A novel survival-based tissue microarray of pancreatic cancer validates MUC1 and mesothelin as biomarkers.
BACKGROUND
One-fifth of patients with seemingly 'curable' pancreatic ductal adenocarcinoma (PDA) experience an early recurrence and death, receiving no definable benefit from a major operation. Some patients with advanced stage tumors are deemed 'unresectable' by conventional staging criteria (e.g. liver metastasis), yet progress slowly. Effective biomarkers that stratify PDA based on biologic behavior are needed. To help researchers sort through the maze of biomarker data, a compendium of ∼2500 published candidate biomarkers in PDA was compiled (PLoS Med, 2009. 6(4) p. e1000046).


RESULTS
Building on this compendium, we constructed a survival tissue microarray (termed s-TMA) comprised of short-term (cancer-specific death <12 months, n = 58) and long-term survivors (>30 months, n = 79) who underwent resection for PDA (total, n = 137). The s-TMA functions as a biological filter to identify bona fide prognostic markers associated with survival group extremes (at least 18 months separate survival groups). Based on a stringent selection process, 13 putative PDA biomarkers were identified from the public biomarker repository. Candidates were tested against the s-TMA by immunohistochemistry to identify the best markers of tumor biology. In a multivariate model, MUC1 (odds ratio, OR = 28.95, 3+ vs. negative expression, p = 0.004) and MSLN (OR = 12.47, 3+ vs. negative expression, p = 0.01) were highly predictive of early cancer-specific death. By comparison, pathologic factors (size, lymph node metastases, resection margin status, and grade) had ORs below three, and none reached statistical significance. ROC curves were used to compare the four pathologic prognostic features (ROC area = 0.70) to three univariate molecular predictors (MUC1, MSLN, MUC2) of survival group (ROC area = 0.80, p = 0.07).


CONCLUSIONS
MUC1 and MSLN were superior to pathologic features and other putative biomarkers as predicting survival group. Molecular assays comparing cancers from short and long survivors are an effective strategy to screen biomarkers and prioritize candidate cancer genes for diagnostic and therapeutic studies.
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America [corrected].
Jordan M
JM
Winter
Laura H
LH
Tang
David S
DS
Klimstra
Murray F
MF
Brennan
Jonathan R
JR
Brody
Flavio G
FG
Rocha
Xiaoyu
X
Jia
Li-Xuan
LX
Qin
Michael I
MI
D'Angelica
Ronald P
RP
DeMatteo
Yuman
Y
Fong
William R
WR
Jarnagin
Eileen M
EM
O'Reilly
Peter J
PJ
Allen
D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D000090204:Mesothelin; D008875:Middle Aged; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D055262:Mucin-2 / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D012372:ROC Curve; D017741:Survivors; D046888:Tissue Array Analysis
D014408:Biomarkers, Tumor; D058851:GPI-Linked Proteins; C000715527:MSLN protein, human; D018396:Mucin-1; D055262:Mucin-2; D000090204:Mesothelin