Dc. Betticher et al., G(1) CONTROL GENE STATUS IS FREQUENTLY ALTERED IN RESECTABLE NONSMALLCELL LUNG-CANCER, International journal of cancer, 74(5), 1997, pp. 556-562
Progression through the mammalian cell cycle is controlled by a series
of cyclins, cyclin-dependent kinases (cdks) and cdk inhibitors. Cycli
n DI, cdk4 and the tumour suppressors p16 and retinoblastoma protein (
pRb) are thought to comprise a linked system governing cell passage th
rough the G(1) phase of the cell cycle. Extending an earlier study on
cyclin DI expression, a series of resectable non-small cell lung carci
nomas (NSCLCs) was examined for defects in other elements of this cont
rol system. Forty-six of fifty-one NSCLC specimens exhibited at least
one alteration of these cell-cycle regulators, Immunohistochemical ana
lysis revealed that 33% and 47% of the tumours failed to express pRb a
nd p16, respectively. Failure to detect pRb did not correlate with los
s of heterozygosity at the RBI locus, Eleven of 12 tumours showing pos
itive (normal) pRb staining over-expressed nuclear localised cyclin DI
, including 8 with amplification of the cyclin DI gene (CCND1). Howeve
r, in a number of lesions (n = 5) where cyclin DI was over-expressed b
ut localised to the cytoplasm, pRb expression was undetectable, Sequen
cing of exons I and 2 of the p16 gene (CDKN2) revealed 3/51 tumours wi
th somatic mutations (in addition to I case with a germ-line alteratio
n). All of these lesions were positive for p16 protein. No clear homoz
ygous deletions of CDKN2 were observed by multiplex PCR. As assessed b
y immunostaining using a p16 monoclonal antibody, there was an inverse
correlation of pRb and p16 down-regulation. Whilst patients with tumo
urs overexpressing cyclin DI had a significantly lower incidence of lo
cal relapse, the group whose tumours failed to express pRb had a signi
ficantly greater risk of local relapse and tended to have shortened ev
ent-free survival. Our data show that alteration of at least one cell
cycle-regulator gene occurs in the majority of resectable NSCLCs. (C)
1997 Wiley-Liss, Inc.