* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Compare and contrast the two major genetic pathways of hereditary
Survey
Document related concepts
Artificial gene synthesis wikipedia , lookup
Population genetics wikipedia , lookup
Site-specific recombinase technology wikipedia , lookup
History of genetic engineering wikipedia , lookup
Medical genetics wikipedia , lookup
Polycomb Group Proteins and Cancer wikipedia , lookup
Epigenetics of neurodegenerative diseases wikipedia , lookup
Public health genomics wikipedia , lookup
Nutriepigenomics wikipedia , lookup
Designer baby wikipedia , lookup
BRCA mutation wikipedia , lookup
Cancer epigenetics wikipedia , lookup
Frameshift mutation wikipedia , lookup
Microevolution wikipedia , lookup
Point mutation wikipedia , lookup
Transcript
Michael G. Woo ELECTRONIC SUBMISSION FOR CONSIDERATION IN THE UNIVERSITY OF TORONTO MEDICAL JOURNAL A Comparison of the Two Major Genetic Pathways of Hereditary Colon Cancer Michael G. Woo1,2* (MSc., PhD. candidate) 1Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada 2Chronic Disease Program, Ottawa Hospital Research Institute, The Ottawa Hospital (Civic Campus), Ottawa, Ontario, Canada *Correspondence to: E-mail: [email protected] UTMJ REVIEW ARTICLE SUBMISSION Page 1 of 13 Michael G. Woo ABSTRACT The lifetime risk of colorectal cancer (CRC) is approximately 5 percent in the general population1-2. However, approximately 20 percent of colorectal cancer occurs in people who have a family history of CRC1, which suggests that there is a heritable basis for this disease. Indeed, a small proportion of these cases are inherited in an autosomal dominant manner, diagnosed as familial adenomatous polyposis (FAP) or nonpolyposis colorectal cancer (HNPCC)3. The identification and cloning of the genes responsible for FAP and HNPCC has allowed for considerable advances in the understanding of cancer genetics. Strategies for patient selection has improved based on family pedigree analysis, the well characterized and well defined sequence of events involved in the various stages of CRC tumour development, and the availability of biopsies for genetic studies. In this review, we will compare and contrast the two major genetic pathways of hereditary colorectal cancer, familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, with respect to the clinical presentation and pathological manifestations. KEYWORDS: hereditary colorectal cancer (CRC), familial adenomatous polyposis (FAP), nonpolyposis colorectal cancer (HNPCC), Lynch syndrome, APC, microsatellite instability (MSI), mismatch-repair (MMR). UTMJ REVIEW ARTICLE SUBMISSION Page 2 of 13 Michael G. Woo INTRODUCTION In Canada, colorectal cancer (CRC) is the third most common cause of cancer by gender. In 2010, it is estimated that 22,500 Canadians will be diagnosed with CRC and 9,100 will die from this disease 4. The onset of CRC typically occurs in individuals over the age of 50 and develops from environmental and genetic factors 5-6. Approximately 5% of CRC are the consequence of highly penetrant germline mutations, resulting in the development of various hereditary colorectal cancer syndromes 7. The two major forms of hereditary colorectal cancer are: (1) familial adenomatous polyposis (FAP) and (2) hereditary nonpolyposis colon cancer (HNPCC or Lynch syndrome). These account for less than 1%, and close to 5% of colorectal cancers respectively 2, 8-9. Although both symptoms are hereditary, they differ in clinical and molecular features. FAP is generally associated with cancer of the distal colon and is a consequence of mutations in the adenomatous polyposis coli (APC) gene 2. Lynch syndrome generally involves cancer development in the proximal colon, with cancer cells arising from microsatellite instability (MSI) and is associated with mutations in the genes involved with DNA mismatch-repair (MMR) 2, 10. The hereditary forms of CRC are prime models of the genetic basis of cancer development. The following review discusses the genetic basis of hereditary CRC with a description of the clinical and pathological manifestations contrasting FAP and HNPCC. UTMJ REVIEW ARTICLE SUBMISSION Page 3 of 13 Michael G. Woo FAMILIAL ADENOMATOUS POLYPOSIS Clinical Features FAP is an autosomal dominant disease affecting an estimated 1 in 15,000 births 11. The most characteristic clinical feature of FAP is the presence of hundreds to thousands of adenomatous polyps spread throughout the colon 2. These polyps typically develop during puberty, and are characterized as polyps of less than 1 cm in size. These can appear pedunculated or sessile, and are histologically characterized as tubular, villous, or tubulovillous 9. If left untreated, these polyps proliferate and degenerate into malignant adenocarcinomas with nearly 100% certainty of the patient developing CRC by the age of 40 to 50 years 3, 9. As a result, surgery is often required to prevent cancer development typically