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Identification and Validation of a Biomarker Signature in Patients With Resectable Pancreatic Cancer via Genome-Wide Screening for Functional Genetic Variants


Dimitrakopoulos, Christos; Vrugt, Bart; Flury, Renata; Schraml, Peter; Knippschild, Uwe; Wild, Peter; Hoerstrup, Simon; Henne-Bruns, Doris; Wuerl, Peter; Graf, Rolf; Breitenstein, Stefan; Bond, Gareth; Beerenwinkel, Niko; Grochola, Lukasz Filip (2019). Identification and Validation of a Biomarker Signature in Patients With Resectable Pancreatic Cancer via Genome-Wide Screening for Functional Genetic Variants. JAMA Surgery, 154(6):e190484.

Abstract

Importance

Surgery currently offers the only chance for a cure in pancreatic ductal adenocarcinoma (PDAC), but it carries a significant morbidity and mortality risk and results in varying oncologic outcomes. At present, to our knowledge, there are no tests available before surgical resection to identify tumors with an aggressive biological phenotype that could guide personalized treatment strategies.

Objective

Identification of noninvasive genetic biomarkers that could direct therapy in patients whose cases are amenable to pancreatic cancer resection.

Design, Setting, and Participants

This multicenter study combined a prospective European cohort of patients with PDAC who underwent pancreatic resection (from University Hospital of Zurich, Zurich, Switzerland; Cantonal Hospital of Winterthur, Winterthur, Switzerland; and University Clinic of Ulm, Ulm, Germany) with data from the Cancer Genome Atlas database in the United States, which includes prospectively registered patients with PDAC. A genome-wide screening for functional single-nucleotide polymorphisms (SNPs) that affect PDAC survival was conducted using the European cohort for identification and the Cancer Genome Atlas cohort for validation. We used Cox proportional hazards models to screen for high-frequency polymorphic variants that are associated with allelic differences in tumor-associated survival and either result in an altered protein structure and function or reside in known regulatory noncoding genomic regions. The false-discovery rate method was applied for multiple hypothesis-testing corrections. Data analysis occurred from November 2017 to May 2018.

Exposures

Pancreatic resection.

Main Outcomes and Measures

Tumor-associated survival.

Results

A total of 195 patients in the European cohort were included, as well as 136 patients in the Cancer Genome Atlas cohort (overall median [range] age, 66 [19-87] years; 156 [47.1%] were women, and 175 [52.9%] were men). Two SNPs in noncoding, functional regions of genes that regulate cancer progression, invasion, and metastasis were identified (CHI3L2 SNP rs684559 and CD44 SNP rs353630). These were associated with survival after PDAC resection; patients who carry the risk alleles at 1 of both SNP loci had a 2.63-fold increased risk for tumor-associated death compared with those with protective genotypes (hazard ratio for survival, 0.38 [95% CI, 0.27-0.53]; P = 1.0 × 10-8).

Conclusions and Relevance

The identified polymorphisms may serve as a noninvasive biomarker signature of prospective survival after pancreatic resection that is readily available at the time of PDAC diagnosis. This signature can be used to identify a subset of high-risk patients with PDAC with very low survival probability who might be eligible for inclusion in clinical trials of new therapeutic strategies, including neoadjuvant chemotherapy protocols. In addition, the biological knowledge about these SNPs could help guide the development of individualized genomic strategies for PDAC therapies.

Abstract

Importance

Surgery currently offers the only chance for a cure in pancreatic ductal adenocarcinoma (PDAC), but it carries a significant morbidity and mortality risk and results in varying oncologic outcomes. At present, to our knowledge, there are no tests available before surgical resection to identify tumors with an aggressive biological phenotype that could guide personalized treatment strategies.

Objective

Identification of noninvasive genetic biomarkers that could direct therapy in patients whose cases are amenable to pancreatic cancer resection.

Design, Setting, and Participants

This multicenter study combined a prospective European cohort of patients with PDAC who underwent pancreatic resection (from University Hospital of Zurich, Zurich, Switzerland; Cantonal Hospital of Winterthur, Winterthur, Switzerland; and University Clinic of Ulm, Ulm, Germany) with data from the Cancer Genome Atlas database in the United States, which includes prospectively registered patients with PDAC. A genome-wide screening for functional single-nucleotide polymorphisms (SNPs) that affect PDAC survival was conducted using the European cohort for identification and the Cancer Genome Atlas cohort for validation. We used Cox proportional hazards models to screen for high-frequency polymorphic variants that are associated with allelic differences in tumor-associated survival and either result in an altered protein structure and function or reside in known regulatory noncoding genomic regions. The false-discovery rate method was applied for multiple hypothesis-testing corrections. Data analysis occurred from November 2017 to May 2018.

Exposures

Pancreatic resection.

Main Outcomes and Measures

Tumor-associated survival.

Results

A total of 195 patients in the European cohort were included, as well as 136 patients in the Cancer Genome Atlas cohort (overall median [range] age, 66 [19-87] years; 156 [47.1%] were women, and 175 [52.9%] were men). Two SNPs in noncoding, functional regions of genes that regulate cancer progression, invasion, and metastasis were identified (CHI3L2 SNP rs684559 and CD44 SNP rs353630). These were associated with survival after PDAC resection; patients who carry the risk alleles at 1 of both SNP loci had a 2.63-fold increased risk for tumor-associated death compared with those with protective genotypes (hazard ratio for survival, 0.38 [95% CI, 0.27-0.53]; P = 1.0 × 10-8).

Conclusions and Relevance

The identified polymorphisms may serve as a noninvasive biomarker signature of prospective survival after pancreatic resection that is readily available at the time of PDAC diagnosis. This signature can be used to identify a subset of high-risk patients with PDAC with very low survival probability who might be eligible for inclusion in clinical trials of new therapeutic strategies, including neoadjuvant chemotherapy protocols. In addition, the biological knowledge about these SNPs could help guide the development of individualized genomic strategies for PDAC therapies.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Visceral and Transplantation Surgery
04 Faculty of Medicine > Institute for Regenerative Medicine (IREM)
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Surgery
Language:English
Date:3 April 2019
Deposited On:25 Jul 2019 10:59
Last Modified:29 Jul 2020 10:58
Publisher:American Medical Association (AMA)
ISSN:2168-6254
OA Status:Closed
Publisher DOI:https://doi.org/10.1001/jamasurg.2019.0484
PubMed ID:30942874

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