Abstract
LRP1 (low-density lipoprotein receptor-related protein 1), a multifunctional endocytic receptor, has recently been identified as a hub within a biomarker network for multi-cancer clinical outcome prediction. As its role in colon cancer has not yet been characterized, we here investigate the relationship between LRP1 and outcome.Materials and MethodsLRP1 mRNA expression was determined in colon adenocarcinoma and paired colon mucosa samples, as well as in stromal and tumor cells obtained after laser capture microdissection. Clinical potential was further investigated by immunohistochemistry in a population-based colon cancer series (n = 307). LRP1 methylation, mutation and miR-205 expression were evaluated and compared with LRP1 expression levels.ResultsLRP1 mRNA levels were significantly lower in colon adenocarcinoma cells compared with colon mucosa and stromal cells obtained after laser capture microdissection. Low LRP1 immunohistochemical expression in adenocarcinomas was associated with higher age, right-sided tumor, loss of CDX2 expression, Annexin A10 expression, CIMP-H, MSI-H and BRAFV600E mutation. Low LRP1 expression correlated with poor clinical outcome, especially in stage IV patients. While LRP1 expression was downregulated by LRP1 mutation, LRP1 promoter was never methylated.ConclusionsLoss of LRP1 expression is associated with worse colon cancer outcomes. Mechanistically, LRP1 mutation modulates LRP1 expression.
Highlights
Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide in men and the second in women
Materials and Methods: LRP1 mRNA expression was determined in colon adenocarcinoma and paired colon mucosa samples, as well as in stromal and tumor cells obtained after laser capture microdissection
LRP1 mRNA levels were significantly lower in colon adenocarcinoma cells compared with colon mucosa and stromal cells obtained after laser capture microdissection
Summary
Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide in men and the second in women. Patients with nonhereditary MSI tumors have better prognosis than those with microsatellite stable (MSS) tumors [1, 2, 8,9,10], and MSI is currently implemented in clinical guidelines as a prognostic biomarker, especially in stage II CRC patients [11]. These histomolecular parameters hardly apprehend disease heterogeneity and are insufficient for recurrence and prognostic prediction in an individual patient. Robust biomarkers that can stratify patient prognosis groups and improve treatment strategies are urgently needed
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