BackgroundFamilial intestinal gastric cancer (FIGC) remains genetically unexplained and without testing/clinical criteria. Herein, we characterised the age of onset and disease spectrum of 50 FIGC families and searched for genetic causes potentially underlying a monogenic or an oligogenic/polygenic inheritance pattern.MethodsNormal and tumour DNA from 50 FIGC probands were sequenced using Illumina custom panels on MiSeq, and their respective germline and somatic landscapes were compared with corresponding landscapes from sporadic intestinal gastric cancer (SIGC) and hereditary diffuse gastric cancer cohorts.ResultsThe most prevalent phenotype in FIGC families was gastric cancer, detected in 138 of 208 patients (50 intestinal gastric cancer probands and 88 unknown gastric cancer histology relatives), followed by colorectal and breast cancers. After excluding benign and intronic variants lacking impact in splicing, 12 rare high-quality variants were found exclusively in 11 FIGC probands. Only two probands carried potentially deleterious variants, but lacked somatic second-hits, weakly supporting the monogenic hypothesis for FIGC. However, FIGC probands developed gastric cancer at least 10 years earlier and carried more TP53 germline common variants than SIGC (p=4.5E-03); FIGC and SIGC could be distinguished by specific germline and somatic variant profiles; there was an excess of FIGC tumours presenting microsatellite instability (38%); and FIGC tumours displayed significantly more somatic common variants than SIGC tumours (p=4.2E-06).ConclusionThis study proposed the first data-driven testing criteria for FIGC families, and supported FIGC as a genetically determined, likely polygenic, gastric cancer-predisposing disease, with earlier onset and distinct from patients with SIGC at the germline and somatic levels.

Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and new therapies are needed. Cancer-associated fibroblasts (CAFs) can promote PDA progression and are recognized promising therapeutic targets. However, the ongoing characterization of PDA CAF heterogeneity and plasticity and the identification of potential tumor-restraining CAF populations have highlighted the need to further dissect the diverse biology of PDA CAFs to develop effective combination therapies. Using pancreatic organoid/fibroblast co-cultures and organoid-derived transplantation mouse models of PDA, we mechanistically investigated the signaling cascade downstream TGF-beta activation, which is a main driver of myofibroblastic CAF (myCAF) formation. We find that the EGFR/ERBB2 pathway is activated by TGF-beta in a subset of myCAFs, in both murine and human PDA, via amphiregulin induction and autocrine signaling. ERBB activation is important for the maintenance of this myCAF subset, with genetic and pharmacological inhibition of this pathway differentially affecting PDA CAF composition both in culture and mouse models. Importantly, analysis of lung cancer and breast cancer patient samples suggests that our observations in PDA are also relevant to these malignancies. Finally, we reveal a role of this EGFR-activated myCAF subset in promoting local metastatic dissemination in PDA and indicate new potential combination strategies. Our study highlights the need to better dissect PDA CAF heterogeneity also in populations typically considered to be tumor-restraining, in order to develop effective combination strategies for future clinical intervention. Our work also reveals how cancer-targeting therapies can directly affect the surrounding microenvironment with potential clinical implications for various malignancies. Citation Format: Gianluca Mucciolo, Joaquín Araos Henríquez, Sara Pinto Teles, Judhell Manansala, Wenlong Li, Eloise G. Lloyd, Priscilla Cheng, Giulia Biffi. An EGFR-activated subset of myofibroblastic cancer-associated fibroblasts supports local metastatic dissemination in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C039.

Gastric Cancer (GC) is one of the most common and deadliest types of cancer in the world. To improve GC prognosis, increasing efforts are being made to develop new targeted therapies. Although FGFR2 genetic amplification and protein overexpression in GC have been targeted in clinical trials, so far no improvement in patient overall survival has been found. To address this issue, we studied genetic and epigenetic events affecting FGFR2 and its splicing regulator ESRP1 in GC that could be used as new therapeutic targets or predictive biomarkers. We performed copy number variation (CNV), DNA methylation, and RNA expression analyses of FGFR2/ESRP1 across several cohorts. We discovered that both genes were frequently amplified and demethylated in GC, resulting in increased ESRP1 expression and of a specific FGFR2 isoform: FGFR2-IIIb. We also showed that ESRP1 amplification in GC correlated with a significant decreased expression of FGFR2-IIIc, an alternative FGFR2 splicing isoform. Furthermore, when we performed a survival analysis, we observed that patients harboring diffuse-type tumors with low FGFR2-IIIc expression revealed a better overall survival than patients with FGFR2-IIIc high-expressing diffuse tumors. Our results encourage further studies on the role of ESRP1 in GC and support FGFR2-IIIc as a relevant biomarker in GC.