The genomics of colorectal cancer: state of the art (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.
2008
Each year 3500 people in Switzerland are diagnosed with colorectal cancer. Approximately 20 percent of all affected patients have two or more first or second-degree relatives with colorectal cancer (at-risk family members). About five percent of these are inherited in an autosomal dominant manner. present in a hemizygous state in the tumor. Furthermore, 100 healthy probands did not carry the alteration and sequence and amino acid alignment with vertebrates showed that it is located in a conserved region of the gene. Taken together, our findings indicate that the alteration in MSH3 may indeed be pathogenic. Recently, another FAP susceptibility gene besides APC was identified. It was shown that biallelic germline mutations in the human homologue of the base excision repair gene MutY (MYH) cause a phenotype of multiple colorectal adenomas and carcinomas, thus describing for the first time an autosomal recessively inherited CRC predisposition. This third part of this thesis aimed to assess the frequency of MYH mutation carriers within a Swiss cohort of 79 unrelated polyposis patients. In addition, comparisons have been made between MYH mutation carriers and APC mutation-negative individuals to establish genotype-phenotype correlations in this cohort of patients. The results of the study were published
Genotypic and Phenotypic Characteristics of Hereditary Colorectal Cancer
Annals of Coloproctology, 2021
The genomic causes and clinical manifestations of hereditary colorectal cancer (HCRC) might be stratified into 2 groups, namely, familial (FCRC) and a limited sense of HCRC, respectively. Otherwise, FCRC is canonically classified into 2 major categories; Lynch syndrome (LS) or associated spectra and inherited polyposis syndrome. By contrast, despite an increasing body of genotypic and phenotypic traits, some FCRC cannot be clearly differentiated as definitively single type, and the situation has become more complex as additional causative genes have been discovered. This review provides an overview of HCRC, including 6 LS or associated spectra and 8 inherited polyposis syndromes, according to molecular pathogenesis. Variants and newly-identified FCRC are particularly emphasized, including MUTYH (or MYH)-associated polyposis, Muir-Torre syndrome, constitutional mismatch repair deficiency, EPCAM-associated LS, polymerase proofreading-associated polyposis, RNF43- or NTHL1-associated se...
Hereditary non-polyposis colorectal cancer — morphologies, genes and mutations
Mutation Research-fundamental and Molecular Mechanisms of Mutagenesis, 1994
Mutations in human homologue of the yeast DNA mismatch repair gene MSH2 (equivalent to bacterial MutS) cause the condition heredity non-polyposis colorectal cancer (HNPCC). Cancers in HNPCC originate within bengin neoplastic polyps termed adenomas. Adenomas are clonal and each may serve as a marker of a single initiating mutation. The progression of adenomas is marked by increasing size, dysplasia and villosity. These characteristics can be taken as the morphological counterparts of the stepwise accumulations implicating ioncogenes and tumour suppressor genes. The aim of this study was to link the morphogenesis of heredity colorectal cancer with recent insights into the role of DNA mismatch repair genes. The frequency and anatomical distribution of adenomas in at-risk members of HNPCC families was the same as in an autopsy population. This suggests that the HNPCC gene does not initiate the process of neoplastic transformation. On the other hand, adenomas in at-risk members of HNPCC families were more likely to show villosity (p<0.001), high grade dysplasia (p=0.002) and probably increased size (p=0.15). These findings are consistent with the observation that the HNPCC gene causes DNA replication errors to develop and accumulate within neoplastic but not normal tissue. The effect of the HNPCC gene is to accelerate the progression of adenoma to carcinoma, but not to initiate adenoma development.
Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC)
Familial Cancer, 2008
The family histories of 130 individuals with documented hereditary non-polyposis colorectal cancer (HNPCC) (caused by mutations in mismatch-repair (MMR) genes MSH2 (n = 64), MLH1 (n = 62) or MSH6 (n = 4)) were obtained, and incidence of cancers in those families was compared to that in the general population. There were a total of 982 cancers in 723 individuals. Colorectal cancer (CRC) was the commonest type (64% and 55% in individuals from families with germline MLH1 and MSH2 mutations respectively). Median age at Keywords Lynch syndrome Á HNPCC Á Gene analysis Á Familial relative risk Á Clustering Abbreviations AER absolute excess risk CNS central nervous system
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.
Molecular Basis of Hereditary Colorectal Cancer
Seminars in Colon and Rectal Surgery, 2011
Advances in molecular biology have defined the molecular basis for colorectal cancer (CRC). Though only a fraction of CRC has been determined to have a hereditary component, the discovery of genetic alterations in these clinical syndromes has permitted definition of similar discoveries in sporadic CRC. Here we will delineate the molecular basis for the most common of these defined syndromes, including familial adenomatous polyposis, hereditary non-polyposis colon cancer, MUTYH associated polyposis, Juvenile polyposis, Peutz-Jeghers syndrome, and Cowden's syndrome. The newest paradigm with implications for the pathogenesis of sporadic CRC is called the cancer stem cell hypothesis. As this paradigm also implicates aberrations in molecular pathways, a brief discussion of this hypothesis is included.
HEREDITARY SYNDROMES ASSOCIATED WITH COLORECTAL CANCER (Atena Editora)
HEREDITARY SYNDROMES ASSOCIATED WITH COLORECTAL CANCER (Atena Editora), 2024
Cancer is a condition characterized by disordered and invasive cell growth in the tissues and organs of the human body. Hereditary intestinal cancer affects parts of the large intestine, such as the colon and rectum, and is influenced by hereditary genetic factors, benign lesions and polyps. Colorectal cancer (CRC) is the most common type, with a strong genetic predisposition related to several syndromes, such as familial adenomatous polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, Lynch syndrome and Muir syndrome. -Tower. Familial adenomatous polyposis is marked by the formation of numerous polyps in the colon and rectum, increasing the risk of malignancy. Lynch Syndrome, related to mutations in DNA repair genes, increases the incidence not only of colorectal cancer, but also of other types, such as endometrium, ovary and stomach, standing out in the understanding and management of the genetic risk of CRC.
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.