Predicting pancreatic cancer in the UK Biobank cohort using polygenic risk scores and diabetes mellitus
Predicting pancreatic cancer in the UK Biobank cohort using polygenic risk scores and diabetes mellitus
Background & aims: diabetes mellitus (DM) is known to be associated with pancreatic ductal adenocarcinoma (PDAC), particularly new-onset DM (NODM). Others have developed polygenic risk scores (PRS) associated with PDAC risk. We aimed to compare the performance of these PRS in an independent cohort to determine if they can discriminate between NODM and long-standing DM patients with PDAC.
Methods: cases (1042) and matched cancer-free controls (10,420) were drawn from the UK Biobank. Five PRS models were calculated using single nucleotide polymorphisms (SNPs) from previous studies (Nakatochi, Galeotti, Molina, Jia, and Rashkin) and a combination of these. Regression models were used to assess the association between PDAC and PRS adjusted for ancestry, smoking, DM, waist circumference, and family history of digestive cancer. Receiver operator characteristic curves and area under the curve metrics (AUC) were used to assess the performance of each PRS for classifying PDAC risk.
Results: the combined PRS model achieved the highest AUC (0.605), and significantly improved a clinical risk model in this cohort (AUC = 0.83; P = .0002). Individuals within the fifth quintile have a 2.74-fold increased risk of developing PDAC vs those in the first quintile (P < .001), and have a 3.05-fold increased risk of developing PDAC if they have DM vs those without DM (P < .001). The positive predictive value was 11.9% in participants without DM, 23.9% with long-standing DM, and 86.7% with NODM.
Conclusions: the PDAC-related common genetic variants are more strongly associated with DM. This PRS has the potential for targeting individuals with NODM for PDAC secondary screening measures.
Early Detection, Genetic Risk Score, Pancreatic Adenocarcinoma
1665-1674.e2
Sharma, Shreya
2bdfaf83-cb98-4f37-8fd5-063fed5f25f8
Tapper, William J.
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Collins, Andrew
7daa83eb-0b21-43b2-af1a-e38fb36e2a64
Hamady, Zaed Z.R.
545a1c81-276e-4341-a420-aa10aa5d8ca8
21 April 2022
Sharma, Shreya
2bdfaf83-cb98-4f37-8fd5-063fed5f25f8
Tapper, William J.
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Collins, Andrew
7daa83eb-0b21-43b2-af1a-e38fb36e2a64
Hamady, Zaed Z.R.
545a1c81-276e-4341-a420-aa10aa5d8ca8
Sharma, Shreya, Tapper, William J., Collins, Andrew and Hamady, Zaed Z.R.
(2022)
Predicting pancreatic cancer in the UK Biobank cohort using polygenic risk scores and diabetes mellitus.
Gastroenterology, 162 (6), .
(doi:10.1053/j.gastro.2022.01.016).
Abstract
Background & aims: diabetes mellitus (DM) is known to be associated with pancreatic ductal adenocarcinoma (PDAC), particularly new-onset DM (NODM). Others have developed polygenic risk scores (PRS) associated with PDAC risk. We aimed to compare the performance of these PRS in an independent cohort to determine if they can discriminate between NODM and long-standing DM patients with PDAC.
Methods: cases (1042) and matched cancer-free controls (10,420) were drawn from the UK Biobank. Five PRS models were calculated using single nucleotide polymorphisms (SNPs) from previous studies (Nakatochi, Galeotti, Molina, Jia, and Rashkin) and a combination of these. Regression models were used to assess the association between PDAC and PRS adjusted for ancestry, smoking, DM, waist circumference, and family history of digestive cancer. Receiver operator characteristic curves and area under the curve metrics (AUC) were used to assess the performance of each PRS for classifying PDAC risk.
Results: the combined PRS model achieved the highest AUC (0.605), and significantly improved a clinical risk model in this cohort (AUC = 0.83; P = .0002). Individuals within the fifth quintile have a 2.74-fold increased risk of developing PDAC vs those in the first quintile (P < .001), and have a 3.05-fold increased risk of developing PDAC if they have DM vs those without DM (P < .001). The positive predictive value was 11.9% in participants without DM, 23.9% with long-standing DM, and 86.7% with NODM.
Conclusions: the PDAC-related common genetic variants are more strongly associated with DM. This PRS has the potential for targeting individuals with NODM for PDAC secondary screening measures.
Text
PDAC_PRS_manuscript_V_3.2_marked_56_ (1)
- Accepted Manuscript
More information
Accepted/In Press date: 10 January 2021
e-pub ahead of print date: 21 January 2022
Published date: 21 April 2022
Additional Information:
Funding Information: funding Zaed Z.R. Hamady is partly funded by Cancer Research UK grant number C45617/A29908.
Keywords:
Early Detection, Genetic Risk Score, Pancreatic Adenocarcinoma
Identifiers
Local EPrints ID: 457214
URI: http://eprints.soton.ac.uk/id/eprint/457214
ISSN: 0016-5085
PURE UUID: feeb8bcf-214a-41e3-aa06-4d392ea8946f
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Date deposited: 26 May 2022 16:50
Last modified: 17 Mar 2024 07:09
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Author:
Shreya Sharma
Author:
Zaed Z.R. Hamady
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