Neoplasms

All Conditions

Digestive System Diseases

Adenocarcinoma

Colonic Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Herbal and Botanical

All Drugs and Chemicals

Cola

pyrosequencing

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). Clinical and prognostic significance of the LRP-1 gene expression and promoter methylation is actually unknown.

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.

In this work, the investigators will study the methylation pattern of the LRP-1 gene promoter in a well-characterized series of CRC.

The main objective of this study is to study by methylation analysis the role LRP-1 promoter gene methylation in the prognosis of CRC.

The secondary objective of this study is to evaluate the prognostic impact of CIMP.

This study will be the first to explore the LRP-1 gene promoter methylation in in CRC. This study will help to increase knowledge of the prognostic role of LRP-1 gene promoter methylation in CRC and its possible association with clinical, morphological or molecular parameters.

This study is a single center retrospective cohort study.

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, TNM stage, MSI, RAS and BRAF status, presence of synchronous metastases, treatment type and duration, patient follow up to the date of 01/06/2016 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).
* Methylation analysis:

  * LRP1 gene promoter methylation analysis by pyrosequencing.
  * CIMP status determination by High Resolution Melting analysis of MLH1, MINT1, MINT2, MINT31 and CDKN2A genes promoters.

Statistical analysis:

* Data description: mean and standard deviation for quantitative variables; number and percentage for categorical variables.
* Comparison of tumors having a high methylation of the LRP-1 gene promoter and tumors with not or little methylation of the LRP-1 gene promoter 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 methylation of LRP1 promoter and CIMP status, by univariate analysis (log-rank test) and multivariate (Cox model).

LRP1 Methylation and Colon Cancer

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

CHU de Reims

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Lymphoma

Neuroblastoma

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Neuroepithelial

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Lymphosarcoma

Neuroepithelioma

Meng Yao Lu

Charlene Chen

Chung Yi Hu

Wen Ming Hsu

Neuroblastoma (NB) originates from the sympathetic nervous system and is one of the most common cancers in infants and children. In our hospital, nearly 70% of patients are diagnosed with stage 4, metastatic disease with a poor prognosis, despite the use of multimodal therapy including chemotherapy, surgery, autologous stem cell transplantation, radiation therapy, and differentiation therapy. To improve the survival rate and patient care, our NB Study Group has devoted to the research on NB-specific molecular imaging, biomarkers, and target therapy. We have confirmed studies in cancer genetics by showing that N-myc gene (MYCN) amplification and segmental abnormalities on overall genomic profiling both have an adverse effect on treatment outcome. Therefore, there is an unmet need for the development of novel molecular target therapy in NB. Recently, the anaplastic lymphoma kinase (ALK) oncogene has been found to play an important role in the pathogenesis of NB, as well as serving as the driver mutations in approximately 10% of high-risk NB. The availability of ALK inhibitors also enables ALK as a treatment target in NB. In this proposal, we plan to utilize gene sequencing, array-comparative hybridization, and multiplex ligation-dependent probe amplification methods to evaluate the frequencies and characteristics of ALK mutations and amplifications in patients with NB. The gene and protein expression of ALK will also be evaluated by quantitative polymerase chain reaction(PCR) and immunohistochemistry, respectively, and compared with ALK genotype. The overall genomic pattern, clinical characteristics, histopathology, and treatment outcome of ALK-mutated NB patients will be analyzed. The results from this study may serve as the first report on ALK mutations of NB in Taiwan and will be used for the development of standardized genetic diagnosis protocols, as well as the design of future clinical trials targeting ALK.

* purpose Despite the advance of modern multimodal therapy including surgery, chemotherapy, autologous stem cell transplantation, radiation therapy, and differentiation therapy, most children with NB are diagnosed with metastatic diseases and suffer from a dismal outcome. There is an unmet need for the development of novel target therapy in NB. Among all recently identified targets, ALK gene mutations have been found in approximately 10% of high-risk NB patients and are the treatment target of several promising agents that have already been tested in clinical trials, including crizotinib, which is to be available in Taiwan soon. This study aims to evaluate the prevalence of mutations and copy number aberrations of the ALK oncogene in prospective and previously treated NB patients' tumor sample (from surgical specimens) and germ-line (peripheral blood lymphocytes). The messenger ribonucleic acid(mRNA) and protein expression levels of ALK will also be analyzed. The results will be correlated with the clinical characteristics and pathological findings of this NB cohort.
* technique Prospective cases: Cryopreservation of tumor samples Retrospective cases: Archived tumor Sequencing: point mutation array-based comparative genomic hybridization(aCGH) \& MLPA（multiplex ligation-dependent probe amplification）：analyze copy number alterations (CNAs) compare to clinical data
* expected results The results from this study may serve as the first report on ALK gene mutations of NB in Taiwan. We anticipate that 5-15% of NB tumors carry with common ALK mutations. Genome-wide CNAs profiling by aCGH can help us to categorize the genomic types of NB patients based on published guidelines, while the presence of ALK mutation or amplification may or may not be associated with subtypes with worse outcome. Some patients may have high ALK expression level without bearing common mutations on ALK gene locus, and we may identify novel mutation points in this patient cohort. Finally, we will probably find significant prognostic value of ALK gene mutation, which may be independent from other known risk factors, such as age, stage, MYCN amplification, and genomic pattern.

Based on these results, we are able to develop standardized protocol for diagnosing ALK mutations for Taiwanese NB patients. With the development of ALK genetic testing, a phase II clinical trial of an ALK inhibitor in high-risk NB patients with relapsed or refractory disease may subsequently be conducted and may improve the treatment outcome of the patients.

Biopsy tumor tissue(mail tumor or bone marrow) or Blood

A Pilot Study on ALK Gene Mutations in Neuroblastoma

We anticipate that 5-15% of NB tumors carry with common ALK mutations. Genome-wide CNAs profiling by aCGH can help us to categorize the genomic types of NB patients based on published guidelines, while the presence of ALK mutation or amplification may or may not be associated with subtypes with worse outcome. Some patients may have high ALK expression level without bearing common mutations on ALK gene locus, and we may identify novel mutation points in this patient cohort. Finally, we will probably find significant prognostic value of ALK gene mutation, which may be independent from other known risk factors, such as age, stage, MYCN amplification, and genomic pattern.

National Taiwan University Hospital

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
LRP1 Methylation and Colon Cancer	NCT02786602	Colon Cancer	pyrosequencing	18 Years -	CHU de Reims
A Pilot Study on ALK Gene Mutations in Neuroblastoma	NCT01986595	Neuroblastoma		- 50 Years	National Taiwan University Hospital
A Pilot Study on ALK Gene Mutations in Neuroblastoma	NCT01986595	Neuroblastoma		- 50 Years	National Taiwan University Hospital

Spots Global Cancer Trial Database for pyrosequencing