Prognostic implications of molecular and immunohistochemical profiles of the Rb and p53 cell cycle regulatory pathways in primary non-small cell lung carcinoma.
OBJECTIVE
Many studies have highlighted the aberrant expression and prognostic significance of individual proteins in either the Rb (particularly cyclin D1, p16INK4A, and pRb) or the p53 (p53 and p21Waf1) pathways in non-small cell lung cancer. We hypothesize that cumulative abnormalities within each and between these pathways would have significant prognostic potential regarding survival.


METHODS
Our study population consisted of 106 consecutive surgically resected cases of predominantly early-stage non-small cell lung cancer from the National Cancer Institute-Mayo Clinic series, and assessment of proteins involved both immunohistochemical (cyclin D1, p21Waf1, pRb, p16INK4A, and p53) and mutational analysis (p53) in relationship to staging and survival.


RESULTS
Cyclin D1 overexpression was noted in 48% of the tumors, p16INK4A negative in 53%, pRb negative in 17%, p53 immunopositive in 50%, p53 mutation frequency in 48%, and p21(Waf1) overexpression in 47%, none with prognostic significance. Cyclin D1 overexpression in pRb-negative tumors revealed a significantly worse prognosis with a mean survival of 2.3 years (P = 0.004). A simultaneous p53 mutation dramatically reduced the mean survival time to 0.9 years (P = 0.007). Cyclin D1 overexpression with either a p53 mutation or a p53 overexpression was also associated with a significantly poorer prognosis (P = 0.0033 and 0.0063, respectively).


CONCLUSIONS
Some cumulative abnormalities in the Rb and p53 pathways (e.g., cyclin D1 overexpression and p53 mutations) significantly cooperate to predict a poor prognosis; however, the complexity of the cell cycle protein interaction in any given tumor warrants caution in interpreting survival results when specific protein abnormalities are taken in isolation.
Burke
Louise
L
Department of Pathology, Cork University Hospital, Cork, Ireland.
Flieder
Douglas B
DB
Guinee
Donald G
DG
Brambilla
Elizabeth
E
Freedman
Andrew N
AN
Bennett
William P
WP
Jones
Raymond T
RT
Borkowski
Andrew
A
Caporaso
Neil A
NA
Fleming
Marian
M
Trastek
Victor
V
Pairolero
Peter
P
Tazelaar
Henry
H
Midthun
David
D
Jett
James R
JR
Liotta
Lance A
LA
Travis
William D
WD
Harris
Curtis C
CC
D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D002453:Cell Cycle; D019938:Cyclin D1 / Q000096:biosynthesis; D004252:DNA Mutational Analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D011485:Protein Binding; D016160:Retinoblastoma Protein / Q000096:biosynthesis* / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1