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Finding relationships among biological entities. LOGIC AND CRITICAL THINKING IN THE BIOMEDICAL SCIENCES 2020. [PMCID: PMC7499094 DOI: 10.1016/b978-0-12-821364-3.00005-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Confusion over the concepts of “relationships” and “similarities” lies at the heart of many battles over the direction and intent of research projects. Here is a short story that demonstrates the difference between the two concepts: You look up at the clouds, and you begin to see the shape of a lion. The cloud has a tail, like a lion’s tale, and a fluffy head, like a lion’s mane. With a little imagination the mouth of the lion seems to roar down from the sky. You have succeeded in finding similarities between the cloud and a lion. If you look at a cloud and you imagine a tea kettle producing a head of steam and you recognize that the physical forces that create a cloud and the physical forces that produced steam from a heated kettle are the same, then you have found a relationship. Most popular classification algorithms operate by grouping together data objects that have similar properties or values. In so doing, they may miss finding the true relationships among objects. Traditionally, relationships among data objects are discovered by an intellectual process. In this chapter, we will discuss the scientific gains that come when we classify biological entities by relationships, not by their similarities.
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Cavazza A, Radia C, Harlow C, Monahan KJ. Experience of the implementation and outcomes of universal testing for Lynch syndrome in the United Kingdom. Colorectal Dis 2019; 21:760-766. [PMID: 30815953 DOI: 10.1111/codi.14597] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Accepted: 02/07/2019] [Indexed: 12/12/2022]
Abstract
AIM Colorectal cancer (CRC) is diagnosed in approximately 45 000 people annually in the UK, and it is estimated that Lynch syndrome (LS) accounts for 3.1% of these cases. In February 2017, National Institute for Health and Care Excellence (NICE guideline DG27 recommended universal testing of new cases of CRC for mismatch repair (MMR) status. The aim of this study was to implement universal testing for LS in CRC patients in a secondary care setting. METHOD We prospectively collected data on consecutive newly diagnosed CRC patients at our centre from November 2016 to August 2018, including evidence of MMR status determined by immunohistochemistry. We recorded clinicopathological data including age at diagnosis, stage, tumour site, reported histological findings and MMR tumour status. Statistical analysis was performed using the chi-square test and the two-tailed t-test for binary and continuous variables, respectively. RESULTS A cohort of 203 consecutive patients were diagnosed with CRC during this period. Universal MMR testing was performed for the 198 CRC patients in whom a diagnosis of adenocarcinoma was confirmed, with colonoscopic biopsy used as the source material in 68.6% of cases. Twenty-three CRCs (11.6%) were MMR deficient (dMMR). Most dMMR CRCs (21/23) were early stage tumours (Dukes A or B, P = 0.002). In 39 Dukes B CRCs in patients under 70 years of age, the result of MMR testing influenced decision-making about personalized treatment with 5-fluorouracil based chemotherapy. CONCLUSION Our results demonstrate that universal testing of all new cases of CRC for features suggestive of LS is feasible and effective in the UK. Our data also indicate the importance of genetic testing and personalized oncological care.
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Affiliation(s)
- A Cavazza
- Imperial College London and The Family History of Bowel Cancer Clinic, Department of Gastroenterology, West Middlesex University Hospital, Chelsea and Westminster Hospitals NHS Trust, London, UK
| | - C Radia
- Imperial College London and The Family History of Bowel Cancer Clinic, Department of Gastroenterology, West Middlesex University Hospital, Chelsea and Westminster Hospitals NHS Trust, London, UK
| | - C Harlow
- Imperial College London and The Family History of Bowel Cancer Clinic, Department of Gastroenterology, West Middlesex University Hospital, Chelsea and Westminster Hospitals NHS Trust, London, UK
| | - K J Monahan
- Imperial College London and The Family History of Bowel Cancer Clinic, Department of Gastroenterology, West Middlesex University Hospital, Chelsea and Westminster Hospitals NHS Trust, London, UK
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Abstract
Starting from a survey of the studies on familial aggregation of colorectal cancer, we introduce the aims of genetic epidemiology. One of its main goals is to assess population frequency of cancer susceptibility genes and to determine the age-specific risks for carriers with respect to non-carriers. In section two, segregation analysis investigations are reviewed, and inferences on the relevance of genetic components of susceptibility to colorectal cancer are drawn. In section three, the HNPCC paradigm is discussed in the light of the Knudson model of tumorigenesis and recent advances of molecular research. In the last section we show an example of genotype/environment interaction in the etiology of a particular cancer and present a conceptual framework for studies on cancer genetic epidemiology in terms of attributable and relative risk.
