Prognostic Impact of the Endocytic Receptor LRP-1 Gene Promoter Methylation in a Retrospective Study of Colonic Adenocarcinomas

Colorectal cancer (CRC) is a major public health problem in France and worldwide. CRC is the third most common cancer in incidence and mortality in France. The vast majority of these cancers are adenocarcinomas that arise sporadically and develop from precursor lesions: adenoma. All CRC with the same disease stage do not have the same prognosis. Various parameters have been identified as factors influencing the prognosis and allows adjustment of the treatment. The poor histoprognostic factors are vessels and nerves invasion by the tumor or the mucinous adenocarcinoma subtype. At the molecular level, the presence of microsatellite instability (MSI) improves the prognosis, while the presence of a BRAF mutation is an independent poor prognostic factor.

The different molecular pathways of colonic carcinogenesis are the chromosomal instability pathway, the microsatellite instability pathway inducing errors in DNA mismatch repair and the CpG Island Methylator Phenotype (CIMP). The hypermethylation of CpG islands of genes promoters leads to an over or most frequently under gene expression. CIMP is observed in near 15% of CRC and is associated with specific clinical and pathological features: older patients, female predominance, right colonic involvement, poorly differentiated or mucinous adenocarcinomas. From a molecular point of view, the high CIMP phenotype is strongly associated with the presence of BRAFV600E mutation, the absence of RAS mutation and the presence of microsatellite instability. The prognostic value of CIMP is actually controversial. A recent meta-analysis found that the CIMP phenotype was associated with a poor prognosis. Methylation of some genes promoters as CDKN2A is associated with a poor prognosis.

LRP-1 (low density lipoprotein receptor-related protein 1) is a multifunctional endocytic receptor that belongs to the LDL receptors the family. It mediates the clearance of many extracellular enzymes involved in the spread of cancer cells: metalloproteinases and serine proteinases. Decrease of LRP-1 activity or loss of LRP-1 expression correlates with increased aggressiveness of cancer cells in certain types of cancer. The expression of LRP-1 has almost never been studied in CRC. Only one immunohistochemical study of LRP-1 protein expression in colonic adenocarcinoma has been published to date. This study shows that tumor cells express LRP-1, but in nearly half the cases, weaker than in normal cells colic. The mechanisms involved in the decrease of expression are not known.

An epigenetic mechanism might be involved as hypermethylation of the of LRP-1 gene promoter, especially as the promoter of this gene is rich in CpG islands (methylation targets).

The clinical impact of the level of LRP-1 expression on overall survival of cancer patients has been assessed in two studies: one on patients suffering from hepatocellular carcinoma and one on patients suffering from primitive lung adenocarcinomas. In both studies, the decrease of immunohistochemical and gene expression of LRP-1 correlated with overall survival decrease. The clinical and prognostic impact of LRP-1 expression in CRC and its association with a particular molecular or morphological profile has not been studied to date.