Clinical and epidemiological oncosignals in heritable connective tissue disorders: the role of the dual TGF-β paradox in gastric molecular carcinogenesis - Part I

Heritable and undifferentiated connective tissue disorders (HCTD/UCTD), including Marfan syndrome and related phenotypes, are increasingly recognized as independent risk factors for malignancy. Population-based studies demonstrate a significantly higher incidence of neoplastic diseases among these patients, with a particularly elevated relative risk for gastric adenocarcinoma (~4.6). Clinical observations, including the author’s own data, confirm a tendency toward the early development of tumors of various localizations, indicating a pathogenetic link between connective tissue dysplasia and oncogenesis. A key molecular driver is the constitutive paradoxical activation of the TGF-β signaling pathway: mutations in extracellular matrix genes (e. g., FBN1) and receptor components (TGFBR1/2) do not suppress but rather enhance systemic TGF-β expression and activity - a phenomenon known as the “TGF-β paradox” in HCTD. In oncology, however, TGF-β exhibits a well-known dual role: acting as a tumor suppressor in early carcinogenesis while promoting invasion and metastasis at advanced stages - a context-dependent switch confirmed in both in vitro and in vivo models. The unique pathogenetic background of chronic TGF-β hyperactivation in HCTD (the first paradox), combined with the context-dependent oncologic second paradox, creates a profibrogenic and pro-transforming microenvironment that predisposes connective tissue to neoplastic remodeling. Together, these mechanisms underscore the systemic role of the TGF-β axis in tissue homeostasis and cancer initiation. Part I discusses the clinical and epidemiological evidence for increased cancer risk in HCTD/UCTD and the pathogenetic relationship between the TGF-β paradox and gastric carcinogenesis, focusing on early molecular events within the Correa cascade that establish the groundwork for neoplastic transformation of the gastric mucosa.

Marfan syndrome, connective tissue dysplasia, chronic gastritis, H. pylori-independent gastritis, gastric mucosal atrophy, intestinal metaplasia, precancerous gastric lesions, gastric adenocarcinoma, TGF-β paradox, TGF-β signaling pathway, SMAD signaling / SMAD-dependent regulation, extracellular matrix (ECM), myofibroblasts, tumor microenvironment (TME)

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