Abstracts/Lung Cancer 10 (1993) 266-286 271

forretmoicaad. is localized in a chromosomal region frequently deleted

m lung cancer cells. Tbe gene is expressed in normal lung tissue and in

the majority of tbe cell lines derived from lung tllmors but not in most

of the hnes derived from lung hlmors with epidermoid characteristics.

Tostudy thepossibleroleofRARl3 ingmwthcontrol ofepidermoid lung

urnor-denved cells. transfectants expressing RARR were generated

from nonexpressing epidermoid tumor-derived cell lines. Four clones were derived from lme CALU- I, three of whach showed a 20.60% mcrease in doubling tune in the presence of retinoic acid. Parental and control-transf~tulcellswereunaffectzdorslightlystimulated. All four clones expressing RARR were less tumorigenic in nude race than were theuntransfectcdorcontrol-transfectedcells, withabouta5046 mcldence

of take vs. 95 %. When tumors did develop from RARI- positive cells, they showed a reduced rate of growth, an increased latency, and, in SIX

of seven tumors tested, a much reduced level of RARR expression.

Transfectants derived from a second tumor line, Hl57, also showed a

markedly reduced incidence of take m nude mice. Together with the known effects of retinoic aad on differentiation and carcinogenesn, our

resultbsupport thehypothesisthatRAR timctionsasatumorsuppressor gene in epidermoid lung tumorigenesls.

ras Oncogene activation and the expression of ras-related genes in

human lung cancer Rodenhuis S. Groat PC, Salomons G, Slebos PJC. Deparrmenr 0~

Medical Oncology, Netherlands Cancer InMute, Plesmanlaon 121,

IO66 CX Amsterdam. Lung Cancer (Ireland) 1993:9:59-67. Mutational activation of a ras oncogene is detected in about 30% of

human adenwarcinomasof the lung. Most mutations involvecodon I2 of the K-ras gene. K-ras mutations are rare m non-adennocarcmomas and

very rare or non-existent in small-cell lung cancer. K-ras mutations occur wth significantly higher frequency in smokers than m non-

smokers and Indicate a poor prognosis, even in patients with (cluucally)

early disease after apparently radical operatron. It is still uncsrtam whether the poor prognosis is in part caused by increased rwstance to radlatlon and/or chemotherapy of ras mutation-positive tllmors. A possible role of ras-related genes that code for small monomeric GTP

binding proteins in human lung cancer 1s under investigatnon. The rasac

and racA genes were expressed in most, and Krev in all I6 lung cancer

samples and 5 lung cancer cell lmes mvestigated. No pomt mutations were revealed by Single-Strand Conformation Polymorphism (SSCP)

analysts m anyofthesegenes, butthreesampleshadunexpectedsmallrr- sized bandson Krwanalysis, bothunderdenaturingandnon-denaturing

condittons. The stgniticanca of this finding IS being investigated.

Relationship of H-rwl, L-myc, and p53 polymorphisms with lung cancer risk and prognosis Weston A, Caporaso NE, Perrin LS, Sugimura H, Tamai S, Krontins TG et al. National Cancer Inrrirure, Bethesda, MD 20892. Environ

Health Perspect 1992;98:61-7 Proto-oncogenes (Has-l and L-myc) and tumor-suppressor gene

(~53) loci have bean impbcated in lung carcinogenesis. DNA restriction

fragment length polymorphisms at these gene loci are bang. evaluated

in a case-control study as markers predictive of risk for cancer or of prognosis when cancer is present. Tbe casesand controls hada cigarette-

smoking history of 40 or more pack years or other abnormalities in

pulmonary timctlon tests. their ages were closely matched (64 years for cases and 61 years for controls) and the ratio of Caucasians to African Americans was close to unity (cases, 0.95:1.00, controls, 1.00:0.88).

TheH-r&s-l genecontainsMinSertjondele(ionpolymorphism. lnhentance of rare H-ras-1 alleles, defined by Mspl dig&Ion, confers a relative risk forhmgcancerof2.0(95% confidenceinterval,0.5-7.3) forCaucasians and 3.2 (0.9-l 1.6) for African Americans (74 cases, 67 controls). The

L-myc gene sequence has a restriction site (EcoRl) polymorphism behveen the second and third axons. Inheritance of restriction site-

present alleles was reported to confer poor prognosis (presence of lymph node m&stases) in Japanese lung cancer patients. This hypothesis was tested in bath case-control study subjects (56 cases, 55 controls) and

additaonal surgnxl casea (40) but no evidence was found to support the hypothesis in the U.S. population. The ~53 gene is a tumor-suppressor gene that can encode either a proline or an arginine in the 72nd resadue. No associations was found behveen the minor allele (praline) and

dmgnosw of lung cancer (76 cases, 68 controls). Importantly, the

observed allelic distributions at each of these genetic loa (H-ras-I. L-

myc, and ~53) were found to be significantly different between African

Americans and Caucasians in P U.S. population.