in the form of total proctocolectomy with ileoanal anastomosis and routine screening for polyp recurrence 2. A less aggressive form of this syndrome is called “attenuated familial polyposis (AFAP)” or “adenomatous polyposis coli (AAPC)”. Patients with AFAP develop fewer colonic adenomatous polyps (100 or less) that are smaller and flatter in size than those in FAP 9. As a result, the onset of CRC in these patients occurs at a later age than with classic FAP. In addition to gastrointestinal polyposis, there are several extra-intestinal manifestations associated with FAP 12. One major manifestation is the development of intra-abdominal desmoid tumours that develop as a result of surgical trauma, hormonal exposure and/or mutations to the APC gene 9. Although not malignant, these tumours are locally invasive fibrinous masses that typically localize to the small bowel mesentery. They UTMJ REVIEW ARTICLE SUBMISSION Page 4 of 13 Michael G. Woo cause complications by obstructing the small bowel or ureters, occluding mesenteric blood vessels and larger veins as well as compressing peripheral nerves. As such, desmoids are a significant cause of morbidity and is reported to cause ~21% of deaths of FAP patients 9. As well, approximately 66% of FAP patients will have congenital hypertrophy of the retinal pigment epithelium (CHPRE). CHPRE in FAP is best detected by opthalmoscopy after papillary dilation and appears as multiple lesions (>4) that are bilateral or large 13. Although these lesions do not affect vision or have any malignant potential, CHRPE is a useful predictor of FAP susceptibility and can be detected at birth. Other manifestations include, gastric fundic gland polyps characterized by cystic dilatation and irregular budding, hepatoblastoma, brain tumours, foveolar epithelial dysplasia, supernumerary teeth, and adrenal cortical adenomas 8-9. Thyroid cancer, gastric, duodenal and ampullary adenocarcimonas may also arise in cases affected by FAP 2. Molecular Features In the late 1980s and early 1990s, cytogenetic analysis, linkage and positional cloning studies showed that mutations in the Adenomatous polyposis coli (APC) tumoursuppressor gene underlie FAP 2. Emphasizing its role in the development of CRC, reports also indicate that somatic mutations of APC are important early events in 6080% of sporadic CRC cases 2, 14. UTMJ REVIEW ARTICLE SUBMISSION Page 5 of 13 Michael G. Woo The APC gene, found on human chromosome 5, contains 15 exons and codes for a predicted 310-kDa wild-type APC protein 2. Germline mutations in the APC have been shown to occur throughout the 15 exons, most of which are nonsense mutations causing altered reading frames leading to truncated forms of the APC proteins 12. Alternative splicing of the APC protein affects its stability and activity and has made it possible to accurately characterize the various FAP-associated syndromes based on a genotype–phenotype correlation. For example, classic FAP is characterized by mutations present in codons 169-1,600 but mutations found upstream of codon 158 or downstream of codon 1900 results in an attenuated FAP 12-13. The attenuated variant of FAP is characterized by reduced amount of polyposis attributed to the hypomorphic mutation of the APC gene 12. The APC tumour suppressor protein is involved in the canonical Wnt signaling pathway, where -catenin is the central signaling molecule. This pathway controls cellular proliferation, differentiation and morphogenesis throughout human development and dysregulation of this pathway is a hallmark of many cancers including CRC. APC, along with Axin, glycogen synthase kinase (GSK)-3, and casein kinase I (CKI), are components of a degradation complex that mediates -catenin ubiquitination and turnover 2, 15. Mutations to the APC gene stabilize cytoplasmic -catenin, allowing for its accumulation and translocation to the nucleus resulting in activation of target genes. Aberrant activation of Wnt genes promote tumour growth and invasion (ex. c-myc and cyclinD1) 2. Other genes involved in the tumorigenesis of FAP include Tp53 and KRAS. UTMJ REVIEW ARTICLE SUBMISSION Page 6 of 13 Michael G. Woo HEREDITARY NONPOLYPOSIS COLORECTAL CANCER (HNPCC) Clinical Features Hereditary non-polyposis colorectal cancer is a misnomer as this syndrome predisposes patients to cancer of the colon in addition to cancers of various other organs (such as the endometrium, stomach, ovaries) 12. As well, the term “nonpolyposis” is misleading as adenomatous polyps do indeed develop and can transition to carcinomas 9. As such, the name Lynch syndrome, credited to the oncologist Dr. Henry Lynch, who devoted much of his practice to the treatment of this form of hereditary colorectal cancer, is more appropriate 13. As with FAP, Lynch syndrome is an autosomal dominant disease. It is the most common cause of heritable CRC affecting multiple generations and it accounts for 3-5% of all CRC cases in the US 16. Lynch