# Discovering Hereditary Risk Through Surveillance: A Prospective Genetic Analysis of Individuals With Familial Pancreatic Cancer

## TL;DR

This study shows that genetic testing in people with a family history of pancreatic cancer reveals hidden risks and that cancer can occur even without known genetic mutations.

## Contribution

The study demonstrates that pancreatic cancer can develop in high-risk individuals without pathogenic germline variants, expanding the case for surveillance beyond genetic criteria.

## Key findings

- 8.8% of high-risk individuals carried pathogenic variants, some in genes not covered by traditional BRCA testing.
- 47% of carriers in high-penetrance genes would not have met national testing criteria based on family history alone.
- Pancreatic cancer was diagnosed in two mutation-negative individuals, showing cancer can occur without known mutations.

## Abstract

Little is known about the genetic background of individuals with familial pancreatic cancer (PC). Integrating germline testing into surveillance may uncover previously unrecognized hereditary susceptibility and expand prevention strategies beyond BRCA testing alone. This study evaluated the genetic landscape of high‐risk individuals due to familiality (HRI‐FHs) enrolled in a national surveillance program.

Five hundred HRI‐FHs from seven centers underwent surveillance and germline testing with a 41‐gene NGS panel. Pathogenic/likely pathogenic variants (PGVs) and variants of unknown significance (VUS) were identified and correlated with clinical and imaging findings.

Overall, forty‐four (8.8%) out of 500 HRI‐FHs carried at least one PGV, including 3.4% in high‐penetrance genes (ATM, BRCA1/2, PALB2, BRIP1). Notably, 8 out of 17 (47%) of ATM, BRCA1/2, PALB2 carriers would not have met the national testing criteria based solely on their family history. An additional 5.4% (27/500) carried PGVs in genes linked to other hereditary conditions (CFTR, MUTYH, CTRC, SPINK1, APC), and 39.6% harbored at least one VUS. PGV status, age, and female gender were independent predictors of radiological abnormalities. Two PCs were diagnosed, both in mutation‐negative individuals.

Integrating germline testing into surveillance redefines the management of familial PC. It uncovers hereditary susceptibility beyond classical criteria and supports cascade testing. PC also arises in mutation‐negative HRI. #NCT05724992.

Summarise the established knowledge on this subject◦The prevalence of high‐penetrance pathogenic germline variants in individuals with familial pancreatic cancer under surveillance is low, yet informative beyond traditional testing criteria.What are the significant and/or new findings of this study?◦Pancreatic cancer can also occur in high‐risk individuals without pathogenic germline variants, supporting surveillance regardless of genetic status.

Summarise the established knowledge on this subject

The prevalence of high‐penetrance pathogenic germline variants in individuals with familial pancreatic cancer under surveillance is low, yet informative beyond traditional testing criteria.

What are the significant and/or new findings of this study?

Pancreatic cancer can also occur in high‐risk individuals without pathogenic germline variants, supporting surveillance regardless of genetic status.