Nature Communications

Allelic effects on KLHL17 expression underlie a pancreatic cancer genome-wide association signal at chr1p36.33

K Katelyn E. Connelly K Katherine Hullin E Ehssan Abdolalizadeh J Jun Zhong (Institute of Functional Nano and Soft Materials Laboratory (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices) D Daina Eiser A Aidan O’Brien I Irene Collins S Sudipto Das G Gerard Duncan D Demetrius Albanes G Gabriella Andreotti A Alan A. Arslan L Laura Beane-Freeman S Sonja I. Berndt J Julie E. Buring D Daniele Campa F Federico Canzian Y Yu Chen C Charles C. Chung A A. Heather Eliassen J J. Michael Gaziano E Edward L. Giovannucci P Phyllis J. Goodman C Christopher A. Haiman B Belynda Hicks A Amy Hutchinson M Miranda R. Jones V Verena Katzke C Charles Kooperberg (Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.) P Peter Kraft I I-Min Lee L Loic LeMarchand N Núria Malats M Michelle R. Manning S Satu Männistö R Roger Milne S Steven C. Moore L Lorelei Mucci A Alpa V. Patel (Population Science American Cancer Society Atlanta Georgia USA) U Ulrike Peters (Fred Hutchinson Cancer Research Center, Seattle, WA, USA.) F Francisco X. Real N Nathaniel Rothman H Howard D. Sesso V Veronica W. Setiawan X Xiao-Ou Shu D Debra Silverman M Meir J. Stampfer M Melissa C. Southey G Geoffrey S. Tobias T Thérèse Truong C Caroline Um K Kala Visvanathan N Nicolas Wentzensen (Division of Cancer Epidemiology and Genetics National Cancer Institute, National Institutes of Health Rockville Maryland USA) E Emily White C Chen Yuan W Wei Zheng J Jean Wactawski-Wende W Walter C. Willett R Rachael Z. Stoltzenberg-Solomon S Samuel O. Antwi P Paige M. Bracci S Steven Gallinger M Michael Goggins (Department of Oncology, the Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine) M Manal Hassan E Elizabeth A. Holly R Rayjean J. Hung D Donghui Li (Biohub, Redwood City, CA, USA.) R Rachel E. Neale K Kari G. Rabe H Harvey A. Risch H Herbert Yu S Stephen J. Chanock R Rachael Z. Stolzenberg-Solomon A Alison P. Klein B Brian M. Wolpin J Jason W. Hoskins T Thorkell Andresson J Jill P. Smith L Laufey T. Amundadottir

Abstract

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the U.S. Both rare and common germline variants contribute to PDAC risk. Here, we fine-map and functionally characterize a common PDAC risk signal at chr1p36.33 (tagged by rs13303010) identified through a genome wide association study (GWAS). One of the fine-mapped SNPs, rs13303160 (OR = 1.23 (95% CI 1.15-1.32), P-value = 2.74×10−9, LD r2 = 0.93 with rs13303010 in 1000 G EUR samples) demonstrated allele-preferential gene regulatory activity in vitro and binding of JunB and JunD in vitro and in vivo. Expression Quantitative Trait Locus (eQTL) analysis identified KLHL17 as a likely target gene underlying the signal. Proteomic analysis identified KLHL17 as a member of the Cullin-E3 ubiquitin ligase complex with vimentin and nestin as candidate substrates for degradation in PDAC-derived cells. In silico differential gene expression analysis of high and low KLHL17 expressing GTEx pancreas samples suggested an association between lower KLHL17 levels (risk associated) and pro-inflammatory pathways. We hypothesize that KLHL17 may mitigate cell injury and inflammation by recruiting nestin and vimentin for ubiquitination and degradation thereby influencing PDAC risk.

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Article Details

Volume / Issue Vol. 16, Issue 1
Published April 30, 2025
ISSN 2041-1723
Publisher Nature Portfolio

Journal Info

Nature Communications

Nature Portfolio
ISSN: 2041-1723 Open Access Life Sciences

Authors (79)

K

Katelyn E. Connelly

K

Katherine Hullin

E

Ehssan Abdolalizadeh

J

Jun Zhong

Institute of Functional Nano and Soft Materials Laboratory (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices

D

Daina Eiser

A

Aidan O’Brien

I

Irene Collins

S

Sudipto Das

G

Gerard Duncan

D

Demetrius Albanes

G

Gabriella Andreotti

A

Alan A. Arslan

L

Laura Beane-Freeman

S

Sonja I. Berndt

J

Julie E. Buring

D

Daniele Campa

F

Federico Canzian

Y

Yu Chen

C

Charles C. Chung

A

A. Heather Eliassen

J

J. Michael Gaziano

E

Edward L. Giovannucci

P

Phyllis J. Goodman

C

Christopher A. Haiman

B

Belynda Hicks

A

Amy Hutchinson

M

Miranda R. Jones

V

Verena Katzke

C

Charles Kooperberg

Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.

P

Peter Kraft

I

I-Min Lee

L

Loic LeMarchand

N

Núria Malats

M

Michelle R. Manning

S

Satu Männistö

R

Roger Milne

S

Steven C. Moore

L

Lorelei Mucci

A

Alpa V. Patel

Population Science American Cancer Society Atlanta Georgia USA

U

Ulrike Peters

Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

F

Francisco X. Real

N

Nathaniel Rothman

H

Howard D. Sesso

V

Veronica W. Setiawan

X

Xiao-Ou Shu

D

Debra Silverman

M

Meir J. Stampfer

M

Melissa C. Southey

G

Geoffrey S. Tobias

T

Thérèse Truong

C

Caroline Um

K

Kala Visvanathan

N

Nicolas Wentzensen

Division of Cancer Epidemiology and Genetics National Cancer Institute, National Institutes of Health Rockville Maryland USA

E

Emily White

C

Chen Yuan

W

Wei Zheng

J

Jean Wactawski-Wende

W

Walter C. Willett

R

Rachael Z. Stoltzenberg-Solomon

S

Samuel O. Antwi

P

Paige M. Bracci

S

Steven Gallinger

M

Michael Goggins

Department of Oncology, the Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine

M

Manal Hassan

E

Elizabeth A. Holly

R

Rayjean J. Hung

D

Donghui Li

Biohub, Redwood City, CA, USA.

R

Rachel E. Neale

K

Kari G. Rabe

H

Harvey A. Risch

H

Herbert Yu

S

Stephen J. Chanock

R

Rachael Z. Stolzenberg-Solomon

A

Alison P. Klein

B

Brian M. Wolpin

J

Jason W. Hoskins

T

Thorkell Andresson

J

Jill P. Smith

L

Laufey T. Amundadottir

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