syndrome is characterized by an early onset of CRC with adenocarcinomas usually present in the proximal colon 3, 8. Diagnosis occurs at 44-48 years of age compared to 63 years in sporadic cases, with a penetrance of ~80% by age 70 17. Other distinguishing features that characterize families affected by this syndrome include the presence of common primary cancers throughout the family pedigree, the development of tumours at an earlier age compared to the norm of that cancer type, the pathological features of disease, and the identification of germline mutations in affected family members 3, 12, 17. In contrast to FAP, multiple adenomas are not present at a young age. However, patients diagnosed with Lynch syndrome develop colorectal and extracolorectal cancers UTMJ REVIEW ARTICLE SUBMISSION Page 7 of 13 Michael G. Woo at an earlier age than the general population 9. The extracolonic malignancies these patients develop include small bowel carcinomas, sebaceous skin tumours, hepatobiliary tumours, brain tumours (glioblastoma rather than medulloblastoma which is found to be common in FAP), and in women, endometrial adenocarcinomas and ovarian carcinomas 13, 17. The presence of tumour-infiltrating lymphocytes (TILs) as well as intraepithelial T-lymphocytes is characteristic of high frequency microsatellite instability (MSI-H), a characteristic phenotype of Lynch syndrome 8, 12. Additional features associated with Lynch syndrome include a variety of poorly differentiated tumours, excess mucoid and signet-cell features as well as a Crohn-like reaction 9. The ambiguity between FAP and Lynch syndrome increases at later stages of cancer development, in regards to their clinical presentation. Therefore accurate diagnosis is dependent on the patient’s clinical presentation and genetic background in combination with family history of cancer. In 1991, the International Collaborative Group on Lynch syndrome developed a set of clinical criteria known as the “Amsterdam Criteria” to identify families at risk for Lynch syndrome. These criteria were specifically designed to diagnose individuals with Lynch Syndrome but failed to include the phenotypic extracolonic features 9. After several modifications and revisions to the Amsterdam Criteria as well as an additional set of guidelines (Bethesda and revised Bethesda) that improved on genetic screening analysis, subtypes of CRC are more accurately diagnosed 2, 18. Molecular Features UTMJ REVIEW ARTICLE SUBMISSION Page 8 of 13 Michael G. Woo In the early 1990s, it was discovered that tumours from HNPCC patients shared a common molecular trait known as microsatellite instability (MSI) 10. Microsatellite instabilities are frameshift mutations in gene sequences that contribute to cancer pathogenesis. MSI can be classified as being of high frequency (MSI-H), low frequency (MSI-L) or stable (MSI-S) based on the number of genetic markers affected (BAT26, BAT25, D5S346, D2S123 and D17S250) 2. If two or more of these markers are unstable, the MSI is considered to be of high frequency, as are 90% of cases suspected to display Lynch syndrome 2, 8. The discovery of MSI as a hallmark of Lynch syndrome quickly led to the identification of a class of genes called mismatch-repair (MMR). MMR genes regulate the cellular machinery that repairs DNA replication abnormalities. The DNA mismatch repair system consists of a protein complex that recognizes and repairs DNA nucleotide base mispairs, and small nucleotide insertions/deletions resulting from DNA replication 19-20. Such a crucial role has qualified MMR deficiency as a mutator phenotype, since mutations in these genes facilitate the multiple genetic hits and high mutation rates in certain cancers 12. Lynch syndrome is characterized by germline mutations in DNA mismatch repair (MMR) genes, of which mutations to MLH1, MSH2 MSH6 are the most prominent17 with a penetrance of 80% for CRC 17. Other MMR genes such as PMS1, PMS2 and MLH3 are less common and will not be discussed further. As MMR heterozygous cells repair DNA normally, the wild-type allele must be knocked out in somatic cells for MMR to be impaired. A second “hit” may occur by deletion, mutation or methylation of CpG islands as seen in the MLH1 promoter 12. UTMJ REVIEW ARTICLE SUBMISSION Page 9 of 13 Michael G. Woo Germline mutations in MSH2 and MLH1 can occur throughout the gene and are typically missense and nonsense mutations leading to inframe deletions and large genomic deletions 12. Mutations in these genes account for >90% of Lynch cases 8-9. Although there are no typical “hot spot” mutations in MLH1, various reports indicate a common A→T transversion mutation in intron 5 of MSH2 resulting in loss of expression 12. In most cases the location of the mutation on the gene appears to have no consequence on the penetrance of the genotype, suggesting that most mutations result in null or loss-of-function. In fact, mutations to either MSH2 or MLH1 show little