The debrisoquine metabolic phenotype and DNA-based assays: Implications of misclasification for the association of lung cancer and the debriwquine metnbolic phenotype Capaaso NE, Shields PG, Landi MT, Shsw GL, Tucker MA, Hoover

Ret al. EnvironmenfalEpidemiology8ronch, National Cancer Inrriruru, EPN439, 6130 Erecuriw Boulevard. Rodrw’lle, MD 20892. Enwon Health Perspect 1992;98:101-5.

Debrisequine IS an antihypertensive drug that is metabolized by

cytcx4uomeP450(2D6). Deficimtmetabolismisinhentedasanautosomal recesswe condition. We previously reported m a case-control study that

extensive metabolizxs of debrisoquine were at greater risk of lung

cancer compared to Poor and intermediate metabolizers. Clonmg of the

gene thatencodesP450(2D6)(CYP2D6)led to theidentificationofbeth

weld-type and mutant fomx of the gene. Subsequently, a DNA-

restriction fragment length polymorphism (RFLP) was identified, and a Southern hybridization-based test was developed in an attempt to

define the genotype. when tbe DNA-RFLP test was applied to stored DNA from our study subjects there was neither a signiticant association

with the metabolic phenotype nor an association wth lung cancer. Further work has demonstrated that tbe mild-type gene, which was characterized by a 29-kb allele, can also contain mutations that result m

nonfunctional or absent proteins. When these mutations are present,

Individuals exhibit the poor or intermediate metabolizer phenotype m

spite of the presence of the 29-kb putative wild-type allele. Sequence detemunation of the mutants led to the development of techmques to

exploit the polymerase chain reaction, which, together with Southern analysis, have been reported to detect as many as 95% of poor

metabolizws. Th~stechniqueisbeing used toexamme theassoaatlonof

the extensive metabobzergenotype with lung cancer m the subjects from the case-control study. Preliminary results indicate a weak associatmrl

between the homozygous wild-type genotype and lung cancer; m contrast, the extenswe metabolimr phenotype is strongly assoaated with lung cancer in this subset. Employing this polymerax cham

reaction method only, rmsclassiticataon m the genotype asstgnment continues tooccur, and work is in progress to identify further mutalons

that may account for subjects who are phenotyplcally poor metabohzers

but possess ‘wild-type’ alleles. The phenotyping approach is currently

more sensitive, while the genotyping method may be more specific with

regard to detection of the deficient metabolizer state in the context of

population studies. increasing useof genotyping is anticnpated in future studies.

of two screening assays bed on the polymemse chain &ion Husgahwl-Pwsiamen K. RidanpaaM, Hackman P, Anttila S. Karjalainen

A, Onfelt A et al. lnrrirue of Occupational Health, Topeliukwnkatu 41 aA. SFm2-50 Helsinki. Environ Health Perspect 1992;98: 183-5.

We s&died the prevalence of point mutations m ras oncogenes (K- ras and N-ras) in DNA from white blood cells and tllmor tissue from 36

untreated patients wtb non-small-xll lung cancer all of whom were

smokers or ex smokers. We observed somatic K-ras mutations in one- tbirdoftbeltmg. carcinomasstudiedbutnoN_msmu~tion. K-rascodon I2 mutations were found more frequently in adenwarcioomns than in theotberbistoPatbologicalsubtypesshuiied. MorethanbO% (10/16) of

the lung adenocarcinomas had P codon I2 mutation. most of which men G to T transversions. No mutation was found in white blood cell DNA.

Two polymerasa chain reaction screening methods, oligonucltotide hybridization and deanturing gradient gel electrophoresis (DGGE).

were used to detect tbe mutations. The oligonucleotide method appears to be more sensitive than DGGE, but DGGE proved to be a r&able

nonradioactive method for rapid screening of point mutations in genes relevant to carcinogeoesis.

AlI& dirasity ol the H-m-1 rPriPble number of tandan ~epepts in Norwegian lung cancer patients

Rykrg D, T&e T. Skaug V. Stangelnod L, Ovrebo S, Naalsund A et