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Affiliation(s)
- S Presciuttini
- Dipartimento di Scienze dell'Ambiente e del Territorio, Pisa, Italy
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Cornaggia M, Tibiletti MG, Albarello L, Taborelli M, Dalla Longa E, Capella C. Low Incidence of Hereditary Nonpolyposis Colorectal Cancer Syndrome in a Selected Area of the Lombardy Cancer Registry. TUMORI JOURNAL 2018; 86:439-44. [PMID: 11218182 DOI: 10.1177/030089160008600601] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Aims and background Epidemiological investigations on the frequency of hereditary nonpolyposis colorectal cancer (HNPCC) syndrome are few and have shown a variable worldwide incidence ranging from 1% to 7% of all colorectal cancers (CRCs). In Italy, relevant differences have been observed: 2.8-3% of all CRCs in northern regions and less than 1% in southern regions. The aim of the present study was to investigate the HNPCC incidence in a selected area of northern Italy belonging to the Lombardy Cancer Registry. Methods and study design We analyzed 197 consecutive patients with newly diagnosed CRCs, histologically verified, and resident in two areas of the Lombardy Cancer Registry. For each case, genetic counseling with at least three generations pedigree reconstruction, HNPCC classification according to Amsterdam criteria, molecular analysis for microsatellite instability and immunohistochemistry for hMLH1 and hMSH2 were performed. Results A very low frequency (0.5%) of HNPCC fulfilling the Amsterdam criteria was found in comparison to the other Italian areas. Such an incidence seems to be due to actual population differences and reflects a genetic heterogeneity. Conclusions The data underline the importance of a precise knowledge of actual HNPCC incidence in different populations in order to optimize effectiveness and efficiency of screening programs for the disease.
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Affiliation(s)
- M Cornaggia
- Department of Pathology, Ospedale Multizonale Varese, Italy
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Protein disulfide isomerase A3-specific Th1 effector cells infiltrate colon cancer tissue of patients with circulating anti-protein disulfide isomerase A3 autoantibodies. Transl Res 2016; 171:17-28.e1-2. [PMID: 26772958 DOI: 10.1016/j.trsl.2015.12.013] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 12/17/2015] [Accepted: 12/18/2015] [Indexed: 01/27/2023]
Abstract
To investigate novel colorectal cancer (CRC)-associated antigens that could be targets of humoral or cellular responses, we analyzed the reactivity of serum from a long-surviving CRC patient (for more than 100 months of follow-up) in clinical remission, by serologic proteome analysis. Two-dimensional Western blotting (2D-WB) and mass spectrometry analysis revealed a strong reactivity of this serum against protein disulfide isomerase A3 (PDIA3). Anti-PDIA3 antibodies are not a diagnostic marker of CRC, 2D-WB and Luminex analysis revealed that they were equally present in about 10% of sera from healthy subjects and CRC patients. Kaplan-Meier analysis of survival in CRC patient cohort, after 48 months of follow-up, showed a trend of higher survival in patients with increased levels of autoantibodies to PDIA3. Therefore, the interplay between the presence of these antibodies and T-cell response was investigated. Peripheral blood T cells from CRC patients with high immunoglobulin G (IgG) reactivity to PDIA3 also secreted interferon gamma (IFN-γ) when stimulated in vitro with recombinant PDIA3, whereas those from CRC with low IgG reactivity to PDIA3 did not. PDIA3-pulsed dendritic cells efficiently induced proliferation and IFN-γ production of autologous CD4(+) and CD8(+) T cells. Finally, ex vivo analysis of tumor-infiltrating T lymphocytes from CRC patients with autoantibodies to PDIA3 revealed that PDIA3-specific Th1 effector cells accumulated in tumor tissue. These data indicate that the presence of autoantibodies to PDIA3 favors the development of an efficient and specific T-cell response against PDIA3 in CRC patients. These results may be relevant for the design of novel immunotherapeutic strategies in CRC patients.
