The causes of ordinary colorectal adenomas: the key to the control of colorectal cancer? (original) (raw)
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Genetics of colorectal cancer: hereditary aspects and overview of colorectal tumorigenesis
British Medical Bulletin, 2002
Familial adenomatous polyposis and hereditary non-polyposis colorectal cancer are dominantly inherited conditions with 100% and 80% life-time risk of developing colorectal cancer, respectively. The genetic mutations responsible for these two conditions lie in the adenomatous polyposis coli (APC) and mismatch repair genes. These same genes also play a key role in the formation of sporadic colorectal cancers, which arise on a background of a similar spectrum of mutations to the hereditary cancers. This article examines the genetic mechanisms underlying the hereditary colorectal cancers, as well as genetic predisposition to colorectal cancer in the general population in the absence of a clear-cut genetic syndrome.
Cancer genetics: colorectal cancer as a model
Journal of Human Genetics, 2006
Cancer is essentially a somatic evolutionary process and is, therefore, effectively defined by the genetic and epigenetic changes underlying this process. An understanding of the function of these changes is fundamental to devising new approaches to prevention and treatment. Colorectal cancer (CRC), apart from its obvious importance as one of the most frequent cancers, provides an excellent model for such studies because of the availability of precursor adenoma lesions and the existence of several clear-cut familial inherited susceptibilities. These include familial adenomatous polyposis (FAP), which led to the identification of the APC gene and the importance of the Wnt pathway, and hereditary non-polyposis CRC (HNPCC), which identified the role of the mismatch repair genes in colorectal and other cancers. The presently known range of genetic and epigenetic changes in CRCs and adenomas is reviewed in this paper and the evidence against a requirement for genomic instability presented, together with a discussion of patterns of gene methylation, including especially our work on the homeobox gene, CDX1. Clearly, familial cancers, such as FAP and HNPCC, cannot account for more than perhaps 5% of the incidence of CRC. There is, however, evidence that approximately a further 25-30% have some inherited susceptibility. Based on the association of APC missense variants with multiple adenomas, we proposed that much of this may be due to the cumulative effects of low frequency, low penetrance variants, and the "rare variant hypothesis". The evidence for this from our work on multiple adenoma cases, and certain other examples, is discussed.
Adenomatous polyps and familial incidence of colorectal cancer
European Journal of Cancer and Clinical Oncology, 1984
The frequency of colonic adenomatous polyps and the incidence of colorectal cancer in close relatives were evaluated in a prospective study performed in 100 consecutive patients operated on for colorectal cancer. One hundred patients matched for age and sex, in whom double contrast enema and colonoscopy failed to show cancer, served as control group. Colorectal carcinomas in first-degree relatives were found in 11% of the surgically treated patients and 6% of the control group (the difference is not statistically significant). Solitary or discrete adenomas in patients operated on for colorectal carcinomas were significantly more frequent (32%) than in thecontrolgroup(l8%)(P <0.05). Thisdifferenceisalsostatistically significant when considering only those patients without relatives suffering from carcinoma; however, the same cannot bestatisticaly proven with thesmallgroup of patients with a positivefamily history. l&sent findings do not indicate that single or discrete adenomas synchronous with colorectal cancer are significantly associated with a familial history of large bowel malignancy. These findings are consistent with the hypothesis of environmental factors being involved in adenoma pathogenesis.
Epidemiology and molecular genetics of colorectal cancer
Surgical Oncology, 1998
Colorectal cancer is among the most common cancers a!ecting the western world. By the age of 70 yr, at least 50% of the Western population will develop some form of colorectal tumor, spanning the spectrum from an early benign polyp to an invasive adenocarcinoma. It is estimated that approximately 10% of the benign polypoid lesions will progress to invasive carcinoma. The concept that serial genetic changes are responsible for the transition from benign to neoplastic disease is not new. The description of hereditary cancers and the demonstration of carcinogenic substances inducing DNA damage have provided the foundation for the "eld of molecular oncology. During the past three decades, our understanding of how genetic alterations culminate in cancer has progressed rapidly, though the complete process has not been fully de"ned. The research to date has spanned many oncologic diseases, but has been especially well de"ned in colorectal cancer. The knowledge of the genetic alterations that result in colorectal cancer has important rami"cations for future prevention, detection, and treatment of this disease.
