Loss of heterozygosity predicts poor survival after resection of pancreatic adenocarcinoma

Jan Franko, Alyssa M. Krasinskas, Marina N. Nikiforova, Narcis O. Zarnescu, Kenneth K.W. Lee, Steven J. Hughes, David L. Bartlett, Herbert J. Zeh, A. James Moser

Research output: Contribution to journalArticle

Abstract

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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)1664-1672
Number of pages9
JournalJournal of Gastrointestinal Surgery
Volume12
Issue number10
DOIs
StatePublished - Oct 1 2008
Externally publishedYes

Fingerprint

Loss of Heterozygosity
Adenocarcinoma
Mutation
Neoplasms
Pancreatic Ductal Carcinoma
Neoplasm Staging
Exons
Clinical Trials

Keywords

  • KRAS
  • Loss of heterozygosity
  • Pancreatic adenocarcinoma
  • Surgical resection

ASJC Scopus subject areas

  • Surgery
  • Gastroenterology

Cite this

Franko, J., Krasinskas, A. M., Nikiforova, M. N., Zarnescu, N. O., Lee, K. K. W., Hughes, S. J., ... Moser, A. J. (2008). Loss of heterozygosity predicts poor survival after resection of pancreatic adenocarcinoma. Journal of Gastrointestinal Surgery, 12(10), 1664-1672. https://doi.org/10.1007/s11605-008-0577-9

Loss of heterozygosity predicts poor survival after resection of pancreatic adenocarcinoma. / Franko, Jan; Krasinskas, Alyssa M.; Nikiforova, Marina N.; Zarnescu, Narcis O.; Lee, Kenneth K.W.; Hughes, Steven J.; Bartlett, David L.; Zeh, Herbert J.; Moser, A. James.

In: Journal of Gastrointestinal Surgery, Vol. 12, No. 10, 01.10.2008, p. 1664-1672.

Research output: Contribution to journalArticle

Franko, J, Krasinskas, AM, Nikiforova, MN, Zarnescu, NO, Lee, KKW, Hughes, SJ, Bartlett, DL, Zeh, HJ & Moser, AJ 2008, 'Loss of heterozygosity predicts poor survival after resection of pancreatic adenocarcinoma', Journal of Gastrointestinal Surgery, vol. 12, no. 10, pp. 1664-1672. https://doi.org/10.1007/s11605-008-0577-9
Franko J, Krasinskas AM, Nikiforova MN, Zarnescu NO, Lee KKW, Hughes SJ et al. Loss of heterozygosity predicts poor survival after resection of pancreatic adenocarcinoma. Journal of Gastrointestinal Surgery. 2008 Oct 1;12(10):1664-1672. https://doi.org/10.1007/s11605-008-0577-9
Franko, Jan ; Krasinskas, Alyssa M. ; Nikiforova, Marina N. ; Zarnescu, Narcis O. ; Lee, Kenneth K.W. ; Hughes, Steven J. ; Bartlett, David L. ; Zeh, Herbert J. ; Moser, A. James. / Loss of heterozygosity predicts poor survival after resection of pancreatic adenocarcinoma. In: Journal of Gastrointestinal Surgery. 2008 ; Vol. 12, No. 10. pp. 1664-1672.
@article{6ce27f47cfff4e36ba33a0e426b46086,
title = "Loss of heterozygosity predicts poor survival after resection of pancreatic adenocarcinoma",
abstract = "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. Conclusion: 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.",
keywords = "KRAS, Loss of heterozygosity, Pancreatic adenocarcinoma, Surgical resection",
author = "Jan Franko and Krasinskas, {Alyssa M.} and Nikiforova, {Marina N.} and Zarnescu, {Narcis O.} and Lee, {Kenneth K.W.} and Hughes, {Steven J.} and Bartlett, {David L.} and Zeh, {Herbert J.} and Moser, {A. James}",
year = "2008",
month = "10",
day = "1",
doi = "10.1007/s11605-008-0577-9",
language = "English (US)",
volume = "12",
pages = "1664--1672",
journal = "Journal of Gastrointestinal Surgery",
issn = "1091-255X",
publisher = "Springer New York",
number = "10",

}

TY - JOUR

T1 - Loss of heterozygosity predicts poor survival after resection of pancreatic adenocarcinoma

AU - Franko, Jan

AU - Krasinskas, Alyssa M.

AU - Nikiforova, Marina N.

AU - Zarnescu, Narcis O.

AU - Lee, Kenneth K.W.

AU - Hughes, Steven J.

AU - Bartlett, David L.

AU - Zeh, Herbert J.

AU - Moser, A. James

PY - 2008/10/1

Y1 - 2008/10/1

N2 - 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. Conclusion: 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.

AB - 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. Conclusion: 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.

KW - KRAS

KW - Loss of heterozygosity

KW - Pancreatic adenocarcinoma

KW - Surgical resection

UR - http://www.scopus.com/inward/record.url?scp=52549095605&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=52549095605&partnerID=8YFLogxK

U2 - 10.1007/s11605-008-0577-9

DO - 10.1007/s11605-008-0577-9

M3 - Article

C2 - 18677542

VL - 12

SP - 1664

EP - 1672

JO - Journal of Gastrointestinal Surgery

JF - Journal of Gastrointestinal Surgery

SN - 1091-255X

IS - 10

ER -