Fanconi Anemia: Matrix Remodeling and Oral Carcinogenesis

Fanconi anemia (FA) increases the risk of oral potentially malignant disorders (OPMDs) and oral squamous cell carcinoma; however, the stromal alterations associated with FA-related oral lesions remain poorly defined. We investigated whether extracellular matrix (ECM) remodeling represents a quantifiable feature of FA-associated OPMDs. A total of 119 participants were included: controls with normal mucosa or oral leukoplakia (OL) and individuals with FA. Histopathological and immunohistochemical analyses (p53, Ki-67, α-SMA, and elastin), picrosirius red staining, and multiphoton microscopy combining second-harmonic generation and 2-photon fluorescence were performed, complemented by salivary and transcriptomic profiling. Additionally, Fanca-deficient mice were used to assess stromal remodeling. Compared with sporadic OL, FA-OL exhibited reduced collagen density and elastin autofluorescence, a higher collagen-to-elastin ratio, and diminished p53 immunoreactivity. Salivary procollagen type I N-terminal propeptide showed exploratory associations with matrix-derived optical parameters. RNA sequencing of bulk biopsy tissue revealed an altered matrisome transcriptional signature, including enrichment of ECM structural gene sets and downregulation of selected ECM regulatory programs. In FA-related mouse models, collagen and elastin signals were similarly reduced. Collectively, these multimodal data identify ECM disruption as a reproducible feature associated with FA-OL. Matrix disorganization, together with altered epithelial p53 immunoreactivity, supports the hypothesis that epithelial and stromal alterations coexist across the FA-associated oral lesion spectrum.