Epigenetic Silencing of LRP2 Is Associated with Dedifferentiation and Poor Survival in Multiple Solid Tumor Types

Our plain-English summary of Epigenetic Silencing of LRP2 Is Associated with Dedifferentiation and Poor Survival in Multiple Solid Tumor Types, by M.Q. Rasmussen, G. Tindbæk, M.M. Nielsen, et al (Cancers, 2023).

The study

• Authors: M.Q. Rasmussen, G. Tindbæk, M.M. Nielsen, C. Merrild, T. Steiniche, J.S. Pedersen, S.K. Moestrup, S.E. Degn, M. Madsen
• Journal: Cancers
• Published: 2023;15(6)
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

More than 80% of human cancers originate in epithelial tissues. Loss of epithelial cell characteristics are hallmarks of tumor development. Receptor-mediated endocytosis is a key function of absorptive epithelial cells with importance for cellular and organismal homeostasis. LRP2 (megalin) is the largest known endocytic membrane receptor and is essential for endocytosis of various ligands in specialized epithelia, including the proximal tubules of the kidney, the thyroid gland, and breast glandular epithelium. However, the role and regulation of LRP2 in cancers that arise from these tissues has not been delineated. Here, we examined the expression of LRP2 across 33 cancer types in The Cancer Genome Atlas. As expected, the highest levels of LRP2 were found in cancer types that arise from LRP2-expressing absorptive epithelial cells. However, in a subset of tumors from these cancer types, we observed epigenetic silencing of LRP2. LRP2 expression showed a strong inverse correlation to methylation of a specific CpG site (cg02361027) in the first intron of the LRP2 gene. Interestingly, low expression of LRP2 was associated with poor patient outcome in clear cell renal cell carcinoma, papillary renal cell carcinoma, mesothelioma, papillary thyroid carcinoma, and invasive breast carcinoma. Furthermore, loss of LRP2 expression was associated with dedifferentiated histological and molecular subtypes of these cancers. These observations now motivate further studies on the functional role of LRP2 in tumors of epithelial origin and the potential use of LRP2 as a cancer biomarker.

In plain English

This study did not look at asbestos exposure. The authors analysed public tumor data from The Cancer Genome Atlas, covering 10,534 samples across 33 cancer types, including mesothelioma. They measured the expression of a gene called LRP2, which makes a receptor that takes substances into cells. They also stained tissue from 12 breast cancers from a Danish hospital. LRP2 expression was highest in kidney, breast and thyroid cancers, with mid-to-high levels in mesothelioma. Lower LRP2 expression was associated with poorer survival in several cancer types. For mesothelioma the hazard ratio was 0.87 (p less than 0.01), where a ratio below 1 means lower risk with higher LRP2. In two other mesothelioma datasets the ratios were 0.81 (p = 0.038) and 0.88 (p = 0.108, only a trend). In mesothelioma, LRP2 expression was higher in epithelioid tumors than in biphasic and sarcomatoid tumors. Lower LRP2 expression was correlated with DNA methylation, a chemical tag, at one spot in the gene. The authors stated that their results are correlative and called for further studies of LRP2 as a possible prognostic marker.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Analysis of publicly available cancer genetic and survival databases, plus laboratory staining (immunohistochemistry) of archived breast tissue samples
• Who was studied: 10,534 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA), including mesothelioma. Further data came from the METABRIC breast cancer cohort (more than 2,000 patients), two mesothelioma microarray datasets (Bott et al. and Gordon et al.), and archived samples from Aarhus University Hospital, Denmark: 12 luminal A invasive ductal breast carcinomas diagnosed 2010 to 2014 and healthy breast tissue.
• Exposure: No asbestos or other fiber exposure was studied. The factor examined was the level of LRP2 (megalin) gene expression in tumors, with tumors split into LRP2-high and LRP2-low groups at the lower quartile of expression, and methylation of CpG sites in the LRP2 gene.
• Main results:
  • LRP2 expression was highest in cancers arising from tissues that express LRP2 normally (kidney, breast, thyroid). Mesothelioma, lung adenocarcinoma and lung squamous cell carcinoma showed mid-to-high levels.
  • In TCGA mesothelioma, higher LRP2 was associated with lower risk in a Cox model: hazard ratio 0.87, p less than 0.01. A hazard ratio below 1 indicates decreased risk with higher LRP2. Confidence intervals are shown only in a figure and are not printed in the text.
  • Low LRP2 was also associated with poor outcome in other cancer types:
• KIRC: hazard ratio 0.91, p less than 0.001
• KIRP: hazard ratio 0.88, p less than 0.01
• Thyroid: hazard ratio 0.82, p less than 0.05
• METABRIC breast cancer: hazard ratio 0.90, p less than 0.0001
• Lung adenocarcinoma: hazard ratio 0.95, p less than 0.05
• Skin melanoma: hazard ratio 0.95, p less than 0.05
  • In Kaplan–Meier analysis, patients with LRP2-low mesothelioma tumors had significantly poorer survival (p = 0.01). At this cutoff there were no significant differences for lung adenocarcinoma (p = 0.59) or skin melanoma (p = 0.29).
  • In the Bott et al. mesothelioma cohort, low LRP2 was associated with poor outcome (hazard ratio 0.81, p = 0.038). In the Gordon et al. mesothelioma cohort it trended towards significance (hazard ratio 0.88, p = 0.108).
  • In TCGA mesothelioma, LRP2 expression was higher in epithelioid tumors than in biphasic tumors (p less than 0.01) and sarcomatoid tumors (p less than 0.05).
  • Across tumors, LRP2 expression showed a strong inverse correlation with methylation of CpG site cg02361027 in the first intron of the gene (Pearson's R of minus 0.65). The correlation was strongest in KIRC, KIRP, MESO, THCA and BRCA.
  • LRP2 protein was detected, to a varying degree, in all 12 luminal A invasive breast carcinoma samples stained.
• The authors' conclusion: The authors concluded that LRP2 expression is largely restricted to cancers arising from LRP2-expressing absorptive epithelia. They found that in a subset of these tumors LRP2 is epigenetically silenced, and that this is associated with tumor dedifferentiation and poor survival. They stated that this motivates further studies of LRP2 as a possible prognostic biomarker and therapy target.
• Limitations the authors state:
  • The study relied on bulk RNA sequencing data, which could be confounded by LRP2 expression in non-cancer cells and might not reflect protein levels. The authors addressed this with single-cell and protein data.
  • The results are correlative. The mechanisms of LRP2 regulation in cancer still need study.
  • The role of the methylated first-intron region in controlling LRP2 has not been experimentally proven.

Topics

Medical terms in this study, explained in our Lexicon: Receptor-Mediated Endocytosis, Tubule, Epithelium, Carcinoma, Mesothelioma, Biomarker.

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