265

src Expression in small-cell lung carcinoma and other neuraendo- c&e malignancies Pahlman S, Hammerhng U. Deparrmenr of Pathology, Universrfy

Hospital. S-751 85 Uppsala. Am Rev Respir Dls 1990;142:Suppl. S54- 6.

The prom-oncogene c-w codes for two lyrosine kinases, pp6O(c-src) and pp6O(c-srcN). The latter protein appears to be exclusively ex- pressed in neurons and neuronally differenuated tumors. In cell lines derived from neuroblastomaand small-cell lung carcinoma, src expres- SLOII correlates positively with neuroendocrine differentiation. How- ever,pp60(c-srcN)isexpressedonly inhighlydifferentialedneuroblas- tomas. Although c-src expression in neuroendocrine tumors probably reflects and 1s the result of the differentiation stage at which rhe tumors have been arrested, high c-src expression and kinase activities in non- neuroectodermal tumors, e.g.. colon carcinoma, breast carcinoma, might mslead beapar~ofthemalignantphenotypeandconu~butetoche development of these tumors.

Recessive oncogenes in lung cancer Kaye FJ. Kratzke RA, Gerster JL, Lin PS. NC/-Navy Medical Oncology

Branch. Building 8. Naval Hospital. Bethesda, MD 20817. Am Rev Respir Dls 1990;142:Suppl S44-7.

The observation that carcinogen exposure is strongly associated with the probability of developing pulmonary neoplasms has suggested for many years that acquired somatic mutadons play a key role in the genesis of these environmentally induced cancers. With the advent of new techniques in cytogenetics and in the molecular analysis of DNA exuacted from lung mmors, it has now become possible Lo test this hypothesis and to search for candidate genes that may be brgeted by the chronic exposure of these enwonmental insults. Early work in this field. studying lung tumors of different histologic types, appears Lo lmphcale several disunct chromosomal loci (at chromosomes 3p, 13q. 17p.and others),suggesdngthal sequentialgcneticevencsoccurduring Ihe Initiation and progression pathways Lo pulmonary tumorigenesis. ldcnufying the candIdate geneproductsand understanding thechronol- ogy and stringency of mutational events al these loci wdl be an essenual goal lo understanding the cellular basis of lung tumors and for develop ing strategies for the next generation of diagnostic and therapeutic studies.

The ras oncogenes in human lung cancer Rodenhuis S, Slebos RJC. Department of Medical Oncology, Nether-

lands Cancer Institute, Plesmanlaan 121. 1066 CX Amsterdam. Am Rev Respir DIS 1990,142:SUF’PL S27-30

The three well-characterized genes of the ras gene family H-ras, K- ras, and N-ras. code for closely related 21 -kD prolems that have a role in Ihe transduction of growth signals. The ras proteins acquire uans- formmg potential when a point mutation in tie gene leads 10 replace- men1 of an ammo acid m one of Ihe criucal powions 12, 13, or 61. Overexpression of Ihe normal protein. usually associated with gene amplificauon, can have simdar effects. The detection of mutationally activated ras genes has been facduated by rhe development of oligonu- cleo6de hybridization assays that allow Ihe identlfxauon of each possible mutation at the critical sites. Employment of Ihe polymerase chain reachon has greatly increased the sensitivily of these assays. Studies of human lung cancer have shown lhat adenocarcinoma 1s Ihe only subtype associated with ras mutations. These occur m about 30% of primary tumors. In almost all cases, the mutation is present in codon 12 ofthe K-rasgene. Nomutations havebeen observed todate in tumors of nonsmokers, suggesting Ihat the mutation may result from exposure Lo carcmogenic Ingredients of tobacco smoke. Amphfications of ras genes were sho.vn Lo be very uncommon in clinically early stages of lung cancer. Analysis of Ihe clmical data of patients who were operated on for adenocarcinoma of the lung shows chat K-ras mutations are not associated with particular histologic characteristics of the tumors or wth specific presenting features. Pawnls with K-ras mutations, how- ever, had significantly worse survival than did those withour an activa- ox.

