DPC4/Smad4 expression and outcome in pancreatic ductal adenocarcinoma.
OBJECTIVE
Prognostic indicators in pancreatic cancer (PC) are poorly defined and difficult to quantify preoperatively, hence they may lead to inappropriate patient selection for treatment. We examined the protein expression of key cell-cycle regulatory and cell-signaling molecules that occur at high frequency in PC and assessed their relationship to clinicopathologic parameters, response to operative resection, and outcome.


METHODS
We identified 348 patients with pancreatic ductal adenocarcinoma and assessed the influence of reported clinicopathologic prognostic factors and the expression of the cell-cycle regulatory genes p21(WAF1/CIP1) (CDKN1A), cyclin D1 (CCND1), p53, and p16(INK4A) (CDKN2) and the cell-signaling molecule DPC4/Smad4 (MADH4) using immunohistochemistry in a subgroup of 129 patients.


RESULTS
Independent prognostic factors in resected patients were tumor size greater than 45 mm (P =.0015), involvement of surgical margins (P <.0001), and perineural invasion (P =.014). Loss of DPC4/Smad4 expression cosegregated with resectability (P <.0001) and was associated with improved survival after resection (P <.0001), whereas resection did not improve survival in patients whose tumor expressed DPC4/Smad4 (P =.5). Aberrant expression of p21(WAF1/CIP1), cyclin D1, p53, or p16(INK4A) was not associated with a difference in survival.


CONCLUSIONS
Tumor size (> 45 mm), resection margin involvement, and perineural invasion were independent prognostic factors. Preoperative assessment of DPC4/Smad4 expression has potential as a prognostic indicator in patients with PC since resection did not benefit those patients whose cancers expressed DPC4/Smad4 and accurate assessment of DPC4/Smad4 expression, unlike tumor size, margin status, and perineural invasion, does not require resection.
Biankin
Andrew V
AV
Cancer Research Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Morey
Adrienne L
AL
Lee
C-Soon
CS
Kench
James G
JG
Biankin
Sandra A
SA
Hook
Henry C
HC
Head
Darren R
DR
Hugh
Thomas B
TB
Sutherland
Robert L
RL
Henshall
Susan M
SM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D021441:Carcinoma, Pancreatic Ductal / Q000737:chemistry* / Q000473:pathology* / Q000628:therapy; D019938:Cyclin D1 / Q000032:analysis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis; D004268:DNA-Binding Proteins / Q000032:analysis*; D015536:Down-Regulation; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000737:chemistry* / Q000473:pathology* / Q000628:therapy; D051901:Smad4 Protein; D016019:Survival Analysis; D015534:Trans-Activators / Q000032:analysis*; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D015854:Up-Regulation
D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1