Genetics of Colorectal Cancer: 1 (Cancer Genetics)

K-ras mutations were studied to determine their role in the predictability of response to chemotherapy treatment; Thus, in patients with colorectal tumors and K-ras mutations a worse response to adjuvant treatment with 5 - FU was observed compared with groups of patients who did not have this mutation [ 15 , 16 ]. The loss of function of the APC gene mutation is the most common mutation in colorectal cancer. Regarding the role of p53 status in response to therapy, the study of homozygous cell lines for p 53 mutation showed a high degree of resistance to radiotherapy and some chemotherapies including 5 - FU [ 18 ].

The activation of growth factors is common in colorectal cancer. An essential step in the development of adenomas is prostaglandin signaling. COX-2 is an enzyme that mediates prostaglandin E2 synthesis associated with colorectal cancer. In about two thirds of colorectal cancer, COX level was increased [ 19 ]. EGFR exists on the cell surface and is activated by ligation with various ligands, including epidermal growth factor. Genetic mutations that lead to EGFR overexpression were associated with cancer, mainly lung and colorectal cancer. Clinical data have shown that colorectal cancers with this mutation do not respond to anti-EGFR therapy [ 23 , 24 ].

Vascular growth factor - VEGF is responsible for the appearance new formation vessels, angiogenesis.

1. The genetics of colorectal cancer..
2. Inherited predisposition to colorectal cancer.
3. Stolen Lives: A Tribute to Shadows.
4. .
5. Molecular genetics of colorectal cancer!
6. Genetics of colorectal cancer.

The fatal evolution of colorectal cancers is closely related to this factor. The treatment with VEGF antibody bevacizumab increased the survival of patients compared to patients treated with standard therapy [ 25 ]. An important transposition into medical practice of colorectal cancer genetics data is the developing of molecular diagnosis in order to detect cancer in early stages.

Usually, multitarget panels that detect mutations in the APC gene, p53, K-ras, BAT a marker for microsatellite instability are used and a marker of abnormal apoptosis [ 26 , 27 ]. The studies, which contribute to the understanding of colorectal cancer at the molecular level, have provided data used for genetic tests of family forms, defining predictive markers for the selection of patients susceptible of certain forms of therapy and the development of molecular diagnostic tests for the detection of early non-invasive cancers.

New biological pathways have been identified that may lead to the discovery of new therapeutic agents. Although some high-frequency mutations are attractive targets for the development of new drugs, they could cover targets located downstream on common signaling pathways. National Center for Biotechnology Information , U. Journal List J Med Life v. Author information Article notes Copyright and License information Disclaimer.

Received May 28; Accepted Sep This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

This article has been cited by other articles in PMC. Abstract The occurrence of colorectal cancer is related to the interaction that takes place at several levels between hereditary factors, environmental and individual ones. The following types of genomic instability are described: Microsatellite instability Studying mating errors in DNA bases in patients with colorectal cancer has observed that genes responsible for repairing were inactive.

Aberrant DNA methylation Methylation of the cytosine in the fifth position of the pyrimidine ring is a common alteration in mammals at CpG sequences. Tumor progression The occurrence and development of colorectal cancer remains among the most eloquent evidence of cancer in stages. Tumor suppressor genes and oncogenes associated with colorectal cancer Oncogenes are genes whose expression is intimately associated with cell normal cells transformation to cancer cells. Inactivating mutation causes loss of regulation of spindle microtubules during mitosis.

APC mutations cause chromosomal instability. Inactivating mutation impairs ability to repair strand slippage within nucleotide repeats. Germ-line mutation in hereditary nonpolyposis colorectal cancer; epigenetic silencing causes loss of tumor MLH1 protein expression. MMR gene mutations cause microsatellite instability. TP53 35—55 5 Encoding a protein responsible for cell-cycle regulation inactivating missense mutations paired with loss of heterozygosity at 17p.

