The role of family history in predicting germline pathogenic variant carriers who develop pancreatic cancer: Results of a multicenter collaboration.

Publication Title

Cancer

Authors

Eve Karloski
Beth Dudley
Brenda Diergaarde
Amie Blanco
Jessica N Everett
Elana Levinson
Tara Rangarajan
Peter P Stanich
Kimberly K Childers, Center for Clinical Genetics and Genomics, Providence, Los Angeles, California, USA.Follow
Sandra Brown, Center for Clinical Genetics and Genomics, Providence, Los Angeles, California, USA.Follow
Christine Drogan
Giulia Martina Cavestro
Kelly Gordon, Center for Clinical Genetics and Genomics, Providence, Los Angeles, California, USA.
Aparajita Singh
Diane M Simeone
Hannah Reich
Fay Kastrinos
Dana Zakalik
Heather Hampel
Rachel Pearlman
Ora K Gordon, Center for Clinical Genetics and Genomics, Providence, Los Angeles, California, USA.Follow
Sonia S Kupfer
Marta Puzzono
Raffaella Alessia Zuppardo
Randall E Brand

Document Type

Article

Publication Date

10-1-2024

Keywords

Humans; Germ-Line Mutation; Pancreatic Neoplasms; Female; Male; Middle Aged; Carcinoma, Pancreatic Ductal; Genetic Predisposition to Disease; Aged; Genetic Testing; Adult; Medical History Taking; Heterozygote; Case-Control Studies; Aged, 80 and over; genetic testing; germline mutation; pancreatic cancer; risk factors.; california; los angeles; genomics

Abstract

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) surveillance is recommended for some individuals with a pathogenic or likely pathogenic variant (PV/LPV) in a PDAC susceptibility gene; the recommendation is often dependent on family history of PDAC. This study aimed to describe PDAC family history in individuals with PDAC who underwent genetic testing to determine the appropriateness of including a family history requirement in these recommendations.

METHODS: Individuals with PDAC with a germline heterozygous PV/LPV in ATM, BRCA1, BRCA2, EPCAM, MLH1, MSH2, MSH6, PALB2, or PMS2 (PV/LPV carriers) were assessed for family history of PDAC in first-degree relatives (FDRs) or second-degree relatives (SDRs) from nine institutions. A control group of individuals with PDAC without a germline PV/LPV was also assessed.

RESULTS: The study included 196 PV/LPV carriers and 1184 controls. In the PV/LPV carriers, 25.5% had an affected FDR and/or SDR compared to 16.9% in the control group (p = .004). PV/LPV carriers were more likely to have an affected FDR compared to the controls (p = .003) but there was no statistical difference when assessing only affected SDRs (p = .344).

CONCLUSIONS: Most PV/LPV carriers who developed PDAC did not have a close family history of PDAC and would not have met most current professional societies' recommendations for consideration of PDAC surveillance before diagnosis. However, PV/LPV carriers were significantly more likely to have a family history of PDAC, particularly an affected FDR. These findings support family history as a risk modifier in PV/LPV carriers, and highlight the need to identify other risk factors.

Clinical Institute

Cancer

Specialty/Research Institute

Oncology

DOI

10.1002/cncr.35383