RESUMEN
Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness. However, it is uncertain whether these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency accelerated regeneration after partial hepatectomy. We tested Pkd1 in fatty liver disease, showing that Pkd1 loss was protective against steatosis and glucose intolerance. Mechanistically, Pkd1 loss selectively increased mTOR signaling without SREBP-1c activation. In summary, PKD1 mutations exert adaptive functionality on the organ level without increasing transformation risk.
RESUMEN
Aberrant changes in site-specific core fucosylation (CF) of serum proteins contribute to cancer development and progression, which enables them as potential diagnostic markers of tumors. An optimized data-dependent acquisition (DDA) workflow involving isobaric tags for relative and absolute quantitation-labeling and enrichment of CF peptides by lens culinaris lectin was applied to identify CF of serum proteins in a test set of patients with nonalcoholic steatohepatitis (NASH)-related cirrhosis (N = 16) and hepatocellular carcinoma (HCC, N = 17), respectively. A total of 624 CF peptides from 343 proteins, with 683 CF sites, were identified in our DDA-mass spectrometry (MS) analysis. Subsequently, 19 candidate CF peptide markers were evaluated by a target parallel reaction-monitoring-MS workflow in a validation set of 58 patients, including NASH-related cirrhosis (N = 29), early-stage HCC (N = 21), and late-stage HCC (N = 8). Significant changes (p < 0.01) were observed in four CF peptides between cirrhosis and HCC, where peptide LGSFEGLVn160LTFIHLQHNR from LUM in combination with AFP showed the best diagnostic performance in discriminating HCC from cirrhosis, with an area under curve (AUC) of 0.855 compared to AFP only (AUC = 0.717). This peptide in combination with AFP also significantly improved diagnostic performance in distinguishing early HCC from cirrhosis, with an AUC of 0.839 compared to AFP only (AUC = 0.689). Validation of this novel promising biomarker panel in larger cohorts should be performed.