Inactivating mutation causes loss of regulation of cell-cycle arrest and cell death. Germ-line mutation in Li—Fraumeni syndrome. Inactivation may coincide with malignant transformation of adenomas. TGFBR2 25—30 Receptor responsible for signaling pathways mediating growth arrest and apoptosis; inactivated by frame shift mutation in polyA repeat within TGFBR2 coding sequence in patients with mismatch-repair defects or by inactivating mutation of kinase domain. Germ-line mutation in the cardiofaciocutaneous Syndrome. These criteria were intended principally as a research, rather than clinical, tool.

Mutations have, however, also been found in families who do not fulfil the criteria, particularly those with a preponderance of HNPCC-related extracolonic tumours. As with FAP, there appears to be a correlation between the particular genetic mutation and the phenotypic appearance of the disease.

Conclusions

Similarly, women with hMSH6 mutations appear to be more likely to develop endometrial cancer Individuals at risk in HNPCC kindreds are heterozygous for mutations in the mismatch repair genes and so their normal cells do not have an elevated mutation rate The most vulnerable areas to loss of mismatch repair mechanisms are poly-oligo tracts and base pair repeats known as microsatellites. Nonsense and missense mutations form a large proportion of the disease-causing mutations 29 , making PTT unreliable.

In addition to this, a significant proportion of hMSH2 disease-causing mutations consist of very large deletions that are not detected by standard methods of mutation detection. Immunohistochemical staining for the hMLH1 and hMSH2 proteins may also provide an estimate of the presence or absence of mismatch repair function in a tumour. The Bethesda guidelines which provide recommendations for microsatellite instability testing in colorectal cancer. Current recommendations suggest that screening for HNPCC should begin from the age of 25 years, or at 5 years younger than the youngest affected relative.

Colonoscopy is then performed at one to two yearly intervals. The International Collaborative Group on HNPCC also recommends gastroduodenoscopy, renal tract ultrasound, urine cytology, gynaecological examination, endometrial curettage, transvaginal ultrasound and serum CA measurements on an annual or biennial basis Prophylactic colectomy with ileorectal anastomosis and subsequent rectal surveillance is offered to HNPCC carriers in some centres.

Apart from the classical autosomal dominant diseases, the genetic mechanisms responsible for inherited predisposition to CRC are likely to include less deleterious mutations in the same genes responsible for FAP and HNPCC. These mutations result in APC proteins with amino acid substitutions in functionally critical areas, thus apparently conferring an advantage with respect to tumour function. Analogous variants in other candidate genes involved in the progression of the adenoma-carcinoma sequence may also carry an increased risk of developing colorectal tumours.

Missense mutations in the CDH1 E-cadherin gene have been suggested to be associated with an increased risk of colorectal and gastric cancer in the Korean population Genetic variability probably contributes substantially to multifactorial disease inheritance in this way. The process of genetic testing in individuals considered to be at risk for a clearly inherited susceptibility to CRC includes identification of affected and at-risk individuals, genetic counselling, laboratory testing and accurate interpretation of results.

Genetic testing may be carried out in an individual suspected of having a hereditary form of colorectal cancer, or in relatives of a known genetic carrier. If at all possible, the proband original patient presenting with the disease should be genotyped first. This has the advantage of identifying the responsible mutation and increasing the sensitivity of its subsequent detection in at-risk relatives. This may not always be feasible where a proband has died or refused genetic testing. Corroborating genetic test results with affected individuals from the same family should then confirm the pathogenicity of any mutation found.

Testing for any genetic disorder is inappropriate in the absence of trained genetic counselling and good clinical follow-up. Counselling sessions may focus either on the individual or on a family group. The counsellor's multiple roles include ascertaining precise details of an individual's personal and family history, making an assessment of genetic risk, description of genetic testing, and written informed consent.

It is also important to:. Support should also be provided in the follow-up period with emphasis placed on compliance with recommended screening programmes. If a mutation is detected in the proband, it is then possible to test family members for the same mutation.

Family members with negative results may be re-assured that they do not need to undergo conventional screening, but it should be stressed that they still have the background population risk for CRC. Family members with the mutation should start or continue with screening programmes, and the option of prophylactic surgery should be discussed. There will always be cases where results of genetic testing in the proband are ambiguous or negative.