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Kumamoto K, Ishida H, Suzuki O, Tajima Y, Chika N, Kuwabara K, Ishibashi K, Saito K, Nagata K, Eguchi H, Tamaru J, Iwama T. Lower prevalence of Lynch syndrome in colorectal cancer patients in a Japanese hospital-based population. Surg Today 2015; 46:713-20. [PMID: 26249337 DOI: 10.1007/s00595-015-1232-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 07/21/2015] [Indexed: 12/27/2022]
Abstract
PURPOSE The aim of this study was to investigate the prevalence of Lynch syndrome among Japanese patients with surgically resected colorectal cancer at a single institution. METHODS Of 616 colorectal cancer patients who underwent surgical operation in our institution from January 2005 to August 2010, immunohistochemistry analyses for mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) and microsatellite instability (MSI) testing for surgically resected, formalin-fixed paraffin-embedded colorectal cancer specimens from 138 colorectal cancer patients under 60 years of age were undertaken. Hypermethylation of the MLH1 promoter and BRAF mutation were analyzed where necessary. RESULTS Seven patients were identified as candidates for genetic testing by mismatch repair protein loss (n = 7) or MSI-H (n = 6). Methylation of MLH1 was detected in one case. Three patients were diagnosed with Lynch syndrome, comprising 2.2 % of the total colorectal cancer patients younger than 60 years of age. CONCLUSION The prevalence of Lynch syndrome among hospital-based diagnosed cancer patients may therefore be lower than expected in Japan compared with Western populations.
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Affiliation(s)
- Kensuke Kumamoto
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, 350-8550, Japan.
- Department of Organ Regulatory Surgery, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan.
| | - Hideyuki Ishida
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, 350-8550, Japan
| | - Okihide Suzuki
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, 350-8550, Japan
| | - Yusuke Tajima
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, 350-8550, Japan
| | - Noriyasu Chika
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, 350-8550, Japan
| | - Koki Kuwabara
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, 350-8550, Japan
| | - Keiichiro Ishibashi
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, 350-8550, Japan
| | - Katsuharu Saito
- Department of Organ Regulatory Surgery, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan
| | - Koji Nagata
- Department of Pathology, Saitama International Medical Center, Saitama Medical University, Saitama, 350-1298, Japan
| | - Hidetaka Eguchi
- Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Saitama, 350-1241, Japan
| | - Junichi Tamaru
- Department of Pathology, Saitama Medical Center, Saitama Medical University, Saitama, 350-8550, Japan
| | - Takeo Iwama
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, 350-8550, Japan
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SUN HUILING, PAN YUQIN, HE BANGSHUN, DENG QIWEN, LI RUI, XU YEQIONG, CHEN JIE, GAO TIANYI, YING HOUQUN, WANG FENG, LIU XIAN, WANG SHUKUI. Gene therapy for human colorectal cancer cell lines with recombinant adenovirus 5 based on loss of the insulin-like growth factor 2 imprinting. Int J Oncol 2015; 46:1759-67. [DOI: 10.3892/ijo.2015.2852] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 12/29/2014] [Indexed: 11/06/2022] Open