Gene amplification in human lung cancer: The myc family genes and other proto-oncogenes and growth factor genes Bergh JCS. Department of Oncology. University of Uppsala, Akademi-

ska s]ukhuset. S-751 85 Uppsaia. Am Rev Respir Dls 1990;142:Suppl. s20-6.

The development of human lung cancer may require muluple geneuc deletionsaffectinganumberofchromosomes,e.g., 1.3.11, 13,and 17. These genetic abcrraations may induce the activation of proto-onco- genes (c-jun, ras, c-rafl) and the loss of tumor suppressor genes (~53). Some of the activated prolo-oncogenes and tumor suppressor genes are

more selectively expressed or absent in small-cell lung cancer (L-myc, c-myb, c-w, Rb gene) or non-small-cell lung cancer (c-erbB-2, c-sis, c-fes). These genes may thus be of importance for selection of ddferen- tiation padway. The c-myc oncogene is frequendy amphfied m small- cell lung cancer cell lmes in a much higher frequency than in viva. This indicates that c-myc seems to be related to tumor progression and a relatively late event in the lung cancer development. The uncontrolled productionofmulliplegrowthfaclorshasbeen idenufiedin human lung canccrcell lines. These factors can promoteand inhiblttheproliferalion via paracrine and autocrine loops via specific receptors. The products from some of the activated proto-oncogenes (c-sis, c-erbB-2) are sequences homologous toacertamgrowth factor(PDGF)andareceptor (EGF) identdied in lung cancer. The prod&on and action of these growth factors may be of major importance for further acuvation of promoncogenes via intracellular slgnal lransductlon and specific onco- genie aclivauon leading to further tumor progression.

A novel alteration in the epidermal growth factor receptor gene is frequently detected in human non-small cell lung cancer Schneider PM, Hung M-C, Ames RS. Putnam EA, Akpaklp B, Roth JA. Department of Thoracic Surgery, University of Texas. M.D. Anderson

Cancer Center, ISIS Hoicombe Blvd., Houston. TX 77030. Lung Can- cer (The Netherlands) 1990;6:65-72.

We studied 60 patients with non-small cell lung cancer (NSCLC) for alterations in theepidermal growth factor receptor (EGFR) gene. 24/60 (40%) demonswaled cleavage of a 4.2 kb EcoRI fragment in the tumor DNA which was not observed in DNA from paired normal lung. This frdgmenl corresponds to a genomic region that encodes for part of Ihe intracellular tyrosine knasedomain of the EGFR. We demonwaled char an alteration is present which leads to an increased cleavage efficiency ofresuicuon endonuclease EcoRI for a specific EcoRI site in this4.2 kb fragment.

Mutations in the ~53 gene are frequent in primary, resected non- small cell lung cancer Chiba I, Takahashl T. Nau MM cl al. NC/-Navy Medical Oncology

Branch, Notional Cancer Institute, National naval Medrcol Center,

Bethesda, MD 20814. Oncogene 1990;5:1603-10. The ~53 gene has been implicated as a tumor suppressor gene wuh

mutadons found m common human cancers. We exammed 5 I early stage, primary, resected non-small cell lung cancer specimens usmg an RNAase prowlion assay and cDNA sequencmg. Mutations changmg Ihe ~53 coding sequence were found in 23/51 (45%) tumor specimens, but not in the corresponding normal lung, were disulbuled between codons 132 10 283. and included tumors wuh and wuhout 17p allele loss. Fifteen of Ihe 23 mutauons lay m the predicted binding regions for SV40 large T anligcn, and 14 were. located m regions highly conserved between species. G lo T uansvcrsions were a common result of ~53 mutadons in lung cancer compared to other cancers suggesung expo- sure to different mutagens. In univarlate and multivariate analysis the presence of ~53 mutations was associated wth younger age and squamous histology. However, Ihe presence of p53 mutations was not significantly associated wuh tumor stage, nodal status or sex and was found in all histologic types of lung cancer. We conclude rhal somatic mutations in Ihe p53 gene play an important role in the pathogenesls of early stage non-small cell lung cancer.