In these cases, it is inappropriate to perform genetic analysis on other family members. Linkage analysis may provide some useful information in large families. If no mutation is identified, all at-risk family members should continue to be clinically screened.

• Mein total genialer Doppelgänger (German Edition).
• Introduction.
• Molecular genetics of colorectal cancer.
• Turkish easy ! For your journey.
• Stutter Boy;
• Al precio que sea (Deseo) (Spanish Edition).
• MARY KATHERINE!

The same situation arises if the proband declines genetic testing. Genetic screening generally refers to the testing of members of a defined subset of the population e. This should only be done when there is clear benefit that can be provided for those individuals shown to carry the genetic susceptibility factor. For example, essentially all births in the UK are tested for the presence of mutations causing phenylketonuria PKU since the disease onset severe mental retardation can then be prevented by a diet deficient in the amino acid phenylalanine.

Similarly, individuals carrying, for example, the APC IK or EQ mutations which predispose to multiple adenomas could undergo colonoscopic screening regularly at appropriate intervals after a certain age, and any adenomas removed prophylactically. This strategy should completely eliminate any risk of these individuals developing CRC. As the technology for large-scale screening for mutations develops, there may eventually be a strong case for some form of genetic screening for the variety of mutations which predispose to multiple adenomas, and so to CRC. All cells exist under strict regulation of signals for growth, apoptosis, differentiation, cell—cell interactions and cell—extracellular matrix interactions.

Tumorigenesis is a process involving multiple sequential genetic events resulting in activation of oncogenes and inactivation of tumour suppressor genes, which allow escape from the tight constraints that control normal cells. The nature of these events includes mutation, loss of heterozygosity LOH , epigenetic silencing of gene transcription by promoter hypermethylation, gene amplification, gain of function mutations, transcriptional up-regulation and translocations that generate chimeric proteins with oncogenic activity.

Somatic mutations occur randomly. A mutation that provides a cell with a relative survival advantage at the time of occurrence will be selected for and result in clonal expansion of the cell in which it arises. The sequence of acquired mutations, or genetic pathway, in any developing tumour is a reflection of the constraints that become rate limiting at different stages in the evolution of the tumour. For example, whilst early mutations conferring escape from growth control or adhesion may be initiating factors, they may also promote apoptosis.

Expansion of the developing clone relies on the rate of cell proliferation out-matching the rate of cell death. Thus, in this situation, apoptosis becomes rate limiting and the greatest selective pressure for subsequent mutations would be for those conferring escape from apoptosis. Similarly, larger increases in tumour bulk without adequate vascularisation would place evolutionary pressure for mutations stimulating angiogenesis. Cells from a particular tissue have to escape the same micro-environmental restrictions in order to form a cancer, and would be expected to accumulate mutations along a similar genetic pathway.

The presence of a readily evident precursor lesion in colorectal cancer, the adenomatous polyp, has facilitated the characterization of the histopathological and genetic pathways during the transition from adenoma to carcinoma. The histological progression of colorectal cancer from adenoma to carcinoma was first described by Morson and colleagues 35 and the genetic pathway which parallels this transition has been suggested by Fearon, Vogelstein, Bodmer and others Fig. Basic outline of the adenoma to carcinoma sequence.

The temporal order in which key genes may be affected is shown above the histological stages of disease during which they are thought to occur. Broken lines are used where the order of accumulation of genetic events is uncertain. Functional pathways affected are indicated at the bottom of the diagram. Histological evidence of dysplasia is usually taken as the first recognizable step in the adenoma-carcinoma sequence. However, the relationship between aberrant crypt foci and adenomas is still not clear.

Progression of an adenoma is more likely with increased size, severe features of dysplasia villous rather than tubular architecture. Finally, overt features of carcinoma are characterized by local invasion and eventual metastasis. The exact sequence of commonly acquired genetic changes accumulated subsequent to inactivation of APC is variable.

