Association between MICA polymorphisms, s-MICA levels, and pancreatic cancer risk in a population-based case-control study.

Guillaume Onyeaghala,Anna E Prizment,Bharat Thyagarajan,Heather H Nelson,Bruce Walcheck,John Lane,Nathan Pankratz,Kristin E Anderson,Narasimha Reddy Parine

doi:10.1371/journal.pone.0217868

Guillaume Onyeaghala, Anna E Prizment + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0217868

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Journal: PloS one	Publication Date: Jun 5, 2019
Citations: 9	License type: CC BY 4.0

Affiliation: Minnesota Department of Health, University of Minnesota

Abstract

BackgroundPancreatic tumor cells may avoid immune surveillance by releasing the transmembrane major histocompatibility complex class I chain-related A (MICA) protein in soluble form (s-MICA). We hypothesized that the presence of the A5.1 polymorphism in the MICA gene, which encodes a truncated MICA protein, is associated with higher s-MICA levels and increased pancreatic cancer risk.MethodsMICA alleles and s-MICA levels were measured in 121 pancreatic cancer cases and 419 controls. General linear regression with a log transformation assessed geometric means of s-MICA levels across MICA alleles. Unconditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence intervals (CI) for pancreatic cancer associated with MICA alleles.ResultsAfter multivariate adjustment, participants with at least one copy of the A5.1 allele versus no A5.1 allele had 1.35 (95% CI: 1.05–1.74) times greater s-MICA levels (1.65 times higher for cases and 1.28, for controls) and increased risk of pancreatic cancer (OR = 1.91, 95% CI: 1.05–3.48).ConclusionsOur study suggests higher risk of pancreatic cancer among those with the MICA A5.1 polymorphism, which may be explained by an increase in s-MICA secretion and impaired immune response.ImpactThese findings provide further evidence at the genetic and molecular level of the important role of MICA in pancreatic cancer development, and may have important implications with regards to pancreatic cancer screening.

Highlights

Pancreatic cancer is the 4th leading cause of cancer death among men and women in the U.S, with over 40,000 deaths annually[1]
Participants with at least one copy of the A5.1 allele versus no A5.1 allele had 1.35 times greater s-major histocompatibility complex class I-related chain A (MICA) levels (1.65 times higher for cases and 1.28, for controls) and increased risk of pancreatic cancer (OR = 1.91, 95% confidence intervals (CI): 1.05–3.48)
Our study suggests higher risk of pancreatic cancer among those with the MICA A5.1 polymorphism, which may be explained by an increase in s-MICA secretion and impaired immune response

Summary

Introduction

Pancreatic cancer is the 4th leading cause of cancer death among men and women in the U.S, with over 40,000 deaths annually[1]. Understanding specific immune system mechanisms that interact with pancreatic tumor cells could help determine high-risk groups who may benefit from screening and lead to new therapies in the future. Immune cells such as NK cells, gamma delta (γδ) T cells, and alpha beta (αβ) CD8 + T cells can target and eliminate pancreatic tumor cells when their NKG2D (natural-killer group 2, member D) receptors bind to the major histocompatibility complex class I-related chain A (MICA) protein expressed on tumor cells[5,6,7]. Pancreatic tumor cells may avoid immune surveillance by releasing the transmembrane major histocompatibility complex class I chain-related A (MICA) protein in soluble form (s-MICA). We hypothesized that the presence of the A5.1 polymorphism in the MICA gene, which encodes a truncated MICA protein, is associated with higher s-MICA levels and increased pancreatic cancer risk.

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Discussion

Conclusion