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Familial Colorectal Cancer Registry in Hispanics

ABSTRACT: Colorectal cancer (CRC) is the second leading cause of cancer in Puerto Rico (PR) accounting for approximately 1,500 individuals annually, which represent 12% of all cancer cases in the island. The genetic epidemiology of CRC among Hispanic populations is not well studied, hence studies focused on large, well defined ethnic groups such as Puerto Ricans, are clearly warranted. The first step towards evaluating the molecular, environmental, and genetic epidemiology of CRC in PR is to establish a population-based familial CRC registry. The following specific aims have been proposed: Specific Aim 1: To prospectively identify and recruit approximately 300 CRC probands from two distinct geographical areas in PR (Metropolitan and Southern Region). From each proband the investigators will obtain a pedigree extended to second-degree relatives and cousins. Assuming 10% will be positive for a family history of CRC, the investigators will then recruit all 30 probands with a family history of CRC and a sample of 15 family-history negative probands and obtain: paraffin-embedded tumors blocks, blood samples, risk factor and food frequency questionnaires. Specific Aim 2: To prospectively identify and recruit selected relatives (parents, grandparents, and same generation relatives - cousins and siblings) from the 45 probands identified in Specific Aim 1. In addition, for siblings and cousins of probands (i.e. relatives in the same generation as the proband), the investigators will obtain risk factor and food frequency questionnaires, and for colorectal cancer cases, tumor blocks and pathology reports of their cancers. Specific Aim 3: To estimate from this pilot study the following parameters: (a) response rate of probands and their selected relatives; (b) response rate of participants for each data item; (c) family history of CRC and other cancers; (d) number of living first- and second-degree relatives and cousins of probands; (e) number of these relatives who live in the same household and region/municipality; (f) prevalence/distribution of selected risk factors from the administered questionnaires.

DISEASE(S): Lynch Syndrome,Colorectal Adenoma,Colorectal Cancer,Gastric Cancer,Colorectal Neoplasms,Adenoma,Colorectal Neoplasms, Hereditary Nonpolyposis

PROVIDER: 2074266 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:The risk of CRC in families of patients with CRC is well established, but it is less well-defined for families of patients with adenomas. Screening recommendations to families when an index subject has an adenoma on colonoscopy are not clear. Previous studies demonstrating an increased CRC risk in close relatives of subjects with adenomas were mostly limited by the lack of a suitable comparison group, did not offer colonoscopy to all relatives or did not have verification on true status of adenoma history in the relatives. A systematic review has reported that most studies cited for risk of CRC in relatives with adenomas have not addressed the intended question. Currently International guidelines recommended screening colonoscopy in close relatives and at a younger age when there is a proband with an adenoma, however this recommendation has not been fully supported by all societies due to the lack of robust evidence. This gap in knowledge highlights the need of well-designed and adequately powered studies to estimate the risk of colorectal neoplasms in subjects who have first-degree relatives with adenomas. Up to 30% of average risk asymptomatic individuals 50 years or older will have at least one adenoma. Based on current guidelines, nearly half the population will be counseled to undergo a colonoscopy from 40 years old based on a positive family history of adenoma. This will have enormous burden on the healthcare system if screening is implicated in all these individuals. Secondly, not all adenomas carry the same risk. Large or villous adenomas are associated with a nearly 70% increased risk of CRC in first degree relatives (FDR) whereas small adenomas may be associated with a modest increased risk 19. It is therefore important to determine the risk of colorectal neoplasms in families of subjects with non-advanced adenomas to justify more intensive screening in these individuals. Investigators hypothesize that first-degree relatives of patients with non-advanced adenoma have an increased risk of both CRC and adenomas. Investigators aim to quantify this risk, and to identify other individual patient or neoplasm characteristics that may contribute to this increased risk. In addition, Investigators aim to determine molecular alteration profiles of colonic adenoma in siblings of patients with advanced neoplasm.

Project description:Colorectal cancer (CRC) is the third most deadly and fourth most diagnosed cancer worldwide. Despite the progress in early diagnosis and advanced therapeutic options, CRC shows a poor prognosis with a 5-year survival rate of ~45%. PRDM2/RIZ, a member of Positive Regulatory Domain (PRDM) gene family, expresses two main molecular variants, the PR-plus isoform (RIZ1) and the PR-minus (RIZ2). The imbalance in their expression levels in favour of RIZ2 is observed in many cancer types. The full length RIZ1 has been extensively investigated in several cancers where it acts as a tumour suppressor, whereas few studies have explored the RIZ2 oncogenic properties. PRDM2 is often target of frameshift mutations and aberrant DNA methylation in CRC. Accordingly, our analysis of Exome- and transcriptome public datasets available at The Cancer Genome Atlas (TCGA) portal revealed that PRDM2 gene is frequently mutated and transcriptionally deregulated in CRC. However, little is known about its role in CRC. In this study, we first evaluated the expression of the different PRDM2 transcripts by in silico analysis on TCGA CRC datasets. Our in-silico analysis on TCGA datasets revealed a highly significant downregulation of RIZ1 in CRC samples whereas a RIZ2 increase was observed in the same samples. Then, we assayed several CRC cell lines by qRT-PCR analysis for the main PRDM2 transcripts and selected DLD-1 cell line, which showed the lowest RIZ2 levels to mimic TCGA datasets analysis results and consequently to assess the PRDM2/RIZ2 role in CRC cells. RNAseq analysis revealed that RIZ2 overexpression induced an EGF overexpression suggesting that RIZ2 could be involved in the EGF autocrine regulation of DLD-1 cell behaviour. Noteworthy, the forced RIZ2 expression increased cell viability, growth, colony formation, migration and organoid formation thus confirming our previous findings on HEK-293 cells. These effects could be mediated by the release of high EGF levels by RIZ2 overexpressing DLD-1 cells. Our findings add novel insights on the putative RIZ2 tumor-promoting functions in CRC, although additional attempts are warranted to depict the underlying molecular mechanism of action

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Familial Colorectal Cancer Registry in Hispanics

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