There is good evidence to suggest that p53 mutations occur more frequently in high-grade dysplastic polyps and are thought to mark the transition from adenoma to carcinoma 36 , However, the temporal order of disruption of these genetic pathways as they relate to histological progression remains uncertain, and is most probably often different in different tumours.

Each tumour is, after all, the result of an independent somatic evolutionary process involving a series of genetic or epigenetic changes each of which gives the tumour a further growth advantage. The APC protein has many well-characterized functional domains and interacts with numerous other proteins.

It is involved in a wide variety of cellular processes including migration, adhesion, proliferation, and even perhaps aspects of chromosome stability and cytoskeletal organization. The highest frequency of point mutations in both familial and sporadic disease arises from transitions at CpG dinucleotides.

Spontaneous de-amination of methylated cytosine to thymidine at CGA arginine sequences generates a TGA or stop codon, and so the most frequent nonsense mutation is from an arginine to a stop codon. There appears to be an intriguing interdependence between the first and second hits to the APC gene in both FAP and sporadic cancers. Where the first mutation either germline in the case of FAP or somatic in sporadic tumours is a truncating mutation falling within the MCR, the second somatic hit is almost invariably a deletion or loss of heterozygosity LOH.

The genetics of colorectal cancer.

Homozygous deletions of APC are almost never found. Together with the tight clustering of the MCR, this strong selection for truncating mutations implies that mutations truncated specifically in this region have a strong dominant-negative effect and so may confer oncogenic activity to the truncated protein. As it has become clear that CRC is not a single disease, but rather a heterogeneous complex of diseases, it is believed that CRC with similar characteristics most likely share the same pathogenesis and biological behavior.

Historically, CRC classification was only based on clinical and pathological features. Adding molecular features is important because it reflects the mechanisms of carcinogenesis. Based on a link between pathological, molecular and clinical features Jass et al classified CRC in to 5 subtypes: Growing evidence suggests that epigenetic changes might even be higher than the genetic changes and are a major determinant in the origin of the tumor and tumor heterogeneity. To better characterize DNA methylation subgroups in CRC, Hinoue et al performed genome-scale DNA methylation profiling of primary colon tumors and 29 adjacent non-tumor colonic mucosa together with gene expression to assess the biological implications of DNA methylation-mediated gene silencing [ 27 ].

They identified four subgroups, with each subgroup showing characteristic genetic and clinical features, indicating that they represent biologically different subgroups. In addition, the hypermutated tumors were found predominantly in the right colon and mostly hypermethylated. Moreover, these hypermutated tumors are highly immunogenic because of the generation of mutated proteins including frame-shift mutations [ 28 ]. In the other non-hypermutated group, patterns of genomic similarity were found with overall 24 genes that were significantly mutated, including APC and TP Remarkably, these 2 genes were more frequently mutated in the non-hypermutated group than in the hypermutated ones, suggesting that CRC from both groups develop differently on a genetic level.



CRC subtyping has also been addressed using genome-wide gene expression profiling in large patient cohorts [ 29 - 32 ]. Salazar et al performed unsupervised hierarchical clustering of stage I to IV CRC and revealed three main molecular subtypes with different prognosis [ 29 ]. Recently, Budinska et al characterized five main subtypes of CRC in terms of biological motifs, common clinical variables, association with known CRC molecular markers and morphological patterns [ 30 ]. They called their subtypes surface crypt like, lower crypt-like, CIMP-H like, mesenchymal and finally a mixed group.

The authors concluded that their subtypes should be prospectively assessed for their clinical relevance. Two recent studies published in Nature Medicine [ 33 , 34 ] also used gene expression profiling to classify CRC and to correlate with prognosis and response prediction. The third group overlaps partly with the CIMP group CCS3 , might be derived from the serrated pathway and is linked with poor prognosis. Sadanandam et al defined six groups that are related to six different cells of origin in the colon crypt [ 34 ].

In conclusion, we still do not understand the precise molecular events that lead to the development of a CRC with its typical phenotypic changes, but there is clear evidence now for the presence of different subtypes in CRC. On one hand, defining the molecular subgroups in CRC will lead to a better understanding of the disease; on the other hand it should help us guide therapy by providing both prognostic and predictive information.