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Serrated polyposis is an underdiagnosed and unclear syndrome: the surgical pathologist has a role in improving detection. Am J Surg Pathol 2012; 36:1178-85. [PMID: 22790859 DOI: 10.1097/pas.0b013e3182597f41] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Serrated polyposis syndrome (SPS) is poorly defined and patients have an increased but unspecified risk for colorectal carcinoma through the serrated pathway. Despite this association SPS remains relatively obscure and is therefore likely underrecognized. We determined the frequency of SPS among patients with any serrated polyps (SPs) over a 6-month "index" period, and in doing so we assessed the ability of surgical pathologists to improve SPS detection. Particular attention was given to the index procedure to assess the potential predictive value of the findings resulting from a single colonoscopy. A total of 929 patients with at least 1 SP were identified, 17 of whom (1.8%) were determined to meet World Health Organization criteria for SPS. Nine patients met the first criterion (≥ 5 proximal SPs, 2 of which are > 10 mm); 4 met the third criterion (> 20 SPs of any size distributed throughout the colon); and 4 met both criteria. Although no specific SP size or number at the index procedure was clearly superior in its ability to predict SPS, > 50% of cases would be detected if a cutoff of ≥ 3 SPs or a single SP ≥ 15 mm at the index procedure is used. In summary, SPS is rare but more likely underdiagnosed. Additional studies to address the underlying genetic basis for SPS are ongoing in order to shed further light on this syndrome. Surgical pathologists are in a unique position to assist in this endeavor by identifying those patients who either meet or seem to be at high risk of meeting World Health Organization criteria.
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Scholtka B, Schneider M, Melcher R, Katzenberger T, Friedrich D, Berghof-Jäger K, Scheppach W, Steinberg P. A gene marker panel covering the Wnt and the Ras-Raf-MEK-MAPK signalling pathways allows to detect gene mutations in 80% of early (UICC I) colon cancer stages in humans. Cancer Epidemiol 2009; 33:123-9. [DOI: 10.1016/j.canep.2009.05.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2008] [Revised: 05/04/2009] [Accepted: 05/05/2009] [Indexed: 02/06/2023]
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Niessen RC, Sijmons RH, Berends MJW, Ou J, Hofstra RMW, Kleibeuker JH. Hereditary non-polyposis colorectal cancer: identification of mutation carriers and assessing pathogenicity of mutations. Scand J Gastroenterol 2009:70-7. [PMID: 15696853 DOI: 10.1080/00855920410010915] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/01/2023]
Abstract
Hereditary non-polyposis colorectal cancer (HNPCC), also referred to as Lynch syndrome, is an autosomal dominantly inherited disorder that is characterized by susceptibility to colorectal cancer and extracolonic malignancies, in particular endometrial cancer. HNPCC is caused by pathogenic mutations in the mismatch repair (MMR) genes, which play an important role in maintaining genomic stability during DNA replication. Identification of MMR gene mutation carriers is important as this enables them to enrol in surveillance programmes, thus reducing their risk of cancer and increasing survival. Clinical criteria as well as non-clinical criteria have been formulated to select patients for mutation analysis. In this paper we review the approaches used to select patients for mutation analysis. Mutation analysis in the MMR genes may yield mutations of which the pathogenic nature is unclear. Criteria to determine the pathogenicity of such variants are discussed, as well as differences in design of functional assays to assess pathogenicity.