or no difference in penetrance, suggesting both genes to be equally important in MMR. Mutations in the MSH6 gene account for the additional 5-10% of Lynch syndrome and are associated with an attenuated form of the disease. As with AFAP, this syndrome is characterized by lower penetrance of CRC and a later age of onset 12. Interestingly, similar to FAP, the existence of hypomorphic alleles have been proposed to account for Lynch cases characterized by decreased gene expression with no detectable change in sequence. It is suspected that mutations (yet to be identified) affect introns or control regions deregulating expression and degradation of transcripts12. CONCLUSION FAP and Lynch syndrome are the two major forms of hereditary CRC. UTMJ REVIEW ARTICLE SUBMISSION Page 10 of 13 Michael G. Woo Our understanding of the clinical and genetic manifestations associated with heritable colon cancer has vastly improved over the past two decades and provides a leading model for the study of cancer genetics. The discovery of the molecular pathways specific to FAP (APC gene mutations) and Lynch syndrome (MMR in MSH2 and MLH1) have allowed for increased accuracy in diagnosing each CRC subtype. As well, diagnosis is facilitated by the identification of the various stages of tumour progression that generally follows a well defined sequence of events. Both FAP and Lynch syndrome are characterized by the development of adenomatous polyps to fully invasive and metastatic adenocarcinomas. The combination of germline mutations and sporadic (or somatic) mutations in the APC and MMR-associated tumour suppressor genes underlie a disease that can now be monitored and diagnosed through family pedigree analysis. Although the eventual (preventative) strategy is prophylactic surgery the confirmation of genotype-phenotype analysis by genetic screening will reduce CRCassociated morbidity and mortality by extending the age of required surgical treatment, predicting future family cases and by improving surveillance of cancer development. CONFLICTS OF INTEREST There are no conflicts of interest associated with the preparation of this manuscript. UTMJ REVIEW ARTICLE SUBMISSION Page 11 of 13 Michael G. Woo REFERENCES 1. Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002. CA Cancer J Clin 2002;52:23-47. 2. Rustgi AK. The genetics of hereditary colon cancer. Genes Dev 2007;21:2525-38. 3. Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med 2003;348:919-32. 4. Canadian Cancer Society's Steering Committee: Canadian Cancer Statistics 2010. Toronto: Canadian Cancer Society, 2010. Toronto, Canada; 2010. Report No.: April 2008, ISSN 0835-2976. 5. Shields PG, Harris CC. Cancer risk and low-penetrance susceptibility genes in gene-environment interactions. J Clin Oncol 2000;18:2309-15. 6. Ahmed FE. Gene-gene, gene-environment & multiple interactions in colorectal cancer. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 2006;24:1-101. 7. Grady WM. Genetic testing for high-risk colon cancer patients. Gastroenterology 2003;124:1574-94. 8. Gatalica Z, Torlakovic E. Pathology of the hereditary colorectal carcinoma. Fam Cancer 2008;7:15-26. 9. Al-Sukhni W, Aronson M, Gallinger S. Hereditary colorectal cancer syndromes: familial adenomatous polyposis and lynch syndrome. Surg Clin North Am 2008;88:819-44, vii. 10. Powell SM, Zilz N, Beazer-Barclay Y, et al. APC mutations occur early during colorectal tumorigenesis. Nature 1992;359:235-7. 11. Gryfe R. Clinical implications of our advancing knowledge of colorectal cancer genetics: inherited syndromes, prognosis, prevention, screening and therapeutics. Surg Clin North Am 2006;86:787-817. 12. de la Chapelle A. Genetic predisposition to colorectal cancer. Nat Rev Cancer 2004;4:769-80. 13. Terdiman JP, Conrad PG, Sleisenger MH. Genetic testing in hereditary colorectal cancer: indications and procedures. Am J Gastroenterol 1999;94:2344-56. 14. Narayan S, Roy D. Role of APC and DNA mismatch repair genes in the development of colorectal cancers. Mol Cancer 2003;2:41. 15. Caspi M, Zilberberg A, Eldar-Finkelman H, Rosin-Arbesfeld R. Nuclear GSK-3beta inhibits the canonical Wnt signalling pathway in a beta-catenin phosphorylation-independent manner. Oncogene 2008;27:3546-55. 16. Samowitz WS, Curtin K, Lin HH, et al. The colon cancer burden of genetically defined hereditary nonpolyposis colon cancer. Gastroenterology 2001;121:830-8. UTMJ REVIEW ARTICLE SUBMISSION Page 12 of 13 Michael G. Woo 17. Grady WM. Molecular basis for subdividing hereditary colon cancer? Gut 2005;54:1676-8. 18. Umar A, Risinger JI, Hawk ET, Barrett JC. Testing guidelines for hereditary non-polyposis colorectal cancer. Nat Rev Cancer 2004;4:153-8. 19. Rhyu MS. Molecular mechanisms underlying hereditary nonpolyposis colorectal carcinoma. J Natl Cancer Inst 1996;88:240-51. 20. Chung DC, Rustgi AK. DNA mismatch repair and cancer. Gastroenterology 1995;109:1685-99. UTMJ REVIEW ARTICLE SUBMISSION Page 13 of 13