahepatic metastatic nodules of HCC.

Summary Lung cancer is strictly associated with tobacco smoking. Tumours developed in non-smoking subjects account for less than 10% of all lung cancers and show peculiar histopathlIogical features, being prevalentty adenocarcinomas. A number of genetic data suggest that their biological behaviour may be different from that of lung tumours caused by smoking, however the number of cases investigated to date is too low to draw definitive conclusions. We have examined the status of p53 and K-ras genes and the presence of loss of heterozygosity (LOH) at the FHIT locus in a series of 35 lung adenocarcinomas that developed in subjects who had never smoked. Results were compared with those obtained in a series of 35 lung adenocarcinromas from heavy-smoking subjects. In the group of non-smoking subjects p53 mutations and LOH at the FHIT locus were present in seven (20%) cases, and the two alterations were constantly associated (P < 0.0001), whereas they were not related in the series of carcinomas caused by smoking. In tumours developed in heavy-smoking subjects, the frequency of LOH at the FHIT locus was significantly higher (P = 0.006) than in tumours from non-smoking subjects. The frequency of p53 mutations in adenocarcinomas caused by smoking was not different from that seen in non-smoking subjects. However, in the group of smoking subjects we observed mostly G:C -* T:A transversions, whereas frameshift mutations and G:C -* A:T transitions were more frequently found in tumours from non-smoking subjects. No point mutations of the K-ras gene at codon 12 were seen in subjects who had never smoked, whereas they were present (mostly G:C -* T:A transversions) in 34% of tumours caused by smoking (P = 0.002). Our data suggest that lung adenocarcinomas developed in subjects who had never smoked represent a distinct biological entity invoMng a co-alteration of the p53 gene and the FHIT locus in 20% of cases.

No abstract