Pulmonary Vascular Disease: Cystic Fibrosis |

Cancer Risks in Heterozygous Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) DelF508 Carriers FREE TO VIEW

Jaya Prakash Sugunaraj, MD; Uyenlinh Mirshahi, PhD; Amr Wardeh, BS; Catarina Manney, BA; Kandamurugu Manickam, MD; Michael Murray, MD; David Carey, PhD; Jason Stamm, MD
Author and Funding Information

Geisinger Medical Center, Danville, PA

Copyright 2016, American College of Chest Physicians. All Rights Reserved.

Chest. 2016;150(4_S):1132A. doi:10.1016/j.chest.2016.08.1242
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SESSION TITLE: Cystic Fibrosis

SESSION TYPE: Original Investigation Poster

PRESENTED ON: Wednesday, October 26, 2016 at 01:30 PM - 02:30 PM

PURPOSE: The Cystic Fibrosis Transmembrane conductance Regulator (CFTR) delF508 variant, which is responsible for 86% of cystic fibrosis (CF) cases, is present in Caucasian populations at a frequency of 3-5%. The vast majority of CFTR delF508 carriers do not have CF. There is little information on health and disease in heterozygous delF508 individuals. Previous studies have suggested risk-enhancing and risk-reducing effects for various diseases, with sometimes conflicting conclusions. Our aims are to determine if heterozygous delF508, in the absence of CF, is associated with risks for certain cancers. We took a genotype-first approach in a retrospective exploratory case-control study to determine cancer risks of delF508 carriers. We tested this using a unique database of 50,778 whole exome sequences (WES) linked to the extensive electronic health record (EHR) data of patients of Geisinger Health System who consented to participate in the MyCode Community Health Initiative biobanking project.

METHODS: We identified 1468 (2.9%) heterozygous delF508 carriers, after excluding individuals with CF diagnosis. Non-carriers were defined as individuals without delF508 or other non-synonymous CFTR variants. Cases were defined as individuals with biopsy-proven tumors categorized as “invasive” by morphology in the Geisinger cancer registry (from 1943 to August 2015) and controls were defined as those in our cohort not on the registry. One-half of relative pairs (up to third degree) were removed from the analysis to minimize confounding effects. Association of delF508 to cancer was performed using logistic regression assuming a dominant genetic model, with sex and smoking status as covariates. We used a bootstrap method with 1000 resamples to select controls (1:4 ratio) to maintain case-control balance to minimize inflation of p values. For each resample, logistic regression was used to estimate the odds ratio (OR) for association between delF508 and presence of cancer. The bootstrapped OR and confidence intervals (CI) were generated from the resulting resampled OR distribution. Mean ORs + 98% confidence intervals > 1.0 was considered to be significant increase in risk.

RESULTS: Our results showed that carriers of 1 copy of CFTR delF508 are at increased risks for cancers of the liver and intrahepatic bile duct (OR 4.4 [CI 3.2-5.7]), stomach (OR 2.5 [CI 1.6-3.4]), and rectum (OR 2.1 [CI 1.6-2.7]).

CONCLUSIONS: Our study showed increased odds of developing liver, biliary tract, stomach, and rectal cancers in individuals with heterozygous delF508 when compared with non-carriers. We are currently carrying out further studies to extend and replicate these studies.

CLINICAL IMPLICATIONS: Our study is the first to use the unique resources of a health care provider organization to investigate health risks in delF508 carriers. Finding increased cancer risk in these individuals could represent a significant public health concern, and is consistent with the goals of Precision Medicine. Further evaluation of other populations should be studied to confirm these findings, as well as, biological mechanism. In the future, focused medical screening of this subset of the population based on specific genomic variants could help in earlier detection, treatment and even prevention.

DISCLOSURE: The following authors have nothing to disclose: Jaya Prakash Sugunaraj, Uyenlinh Mirshahi, Amr Wardeh, Catarina Manney, Kandamurugu Manickam, Michael Murray, David Carey, Jason Stamm

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