Hepatocellular carcinoma (HCC) accounts for >80% of primary liver cancers and is the fourth most common cause of cancer-related death. Based on populations projections in 2005, HCC should have decreased by 8% by the year 2015. However, HCC has tripled since 1980 and continues to grow while mortality has doubled. Stroma changes are a primary feature in the pathological progression of HCC, molecular subtyping of HCC, and are predictive of outcomes, yet the translational and post-translational modifications (PTMs) of stromal proteins related to pathological cell status remains mostly unknown. Our preliminary data shows high complexity in localization of stromal proteins and, particularly, changes in PTM site regulation of collagen hydroxylated prolines (HYPs) localized to pathology. Stromal HYP variants can distinguish molecular subtypes of HCC that differe by outcome, suggesting that HYP variants may have a direct association with survival and progression. From this we hypothesize that A) Regionalized cell populations within the liver tissue have distinctive stromal signatures that contribute to HCC subtypes; B) The PTM HYP sites are a primary regulator differentiating HCC pathology subtypes in primary collagens collagen types α-1(I) chain (COL1A1), α-1(II) chain (COL1A2), and α-1(III) chain (COL3A1); C) Stromal variants, including post-translational HYP modifications, represent a novel, clinically significant contributor to HCC. The Aims work to define stromal variants co-localized to pathological cell status by HCC molecular subtypes and determine the clinical significance of HCC stromal variants by investigating variant regulation relative to progression by grade and stage as well as outcome. Characterization of stromal variants due to pathological cell origin within the tumor microenvironment may help elucidate and/or monitor the functional state of cancer associated fibroblasts contributing to subtype evolvement. We expect that this work will lead to new mechanistic directions in targeting stroma for therapies and the results may be further developed as ancillary clinical tools that help in patient management. A long-term goal is to improve targeting capabilities of stromal therapies and eliminate HCC mortality.