Cell-cycle and apoptosis regulators (p16INK4A, p21CIP1, beta-catenin, survivin, and hTERT) and morphometry-defined MPECs predict metachronous cancer development in colorectal adenoma patients.
OBJECTIVE
Although adenomas may be precursors to colorectal cancers (CRC), knowledge concerning the development of metachronous CRC is scarce. We assessed whether differential expression of cell-cycle and apoptosis-regulating proteins and a monotonous population of elongated cells (MPECs) in colorectal adenomas could predict metachronous CRC.


METHODS
Application of immunohistochemistry on tissue microarrays in consecutive, population-based colorectal adenomas. Influence of classic features (e.g., intraepithelial neoplasia grade, histological type, size) was examined.


RESULTS
Of 171 patients with colorectal adenoma 86% (n=147) were eligible for study; 10 (7%) developed metachronous CRC. Median time to cancer was 69 months (range, 25-256). Median follow-up was equal for the non-cancer and cancer groups. Elevated expression of cell-cycle regulators p16(INK4A), p21(CIP1), and cytoplasmic/nuclear beta-catenin correlated with increased CRC risk (all P<0.0001), as did elevated expression of the anti-apoptosis protein survivin (P<0.0001) and human telomerase reverse transcriptase (hTERT; P<0.001). Survivin, hTERT, and nuclear beta-catenin were the most predictive molecular markers (hazard ratios [HRs]: 6.3, 9.4, and 5.8, respectively). In a combined multivariate model, MPECs had the best overall prognostic ability (HR 28.2, 95% CI: 3.6-223.0), together with survivin, and hTERT. Within adenomas containing MPECs, several molecular markers further defined high-risk patients.


CONCLUSIONS
Among several markers predictive for metachronous CRC development in colorectal adenomas, MPECs, survivin and hTERT may, when validated, provide information superior to conventional histology, with relevance for the clinical management of patients with colorectal adenoma.
Soreide
Kjetil
K
Department of Pathology, Stavanger University Hospital, Stavanger, Norway.
Buter
Tirza C E
TC
Janssen
Emiel A
EA
Gudlaugsson
Einar
E
Skaland
Ivar
I
Körner
Hartwig
H
Baak
Jan P A
JP
D000236:Adenoma / Q000201:enzymology / Q000473:pathology*; D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000473:pathology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003710:Demography; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins; D053208:Kaplan-Meier Estimate; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000378:metabolism; D016609:Neoplasms, Second Primary / Q000473:pathology*; D016016:Proportional Hazards Models; D000077022:Survivin; D019098:Telomerase / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D051176:beta Catenin; C509186:TERT protein, human; D019098:Telomerase