Mapping the genetic landscape of hereditary diffuse-type gastric cancer progression

Hereditary diffuse gastric cancer (HDGC), caused by pathogenic variants (PVs) in CDH1, typically presents as early-stage mucosal lesions composed of non-proliferative signet ring cells (SRCs). While loss of E-cadherin initiates tumorigenesis, the somatic genetic alterations driving progression to advanced disease remain poorly understood. Our goal was to identify morphological and genetic changes associated with HDGC progression. We performed whole exome sequencing on 38 gastric tumors from 26 HDGC patients, spanning early to advanced stages, and compared genetic alterations across tumor stages. Early-stage HDGC lesions exhibited minimal somatic alterations, with low tumor mutational burden (TMB) and few cancer-related mutations. In contrast, advanced tumors showed a significant increase in TMB and frequent somatic mutations in CDH1, TP53, and genes involved in TGF-β signaling, cell adhesion, and actomyosin contractility (e.g., SMAD4, FAT4, RHOA). Copy number variations (CNVs) were also more prevalent in advanced tumors, including recurrent loss of 3p and 17p and amplification of oncogenes MYC and MET. CNV profiles varied between tumor regions, indicating intratumoral heterogeneity and potential clonal evolution. HDGC progression is marked by a stepwise accumulation of somatic mutations and chromosomal alterations. While early lesions remain genetically quiet, advanced tumors exhibit complex genetic landscapes, including CDH1 inactivation, oncogenic mutations, and CNVs. These findings highlight key molecular events in HDGC progression and may inform future strategies for early detection and targeted intervention.