Ribic et al showed that MSI tumors did not seem to benefit from 5-FU based adjuvant chemotherapy and were possibly even harmed [ 36 ]. In , Sargent et al performed a pooled analysis with new CRC patients in combination with the previously published CRC patients, and confirmed the previous results [ 37 ].

Unfortunately, they did not study the effect in stage II tumors. It has to be mentioned though that the authors did not perform molecular genetic analysis of germline DNA, but used other criteria to define germline versus sporadic, therefore this finding still needs to be validated in other series. Surprisingly, the study revealed a statistically significant survival benefit from the addition of bevacizumab HR 0.

They postulate that a possible explanation might be that dMMR tumor cells, because of their hypermutated status and high immunogenicity, at the micrometastatic level have to evade attack from the immune system in order to progress and VEGF-A is one of the main tumor-derived soluble factors that can create an immune suppressive microenvironment. Besides MSI, also other prognostic factors have been explored, especially in patients with stage II CRC in which the benefit of adjuvant chemotherapy is limited [ 42 ].

Several gene-expression classifiers for predicting CRC relapse have been described [ 29 , 43 , 44 ] such as for example the ColoPrint, an gene signature [ 29 ], but still they are not yet routinely used in daily clinical practice, mainly because of lack of validation sets, limited number of patients, retrospectively collected patient series and lack of assessment in a large patient data set by multivariable analysis.

In the two recently published studies in Nature Medicine [ 33 , 34 ] using gene expression profiling to classify CRC, the authors also correlated their subgroups with benefit from chemotherapy or targeted agents, such as for example response to irinotecan or resistance to cetuximab. Their findings still have to be validated in larger series, which also accounts for the subgroups as proposed by Budinska et al [ 30 ]. However, what was striking in their analysis was the association with their stromal subtype D and the previously published epithelial-mesenchymal transition signature [ 45 ], which showed the poorest survival and might be resistant to chemotherapy.

Finally, anatomically and embryologically, CRC is also divided into proximal colon cancer right from the splenic flexure , distal colon cancer left from the splenic flexure and rectal cancer. The proximal colon originates from the midgut, while the distal colon and rectum arise from the hindgut.

Using Colon Tumor Genetics to Guide Treatment

Also the nourishing arteries and the innervation differs between left and right colon [ 46 ]. Different genetic abnormalities have been found in CRC from different sites. Recently, at the annual American Society of Clinical Oncology ASCO conference, several abstracts have been presented with differences in biology, prognosis and response to treatment in CRC originating in the left versus right side of the colon. In conclusion, our goal should be to take the molecular background of CRC into account in the future design of clinical trials and to find a consensus in which the different types of CRC can be defined and incorporated in the classification systems such as those of the WHO.

Also, retrospective analysis of published clinical trials may identify drug sensitivity associated with certain subtypes. Hans Prenen is supported by the Leuven University Hospitals Clinical research foundation and received a research grant from the Belgian Foundation against Cancer. The authors have not received funding from any source for the conduct of this review paper.

National Center for Biotechnology Information , U. Journal List Ann Gastroenterol v. Julie Bogaert and Hans Prenen. Author information Article notes Copyright and License information Disclaimer. Received Jul 18; Accepted Jul This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.

This article has been cited by other articles in PMC. Colorectal cancer, molecular pathways, genetics, subtypes. Introduction With more than 1. Hereditary colon cancer Familial adenomatous polyposis FAP FAP is characterized by hundreds to thousands of adenomatous colorectal polyps that develop in the second decade of life.

Peutz-Jeghers syndrome PJS PJS is a very rare autosomal dominant genetic disorder, characterized by multiple hamartomatous polyps of the gastrointestinal tract, most often found in the small intestine. Serrated polyposis syndrome SPS SPS, formerly known as the hyperplastic polyposis syndrome, is a relatively rare syndrome characterized by multiple serrated polyps of the colon. Sporadic colon cancer Thanks to the genetic revolution, major progress has been made in understanding the molecular basis of sporadic colon cancer.