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Affiliation(s)
- R C Niessen
- Dept. of Clinical Genetics, University Hospital Groningen, Groningen, The Netherlands
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Cleary SP, Cotterchio M, Jenkins MA, Kim H, Bristow R, Green R, Haile R, Hopper JL, LeMarchand L, Lindor N, Parfrey P, Potter J, Younghusband B, Gallinger S. Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study. Gastroenterology 2009; 136:1251-60. [PMID: 19245865 PMCID: PMC2739726 DOI: 10.1053/j.gastro.2008.12.050] [Citation(s) in RCA: 171] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2008] [Revised: 11/25/2008] [Accepted: 12/18/2008] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The MutY human homologue (MYH) gene is a member of the base-excision repair pathway involved in the repair of oxidative DNA damage. The objective of this study was to determine colorectal cancer (CRC) risk associated with mutations in the MYH gene. METHODS A total of 3811 CRC cases and 2802 controls collected from a multisite CRC registry were screened for 9 germline MYH mutations; subjects with any mutation underwent screening of the entire MYH gene. Logistic regression was used to estimate age- and sex-adjusted odds ratios (AOR). Clinicopathologic and epidemiologic data were reviewed to describe the phenotype associated with MYH mutation status and assess for potential confounding and effect modification. RESULTS Twenty-seven cases and 1 control subject carried homozygous or compound heterozygous MYH mutations (AOR, 18.1; 95% confidence interval, 2.5-132.7). CRC cases with homozygous/compound heterozygous mutations were younger at diagnosis (P=.01), had a higher proportion of right-sided (P=.01), synchronous cancers (P<.01), and personal history of adenomatous polyps (P=.003). Heterozygous MYH mutations were identified in 87 CRC cases and 43 controls; carriers were at increased risk of CRC (AOR, 1.48; 95% confidence interval, 1.02-2.16). There was a higher prevalence of low-frequency microsatellite instability (MSI) in tumors from heterozygous and homozygous/compound heterozygous MYH mutation carriers (P=.02); MSI status modified the CRC risk associated with heterozygous MYH mutations (P interaction<.001). CONCLUSIONS Homozygous/compound heterozygous MYH mutations account for less than 1% of CRC cases. Heterozygous carriers are at increased risk of CRC. Further studies are needed to understand the possible interaction between the base excision repair and low-frequency MSI pathways.
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Affiliation(s)
- Sean P. Cleary
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada,Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada,Cancer Care Ontario, Toronto, Ontario, Canada
| | - Michelle Cotterchio
- Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada,Cancer Care Ontario, Toronto, Ontario, Canada
| | - Mark A. Jenkins
- Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Victoria, Australia
| | - Hyeja Kim
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Robert Bristow
- Radiation Medicine Program and Department of Radiation Oncology, Princess Margaret Hospital (UHN), University of Toronto, Toronto, Ontario, Canada
| | - Roger Green
- Memorial University of Newfoundland, St John’s, Newfoundland, Canada
| | - Robert Haile
- University of Southern California, Los Angeles, California
| | - John L. Hopper
- Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Victoria, Australia
| | | | | | - Patrick Parfrey
- Memorial University of Newfoundland, St John’s, Newfoundland, Canada
| | - John Potter
- Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Ban Younghusband
- Memorial University of Newfoundland, St John’s, Newfoundland, Canada
| | - Steven Gallinger
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada,Cancer Care Ontario, Toronto, Ontario, Canada
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High risk of endometrial cancer in colorectal cancer kindred is pathognomonic for MMR-mutation carriers. Fam Cancer 2008; 8:145-51. [DOI: 10.1007/s10689-008-9219-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2007] [Accepted: 09/16/2008] [Indexed: 11/26/2022]
