Loss of heterozygosity predicts poor survival after resection of pancreatic adenocarcinoma.
BACKGROUND
American Joint Committee on Cancer (AJCC) staging for pancreatic adenocarcinoma is a validated predictor of prognosis but insufficiently discriminates postresection survival. We hypothesized that genetic analysis of resected cancers would correlate with tumor biology and postoperative survival.


METHODS
Resected pancreatic ductal and ampullary adenocarcinomas (n = 50) were analyzed for loss of heterozygosity (LOH) at 15 markers including 5q(APC), 6q(TBSP2), 9p(p16), 10q(PTEN), 12q(MDM2), 17p(TP53), and 18q(DCC/SMAD4). KRAS exon 1 mutations were detected by sequencing. The primary endpoint of this interim data analysis was survival at 18 month median follow-up.


RESULTS
Negative margins were achieved in 43 (86%) cases. AJCC stage was: Ia/b (3), IIa (16), IIb (31). KRAS mutations were detected in 31 cases (62%) and LOH in 26 (52%) with mean fractional allelic loss score 23 +/- 16%. Median survival was significantly shorter with LOH (15.2 months versus not reached; p = 0.021) and KRAS mutations (19.6 months versus not reached; p = 0.038). Combining KRAS mutation with LOH was a powerful negative predictor in Cox regression (HR = 10.6, p = 0.006). Stage, nodal and margin status were not predictive of survival.


CONCLUSIONS
LOH and KRAS mutations indicate aggressive tumor biology and correlate strongly with survival in resected pancreatic ductal and ampullary carcinomas. Genetic analysis may improve risk stratification in future clinical trials.
Franko
Jan
J
UPMC Pancreatic Cancer Center, Division of Surgical Oncology, 497 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA.
Krasinskas
Alyssa M
AM
Nikiforova
Marina N
MN
Zarnescu
Narcis O
NO
Lee
Kenneth K W
KK
Hughes
Steven J
SJ
Bartlett
David L
DL
Zeh
Herbert J
HJ
Moser
A James
AJ
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D000368:Aged; D000369:Aged, 80 and over; D014670:Ampulla of Vater; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000601:surgery; D003138:Common Bile Duct Neoplasms / Q000235:genetics* / Q000601:surgery; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D010865:Pilot Projects; D011237:Predictive Value of Tests; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D016019:Survival Analysis; D018631:ras Proteins / Q000235:genetics
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins