LRP1 and Colon Cancer

June 1, 2016 updated by: CHU de Reims

Prognostic Impact of Immunohistochemical and Molecular Expression of the Endocytosis Receptor LRP1 in 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 CCR 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.

LRP-1 is a multifunctional endocytic receptor that belongs to the family of LDL receptors. It is involved in the clearance of matrix proteases. A loss of expression or a decrease of the LRP-1 activity is correlated with an increase of aggressiveness of cancer cells. This effect was demonstrated in vitro in vesicular thyroid carcinomas after LRP-1 blocking. The decrease in the immunohistochemical expression and LRP-1 genomic in hepatocellular carcinomas and lung adenocarcinomas was correlated with a decrease in the overall survival. In CRC, only one immunohistochemical expression study of LRP-1 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 colonic cells. The clinical and prognostic impact of LRP-1 expression in colon cancer and its association with a particular molecular or morphological profile has not been studied to date.

In this work, the investigators will study the immunohistochemical and genic expression of LRP-1 in a series of colorectal cancers.

Study Overview

Status

Unknown

Conditions

Detailed Description

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 the presence of tumor vessels and nerves invasion 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.

Low density lipoprotein related Protein Receptor 1 (LRP-1) is a multifunctional endocytic receptor that belongs to the family of LDL receptors. He is involved in the clearance of enzymes responsible for the degradation of the extracellular matrix: the matrix proteases. This role of matrix proteolysis modulator associated with a function of cell migration regulator give to this protein an anticancer role. The antitumor property of LRP-1 has been demonstrated in thyroid cancers in vitro. In these studies, loss of LRP-1 expression or a decrease in the LRP-1 activity was correlated with an increase of cancer cells migration and invasion. However, the opposite effect was observed in prostate cancer cell lines.

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. In CRC, only one immunohistochemical expression study of LRP-1 has been published to date. This study shows that adenocarcinomatous cells express LRP-1, but in nearly half the cases, weaker than in normal colonic cells. The clinical and prognostic impact of LRP-1 expression in colon cancer and its association with a particular molecular or morphological profile has not been studied to date.

In this work, the investigators will study the immunohistochemical and genic expression of LRP-1 in a well-characterized series of CRC.

The main objective of this study is to study by genic and immunohistochemical approaches the role of LRP-1 in the aggressiveness of colon adenocarcinomas.

The secondary objective of this study is to search for associations between LRP-1 expression level and morphological or molecular profiles of colonic adenocarcinomas

This study will be the first to explore the expression of LRP-1 in well characterized colon cancers of different morphological and molecular profiles. This study will help to increase knowledge of the prognostic role of LRP-1 in colon cancer and its possible association with clinical, morphological or molecular parameters.

There will be a retrospective cohort study, single center.

The investigators will first design the list of all eligible patients by using a request in the software DIAMIC of th pathology department with component code "colon", damage code "adenocarcinoma " and period "between 2006 and 2012". Patients suffering from Lynch syndrome or other familial cancer syndrome will be excluded of the study. Informed consent will be send to all the selected patients.

Once the patients list will be completed:

  • The patients' medical records will be reviewed for: sociodemographic and clinical data colonic tumor location, presence of synchronous metastases, treatment type and duration, patient follow up to the date of 01/06/2014 point (metastases occurrence, disease recurrence, patient death, ...).
  • A central review of all pathological slides will be performed for these criteria: adenocarcinoma subtype according to WHO 2010 classification, differentiation, association with polyps and their types, pTNM stage, invasion front and budding, stroma type, presence and amount of tumor necrosis).

  • Immunohistochemical analysis on formalin fixed and paraffin embedded tissue will be performed:

    • qualitative and semi-quantitative evaluation of LRP1 immunoexpression with anti-5A6 and 8G1 antibodies
    • RER phenotype research (MLH1, MSH2, MSH6 and PMS2 immunohistochemistry) and BRAF V600E immunohistochemistry

  • Molecular analyzes:

    • analysis of LRP-1 gene expression on frozen tissue
    • for selected cases: search for microsatellite instability, search for BRAF V600E, KRAS (exon 2, 3 and 4) and NRAS (exons 2, 3 and 4) mutation on formalin fixed and paraffin embedded tissue

Statistical analysis:

  • Data description: mean and standard deviation for quantitative variables; number and percentage for categorical variables.
  • Comparison of tumors having a high expression of LRP-1 and tumors not or little expressing LRP-1 by univariate analysis (Student's test and the Wilcoxon test, Chi2 or Fisher's exact) and multivariate (logistic regression).
  • Search factors associated with patient outcomes, including the expression of LRP1, by univariate analysis (log-rank test) and multivariate (Cox model).

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 the presence of tumor vessels and nerves invasion 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.

Low density lipoprotein related Protein Receptor 1 (LRP-1) is a multifunctional endocytic receptor that belongs to the family of LDL receptors. He is involved in the clearance of enzymes responsible for the degradation of the extracellular matrix: the matrix proteases. This role of matrix proteolysis modulator associated with a function of cell migration regulator give to this protein an anticancer role. The antitumor property of LRP-1 has been demonstrated in thyroid cancers in vitro. In these studies, loss of LRP-1 expression or a decrease in the LRP-1 activity was correlated with an increase of cancer cells migration and invasion. However, the opposite effect was observed in prostate cancer cell lines.

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. In CRC, only one immunohistochemical expression study of LRP-1 has been published to date. This study shows that adenocarcinomatous cells express LRP-1, but in nearly half the cases, weaker than in normal colonic cells. The clinical and prognostic impact of LRP-1 expression in colon cancer and its association with a particular molecular or morphological profile has not been studied to date.

In this work, the investigators will study the immunohistochemical and genic expression of LRP-1 in a well-characterized series of CRC.

The main objective of this study is to study by genic and immunohistochemical approaches the role of LRP-1 in the aggressiveness of colon adenocarcinomas.

The secondary objective of this study is to search for associations between LRP-1 expression level and morphological or molecular profiles of colonic adenocarcinomas

This study will be the first to explore the expression of LRP-1 in well characterized colon cancers of different morphological and molecular profiles. This study will help to increase knowledge of the prognostic role of LRP-1 in colon cancer and its possible association with clinical, morphological or molecular parameters.

There will be a retrospective cohort study, single center.

The investigators will first design the list of all eligible patients by using a request in the software DIAMIC of th pathology department with component code "colon", damage code "adenocarcinoma " and period "between 2006 and 2012". Patients suffering from Lynch syndrome or other familial cancer syndrome will be excluded of the study. Informed consent will be send to all the selected patients.

Once the patients list will be completed:

  • The patients' medical records will be reviewed for: sociodemographic and clinical data colonic tumor location, presence of synchronous metastases, treatment type and duration, patient follow up to the date of 01/06/2014 point (metastases occurrence, disease recurrence, patient death, ...).
  • A central review of all pathological slides will be performed for these criteria: adenocarcinoma subtype according to WHO 2010 classification, differentiation, association with polyps and their types, pTNM stage, invasion front and budding, stroma type, presence and amount of tumor necrosis).

  • Immunohistochemical analysis on formalin fixed and paraffin embedded tissue will be performed:

    • qualitative and semi-quantitative evaluation of LRP1 immunoexpression with anti-5A6 and 8G1 antibodies
    • RER phenotype research (MLH1, MSH2, MSH6 and PMS2 immunohistochemistry) and BRAF V600E immunohistochemistry

  • Molecular analyzes:

    • analysis of LRP-1 gene expression on frozen tissue
    • for selected cases: search for microsatellite instability, search for BRAF V600E, KRAS (exon 2, 3 and 4) and NRAS (exons 2, 3 and 4) mutation on formalin fixed and paraffin embedded tissue

Statistical analysis:

  • Data description: mean and standard deviation for quantitative variables; number and percentage for categorical variables.
  • Comparison of tumors having a high expression of LRP-1 and tumors not or little expressing LRP-1 by univariate analysis (Student's test and the Wilcoxon test, Chi2 or Fisher's exact) and multivariate (logistic regression).
  • Search factors associated with patient outcomes, including the expression of LRP1, by univariate analysis (log-rank test) and multivariate (Cox model).

Study Type

Observational

Enrollment (Anticipated)

100

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Reims, France, 51092
        • Recruiting
        • CHU Reims
        • Contact:
          • Camille Boulagnon

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Adult patients with sporadic colonic adenocarcinoma treated by surgery at the Academic Hospital of Reims without any neoadjuvant therapy.

Description

Inclusion Criteria:

  • patients operated for colon adenocarcinoma infiltrating stage II at least
  • operated at Chu Reims between 01/01/2006 and 31/12/2012
  • who have given their consent for this study
  • did not receive treatment neoadjuvant.

Exclusion Criteria:

  • NA

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
LRP1 molecular expression
Time Frame: between 2006 and 2012
between 2006 and 2012

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

CHU de Reims

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2015

Primary Completion (Anticipated)

May 1, 2017

Study Completion (Anticipated)

May 1, 2017

Study Registration Dates

First Submitted

May 20, 2016

First Submitted That Met QC Criteria

June 1, 2016

First Posted (Estimate)

June 2, 2016

Study Record Updates

Last Update Posted (Estimate)

June 2, 2016

Last Update Submitted That Met QC Criteria

June 1, 2016

Last Verified

May 1, 2016

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PO15124

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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