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Missense polymorphisms in the adenomatous polyposis coli gene and colorectal cancer risk. Dis Colon Rectum 2008; 51:1467-73; discussion 1473-4. [PMID: 18612690 PMCID: PMC2768068 DOI: 10.1007/s10350-008-9356-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2007] [Revised: 06/28/2007] [Accepted: 08/16/2007] [Indexed: 02/08/2023]
Abstract
PURPOSE Whereas truncating germline mutations of the adenomatous polyposis coli (APC) gene give rise to familial adenomatous polyposis, missense polymorphisms of APC may confer a weaker risk for colorectal cancer. METHODS We sequenced the entire open reading frame of the APC gene and tested for two common MYH mutations in a population-based series of patients with colorectal cancer and 5 to 99 adenomas. Missense adenomatous polyposis coli alterations identified in this colorectal cancer multiple-polyp population were analyzed in a population-based series of patients with colorectal cancer and healthy control subjects. RESULTS Germline APC or mutY human homologue (MYH) alterations were identified in 16 of 39 colorectal cancer-multiple polyp patients. Four missense APC gene alterations (S130G, E1317Q, D1822V, G2502S) were observed in 13 individuals and 3 additional patients carried presumed pathogenic (APC Y94X, biallelic MYH Y165C and heterozygous MYH G382D) mutations. When independently assessed in 971 patients with colorectal cancer and 954 healthy control subjects, none of the identified missense APC alterations conferred a significantly increased risk for colorectal cancer, odds ratio (95 percent confidence intervals): S130G = 3.1 (0.29-32.25), E1317Q = 1.08 (0.59-2.74), G2502S = 1 (0.65-1.63), D1822V (heterozygous) = 0.79 (0.64-0.98), D1822V (homozygous) = 0.82 (0.63-1.27). CONCLUSIONS Germline missense APC alterations observed in 33 percent of patients with multiple colorectal neoplasms seemed to play a limited role in colorectal cancer risk when independently assessed by a population-based, case-control analysis.
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Picelli S, Vandrovcova J, Jones S, Djureinovic T, Skoglund J, Zhou XL, Velculescu VE, Vogelstein B, Lindblom A. Genome-wide linkage scan for colorectal cancer susceptibility genes supports linkage to chromosome 3q. BMC Cancer 2008; 8:87. [PMID: 18380902 PMCID: PMC2324103 DOI: 10.1186/1471-2407-8-87] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2007] [Accepted: 04/01/2008] [Indexed: 12/26/2022] Open
Abstract
Background Colorectal cancer is one of the most common causes of cancer-related mortality. The disease is clinically and genetically heterogeneous though a strong hereditary component has been identified. However, only a small proportion of the inherited susceptibility can be ascribed to dominant syndromes, such as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Familial Adenomatous Polyposis (FAP). In an attempt to identify novel colorectal cancer predisposing genes, we have performed a genome-wide linkage analysis in 30 Swedish non-FAP/non-HNPCC families with a strong family history of colorectal cancer. Methods Statistical analysis was performed using multipoint parametric and nonparametric linkage. Results Parametric analysis under the assumption of locus homogeneity excluded any common susceptibility regions harbouring a predisposing gene for colorectal cancer. However, several loci on chromosomes 2q, 3q, 6q, and 7q with suggestive linkage were detected in the parametric analysis under the assumption of locus heterogeneity as well as in the nonparametric analysis. Among these loci, the locus on chromosome 3q21.1-q26.2 was the most consistent finding providing positive results in both parametric and nonparametric analyses Heterogeneity LOD score (HLOD) = 1.90, alpha = 0.45, Non-Parametric LOD score (NPL) = 2.1). Conclusion The strongest evidence of linkage was seen for the region on chromosome 3. Interestingly, the same region has recently been reported as the most significant finding in a genome-wide analysis performed with SNP arrays; thus our results independently support the finding on chromosome 3q.
