Survival is associated with genetic variation in inflammatory pathway genes among patients with resected and unresected pancreatic cancer

Kaye M. Reid-Lombardo, Brooke L. Fridley, William R. Bamlet, Julie M Cunningham, Michael G. Sarr, Gloria M Petersen

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Objective: To test whether or not the association between inflammation and pancreatic ductal adenocarcinoma (PC) is facilitated by host susceptibility, specifically by genetic polymorphisms in inflammation-related genes. Summary Background Data: Inflammation has been linked to PC. Reports have cited an increased expression of proinflammatory mediators, such as NF-κB and COX, in PC but not in normal adjacent tissue, suggesting a possible role in carcinogenesis. We sought to further understand the role that genetic variants in the NF-êB inflammatory pathway play in the development and progression of PC. Methods: We genotyped 1536 tag single nucleotide polymorphisms (SNPs) in 102 candidate genes of multiple inflammatory pathways in 1308 white patients with PC who were divided into 3 groups on the basis of the extent of disease: resected for cure (n = 400), locally advanced/unresected (n = 443), and metastatic (n = 465). Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazards regression models. Statistical significance was set at less than 0.001 to control for multiple testing. Results: Median age was 67 (28.0-91.0) years, and 57% were men. Median survival for each of the 3 groups (resected, locally advanced, and metastatic) was 23.7, 9.4, and 6.6 months, respectively (P<0.0001). In the resected group, carriers of a minor allele for either rs3824872 (MAPK8IP1) or rs8064821 (SOCS3)were associated with a 10- and 6-month survival advantage compared with noncarriers in patients with resected disease, with an additional 2-year survival if both minor alleles were present. With locally advanced disease, SNP rs1124736 (IGF1R) was associated with improved survival if they had a copy of the Gallele, hazard ratio of 0.57 (95% confidence interval: 0.42-0.77); P=0.0002. In addition, 4 SNPs in patients with metastatic disease were found to be associated with worse survival and 2 associated with improved overall survival, but the differences in survival were deemed not clinically significant. Conclusions: SNPs in the inflammatory pathway genes MAPK8IP1 and SOCS3 were associated with increased overall survival in patients undergoing potentially curative resection and may be used in the future as markers to predict survival. Future research is needed to determine the functional relevance of these loci.

Original languageEnglish (US)
Pages (from-to)1096-1102
Number of pages7
JournalAnnals of Surgery
Volume257
Issue number6
DOIs
StatePublished - Jun 2013

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Pancreatic Neoplasms
Survival
Genes
Single Nucleotide Polymorphism
Inflammation
Alleles
Genetic Polymorphisms
Survival Analysis
Proportional Hazards Models
Carcinogenesis
Adenocarcinoma
Confidence Intervals

Keywords

  • Inflammation
  • MAPKI8P1
  • NFKB
  • Pancreatic cancer
  • Single nucleotide polymorphisms
  • SOCS3
  • Survival

ASJC Scopus subject areas

  • Surgery

Cite this

Survival is associated with genetic variation in inflammatory pathway genes among patients with resected and unresected pancreatic cancer. / Reid-Lombardo, Kaye M.; Fridley, Brooke L.; Bamlet, William R.; Cunningham, Julie M; Sarr, Michael G.; Petersen, Gloria M.

In: Annals of Surgery, Vol. 257, No. 6, 06.2013, p. 1096-1102.

Research output: Contribution to journalArticle

Reid-Lombardo, Kaye M. ; Fridley, Brooke L. ; Bamlet, William R. ; Cunningham, Julie M ; Sarr, Michael G. ; Petersen, Gloria M. / Survival is associated with genetic variation in inflammatory pathway genes among patients with resected and unresected pancreatic cancer. In: Annals of Surgery. 2013 ; Vol. 257, No. 6. pp. 1096-1102.
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abstract = "Objective: To test whether or not the association between inflammation and pancreatic ductal adenocarcinoma (PC) is facilitated by host susceptibility, specifically by genetic polymorphisms in inflammation-related genes. Summary Background Data: Inflammation has been linked to PC. Reports have cited an increased expression of proinflammatory mediators, such as NF-κB and COX, in PC but not in normal adjacent tissue, suggesting a possible role in carcinogenesis. We sought to further understand the role that genetic variants in the NF-{\^e}B inflammatory pathway play in the development and progression of PC. Methods: We genotyped 1536 tag single nucleotide polymorphisms (SNPs) in 102 candidate genes of multiple inflammatory pathways in 1308 white patients with PC who were divided into 3 groups on the basis of the extent of disease: resected for cure (n = 400), locally advanced/unresected (n = 443), and metastatic (n = 465). Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazards regression models. Statistical significance was set at less than 0.001 to control for multiple testing. Results: Median age was 67 (28.0-91.0) years, and 57{\%} were men. Median survival for each of the 3 groups (resected, locally advanced, and metastatic) was 23.7, 9.4, and 6.6 months, respectively (P<0.0001). In the resected group, carriers of a minor allele for either rs3824872 (MAPK8IP1) or rs8064821 (SOCS3)were associated with a 10- and 6-month survival advantage compared with noncarriers in patients with resected disease, with an additional 2-year survival if both minor alleles were present. With locally advanced disease, SNP rs1124736 (IGF1R) was associated with improved survival if they had a copy of the Gallele, hazard ratio of 0.57 (95{\%} confidence interval: 0.42-0.77); P=0.0002. In addition, 4 SNPs in patients with metastatic disease were found to be associated with worse survival and 2 associated with improved overall survival, but the differences in survival were deemed not clinically significant. Conclusions: SNPs in the inflammatory pathway genes MAPK8IP1 and SOCS3 were associated with increased overall survival in patients undergoing potentially curative resection and may be used in the future as markers to predict survival. Future research is needed to determine the functional relevance of these loci.",
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T1 - Survival is associated with genetic variation in inflammatory pathway genes among patients with resected and unresected pancreatic cancer

