Extrapancreatic Cancer Aggregation in Familial Pancreatic Cancer: A Registry-Based Analysis Integrating IRFARPC and AIRTUM Data

Abstract

Introduction

Familial pancreatic cancer (PC) accounts for approximately 5–10% of all PC cases and is frequently associated with aggregation of extrapancreatic malignancies (EMs) within affected families. Nevertheless, the epidemiologic profile of EMs in familial PC kindreds, including clustering patterns, parental lineage distribution, and age at onset, remains incompletely characterized in large registry-based familial cohorts.

Objectives

To investigate the spectrum, clustering patterns, parental lineage distribution, and early-onset occurrence of extrapancreatic malignancies in families enrolled in the Italian Registry of Families at Risk for Pancreatic Cancer (IRFARPC), and to contextualize age-at-onset patterns against population-based cancer registry estimates (AIRTUM).

Methods

We conducted a registry-based analysis of baseline pedigree data from the IRFARPC (2019–2025), including 1,228 index subjects with familial PC and 3,765 unique relatives (1,846 first-degree and 1,618 second-degree relatives). EMs were evaluated at the family level, and clustering was assessed according to the number of distinct EM sites within each pedigree. Lineage-specific analyses were restricted to second-degree relatives with documented maternal or paternal attribution. Maternal-to-paternal (M/P) ratios were calculated for each EM site to evaluate lineage asymmetry. Age-at-diagnosis distributions and proportions of early-onset cancers (<50 years) were descriptively compared with age- and sex-specific estimates from Italian population-based cancer registries (AIRTUM 2013–2017).

Results

Overall, 47.9% of index subjects reported at least one EM within their family history, while 20.5% showed clustering of ≥2 distinct extrapancreatic cancer sites. Breast (n=306; 19.3% of families), colorectal (n=178; 11.8%), lung (n=124; 9.0%), and prostate cancer (n=105; 7.7%) were the most frequently reported EMs. Breast cancer represented the most common EM in both maternal (5.0%) and paternal (4.7%) lineages and showed a near-symmetric distribution (M/P ratio: 1.07), suggesting a possible autosomal susceptibility pattern. In contrast, lung cancer showed a higher representation along paternal lineages (M/P ratio: 0.61), whereas uterine–ovarian cancers (M/P ratio: 2.12) and hematologic malignancies (M/P ratio: 2.38) showed relative maternal enrichment. PC remained predominantly late onset, with 3.6% of cases diagnosed before age 50, consistent with AIRTUM estimates (3.9%). Conversely, early-onset occurrence was descriptively higher than population-based estimates for uterine–ovarian cancers (+3.8 percentage points vs. AIRTUM) and hematologic malignancies (+2.8 percentage points).

Conclusions

Familial PC is associated with a heterogeneous spectrum of EMs characterized by differential clustering across cancer sites and parental lineages. The balanced maternal–paternal distribution observed for breast cancer supports an autosomal susceptibility pattern, whereas the maternal predominance of uterine–ovarian and hematologic malignancies may be compatible with inherited predisposition pathways, including BRCA1/2-related mechanisms. The paternal predominance observed for lung cancer may also be influenced by shared environmental or behavioral exposures.