Skip to Main Content

An official website of the United States government

The interaction between sex and germline genetics on the risk of pancreatic cancer

Principal Investigator
Name
Barbara Stranger
Degrees
Ph.D.
Institution
Northwestern University
Position Title
Associate Professor of Pharmacology
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
PLCO-1589
Initial CDAS Request Approval
Jun 17, 2024
Title
The interaction between sex and germline genetics on the risk of pancreatic cancer
Summary
Cancer forms a diverse group of diseases characterized by significant morbidity and mortality. In 2018, approximately 1.7 million new cancer diagnoses were expected in the U.S., with annual care costs projected to reach $156 billion by 2020. Nearly all common cancers exhibit some form of sexual dimorphism, affecting incidence, prognosis, tumor aggressiveness, or treatment response. These differences are thought to arise from differences in hormones, sex chromosomes, and environmental exposures between males and females; however, the molecular basis of these disparities remains largely unexplored. Understanding these differences is crucial for precision medicine initiatives in cancer, potentially leading to the discovery of novel biomarkers, therapeutic targets, and improved outcomes.
Aims

We are exploring how sex interacts with germline genetic variation to impact pancreatic cancer risk. To do so, we are re-analyzing genetic data from patients with and without pancreatic cancer using statistical genetics approaches. Previous analyses have considered male and female patients and controls as a homogeneous group. In the present research, we are considering sex as a biological variable that can impact the genetic basis of disease susceptibility.

We will characterize sex differences in the heritable genetic component of pancreatic cancer. We hypothesize that the genetic architecture of susceptibility may differ between males and females. Utilizing data from genome-wide association studies of pancreatic cancer susceptibility, we will test multiple models to test for sexually dimorphic genetic architecture through the following Aims:

Aim 1. Conduct sex-stratified genome-wide association studies for pancreatic cancer susceptibility. This will include re-analysis of a) PanScan genome-wide germline genetic data that was part of a multi-stage genome-wide association study (GWAS) of pancreatic cancer conducted within the framework of the NCI Cohort Consortium, and b) a meta-analysis with the Pancreatic Cancer Case-Control Consortium (PanC4).

Aim 2. Test for sex differences in the genetic basis of pancreatic cancer susceptibility. This will involve: a) Testing for evidence of sexually dimorphic liability thresholds, where one sex requires a greater polygenic burden to achieve disease; b) Testing for specific susceptibility or protective factors encoded on the X or Y chromosome that differentially affect the sexes; c) Determining genetic correlation between male-only and female-only GWASes.

To support this research, we have already obtained approval and accessed PanScan and PLCO genotype data from dbGaP.

Collaborators

Lorenzo Pesce (Northwestern University Feinberg School of Medicine)
Banabithi Bose (Northwestern University Feinberg School of Medicine)