AU - Reid-Lombardo, Kaye M.

AU - Fridley, Brooke L.

AU - Bamlet, William R.

AU - Cunningham, Julie M

AU - Sarr, Michael G.

AU - Petersen, Gloria M

PY - 2013/6

Y1 - 2013/6

N2 - Objective: To test whether or not the association between inflammation and pancreatic ductal adenocarcinoma (PC) is facilitated by host susceptibility, specifically by genetic polymorphisms in inflammation-related genes. Summary Background Data: Inflammation has been linked to PC. Reports have cited an increased expression of proinflammatory mediators, such as NF-κB and COX, in PC but not in normal adjacent tissue, suggesting a possible role in carcinogenesis. We sought to further understand the role that genetic variants in the NF-êB inflammatory pathway play in the development and progression of PC. Methods: We genotyped 1536 tag single nucleotide polymorphisms (SNPs) in 102 candidate genes of multiple inflammatory pathways in 1308 white patients with PC who were divided into 3 groups on the basis of the extent of disease: resected for cure (n = 400), locally advanced/unresected (n = 443), and metastatic (n = 465). Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazards regression models. Statistical significance was set at less than 0.001 to control for multiple testing. Results: Median age was 67 (28.0-91.0) years, and 57% were men. Median survival for each of the 3 groups (resected, locally advanced, and metastatic) was 23.7, 9.4, and 6.6 months, respectively (P<0.0001). In the resected group, carriers of a minor allele for either rs3824872 (MAPK8IP1) or rs8064821 (SOCS3)were associated with a 10- and 6-month survival advantage compared with noncarriers in patients with resected disease, with an additional 2-year survival if both minor alleles were present. With locally advanced disease, SNP rs1124736 (IGF1R) was associated with improved survival if they had a copy of the Gallele, hazard ratio of 0.57 (95% confidence interval: 0.42-0.77); P=0.0002. In addition, 4 SNPs in patients with metastatic disease were found to be associated with worse survival and 2 associated with improved overall survival, but the differences in survival were deemed not clinically significant. Conclusions: SNPs in the inflammatory pathway genes MAPK8IP1 and SOCS3 were associated with increased overall survival in patients undergoing potentially curative resection and may be used in the future as markers to predict survival. Future research is needed to determine the functional relevance of these loci.

AB - Objective: To test whether or not the association between inflammation and pancreatic ductal adenocarcinoma (PC) is facilitated by host susceptibility, specifically by genetic polymorphisms in inflammation-related genes. Summary Background Data: Inflammation has been linked to PC. Reports have cited an increased expression of proinflammatory mediators, such as NF-κB and COX, in PC but not in normal adjacent tissue, suggesting a possible role in carcinogenesis. We sought to further understand the role that genetic variants in the NF-êB inflammatory pathway play in the development and progression of PC. Methods: We genotyped 1536 tag single nucleotide polymorphisms (SNPs) in 102 candidate genes of multiple inflammatory pathways in 1308 white patients with PC who were divided into 3 groups on the basis of the extent of disease: resected for cure (n = 400), locally advanced/unresected (n = 443), and metastatic (n = 465). Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazards regression models. Statistical significance was set at less than 0.001 to control for multiple testing. Results: Median age was 67 (28.0-91.0) years, and 57% were men. Median survival for each of the 3 groups (resected, locally advanced, and metastatic) was 23.7, 9.4, and 6.6 months, respectively (P<0.0001). In the resected group, carriers of a minor allele for either rs3824872 (MAPK8IP1) or rs8064821 (SOCS3)were associated with a 10- and 6-month survival advantage compared with noncarriers in patients with resected disease, with an additional 2-year survival if both minor alleles were present. With locally advanced disease, SNP rs1124736 (IGF1R) was associated with improved survival if they had a copy of the Gallele, hazard ratio of 0.57 (95% confidence interval: 0.42-0.77); P=0.0002. In addition, 4 SNPs in patients with metastatic disease were found to be associated with worse survival and 2 associated with improved overall survival, but the differences in survival were deemed not clinically significant. Conclusions: SNPs in the inflammatory pathway genes MAPK8IP1 and SOCS3 were associated with increased overall survival in patients undergoing potentially curative resection and may be used in the future as markers to predict survival. Future research is needed to determine the functional relevance of these loci.

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KW - MAPKI8P1

KW - NFKB

KW - Pancreatic cancer

KW - Single nucleotide polymorphisms

KW - SOCS3

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