Colorectal cancer: molecular mutations and polymorphisms
Frontiers in oncology, 2013
Colorectal cancer (CRC) is one of the major causes of mortality and morbidity, and is the third most common cancer in men and the second most common cancer in women worldwide. The incidence of CRC shows considerable variation among racially or ethnically defined populations in multiracial/ethnic countries. The tumorigenesis of CRC is either because of the chromosomal instability (CIN) or microsatellite instability (MIN) or involving various proto-oncogenes, tumor-suppressor genes, and also epigenetic changes in the DNA. In this review I have focused on the mutations and polymorphisms of various important genes of the CIN and MIN pathways which have been implicated in the development of CRC. Sameer Colorectal cancer genetics from using Dukes's classification to using the TNM classification system as this is thought to lead to a more accurate, independent description of the primary tumors and its spread (Hardy et al., 2001).
Analysis of Candidate Genes in Occurrence and Growth of Colorectal Adenomas
Journal of Oncology, 2009
Predisposition to sporadic colorectal tumours is influenced by genes with minor phenotypic effects. A case-control study was set up on 295 patients treated for a large adenoma matched with polyp-free individuals on gender, age, and geographic origin in a 1 : 2 proportion. A second group of 302 patients treated for a small adenoma was also characterized to distinguish effects on adenoma occurrence and growth. We focussed the study on 38 single nucleotide polymorphisms (SNPs) encompassing 14 genes involved in colorectal carcinogenesis. Effect of SNPs was tested using unconditional logistic regression. Comparisons were made for haplotypes within a given gene and for biologically relevant genes combinations using the combination test. The APC p.Glu1317Gly variant appeared to influence the adenoma growth (P = .04, exact test) but not its occurrence. This result needs to be replicated and genome-wide association studies may be necessary to fully identify low-penetrance alleles involved in early stages of colorectal tumorigenesis.
COLORECTAL CANCER -EPIDEMIOLOGICAL PERSPECTIVES IN THE ONCOGENETIC CONTEXT
COLORECTAL CANCER-EPIDEMIOLOGICAL PERSPECTIVES IN THE ONCO-GENETIC CONTEXT (Abstract): The neoplastic pathology is one of the challenges of mo d-ern medicine, both in terms of epidemiology (morbidity, mortality and risk factors), as well as in terms of prevention, diagnosis or treatment. The progress of knowledge regarding risk factors and the identification of new diagnosis or therapy methods in the manageme nt of patients with colorectal cancer have led to a series of approach changes which create new pe r-spectives not only for those affected by the disease, but also for their families. Risk factors for CRC include: modifiable factors (endogenous and exogenous factors) and non-modifiable factors (genetic factors). The risk of an individual belonging to the general pop u-lation to develop CRC at a certain point in life is of 5%, while the risk of a subject with Lynch syndrome may reach 70-80%. The genes which potentially increase the risk of CRC include: MMR, MLH1, MSH2, MSH6 (high-penetrance genes) and APC, BRAF, CTNNB1 / beta-catenin, FBXW7, KRAS, PIK3CA, SRC and P53 (low-penetrance genes). The most used methods of screening for the general population are: the HE MOCCULT test, the colon-oscopy and the flexible sigmoidoscopy, while for the groups at risk (with one or more risk factors) these include: the oncogenetic investigation (including the assessment of family hi story of familial adenomatous polyposis (or FAP), attenuated FAP (AFAP), hereditary non-polyposis CRC (HNPCC), personal history of colorectal cancer or adenoma, chronic ulcer a-tive colitis and Crohn's disease and molecular testing of individuals with risk factors).
Ecancermedicalscience, 2015
Colorectal cancer is a serious health problem, a challenge for research, and a model for studying the molecular mechanisms involved in its development. According to its incidence, this pathology manifests itself in three forms: family, hereditary, and most commonly sporadic, apparently not associated with any hereditary or familial factor. For the types having inheritance patterns and a family predisposition, the tumours develop through defined stages ranging from adenomatous lesions to the manifestation of a malignant tumour. It has been established that environmental and hereditary factors contribute to the development of colorectal cancer, as indicated by the accumulation of mutations in oncogenes, genes which suppress and repair DNA, signaling the existence of various pathways through which the appearance of tumours may occur. In the case of the suppressive and mutating tracks, these are characterised by genetic disorders related to the phenotypical changes of the morphological progression sequence in the adenoma/carcinoma. Moreover, alternate pathways through mutation in BRAF and KRAS genes are associated with the progression of polyps to cancer. This review surveys the research done at the cellular and molecular level aimed at finding specific alternative therapeutic targets for fighting colorectal cancer.