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Affiliation(s)
- Simone Picelli
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
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Küry S, Buecher B, Robiou-Du-Pont S, Scoul C, Colman H, Lelièvre B, Olschwang S, Houérou CL, Neel TL, Faroux R, Ollivry J, Lafraise B, Chupin LD, Bézieau S. The Thorough Screening of the MUTYH Gene in a Large French Cohort of Sporadic Colorectal Cancers. ACTA ACUST UNITED AC 2007; 11:373-9. [DOI: 10.1089/gte.2007.0029] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- Sébastien Küry
- Laboratoire d'Etude de l'ADN, Faculté de Médecine de Nantes, 44035 France
- Institut des Maladies de l'Appareil Digestif et CIC INSERM, Centre Hospitalier Universitaire de Nantes 44093, France
| | - Bruno Buecher
- Institut des Maladies de l'Appareil Digestif et CIC INSERM, Centre Hospitalier Universitaire de Nantes 44093, France
- Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire de Nantes 44093, France
| | - Sébastien Robiou-Du-Pont
- Laboratoire d'Etude de l'ADN, Faculté de Médecine de Nantes, 44035 France
- Institut des Maladies de l'Appareil Digestif et CIC INSERM, Centre Hospitalier Universitaire de Nantes 44093, France
| | - Catherine Scoul
- Laboratoire d'Etude de l'ADN, Faculté de Médecine de Nantes, 44035 France
- Institut des Maladies de l'Appareil Digestif et CIC INSERM, Centre Hospitalier Universitaire de Nantes 44093, France
| | - Hélène Colman
- Laboratoire d'Etude de l'ADN, Faculté de Médecine de Nantes, 44035 France
- Institut des Maladies de l'Appareil Digestif et CIC INSERM, Centre Hospitalier Universitaire de Nantes 44093, France
| | - Bénédicte Lelièvre
- Laboratoire d'Etude de l'ADN, Faculté de Médecine de Nantes, 44035 France
- Institut des Maladies de l'Appareil Digestif et CIC INSERM, Centre Hospitalier Universitaire de Nantes 44093, France
| | - Sylviane Olschwang
- Département d'Oncologie Génétique, Prévention et Dépistage, Institut Paoli-Calmettes, Marseille 13273, France
| | - Claire Le Houérou
- Institut des Maladies de l'Appareil Digestif et CIC INSERM, Centre Hospitalier Universitaire de Nantes 44093, France
| | - Tanguy Le Neel
- Laboratoire d'Etude de l'ADN, Faculté de Médecine de Nantes, 44035 France
- Biofortis, Nantes 44200, France
| | - Roger Faroux
- Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire de la Roche-Sur-Yon, 85000 France
| | - Jean Ollivry
- Association des Gastroentérologues de Vendée, 85300 Challans, France
| | | | | | - Stéphane Bézieau
- Laboratoire d'Etude de l'ADN, Faculté de Médecine de Nantes, 44035 France
- Institut des Maladies de l'Appareil Digestif et CIC INSERM, Centre Hospitalier Universitaire de Nantes 44093, France
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Dundar M, Caglayan AO, Saatci C, Karaca H, Baskol M, Tahiri S, Ozkul Y. How the I1307K adenomatous polyposis coli gene variant contributes in the assessment of risk of colorectal cancer, but not stomach cancer, in a Turkish population. ACTA ACUST UNITED AC 2007; 177:95-7. [PMID: 17854661 DOI: 10.1016/j.cancergencyto.2007.05.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2007] [Revised: 04/25/2007] [Accepted: 05/10/2007] [Indexed: 11/20/2022]
Abstract
Germline and somatic truncating mutations of the adenomatous polyposis coli gene (APC) are thought to initiate colorectal tumor formation in familial adenomatous polyposis syndrome and sporadic colorectal carcinogenesis, respectively. Recently, an isoleucine-lysine polymorphism at codon 1307 (I1307K) of the APC gene has been identified in 6-7% of the Ashkenazi Jewish population. To assess the risk of this common APC allelic variant in colorectal carcinogenesis, a cohort of unselected Turkish subjects with stomach or colorectal cancer (or both) was analyzed for the APC I1307K polymorphism. Genomic DNA was extracted from patients by obtaining all stomach and colon malign polipose tissues using nuclei lysis methods. Detection of the I1307K mutation was performed using the commercial Pronto APC kit according to the manufacturer's instructions. The APC I1307K allele was identified in 7 of 57 stomach carcinoma patients (12.3%; P > 0.05) and 30 of 56 colon carcinoma patients (53.6%; P < 0.05) using antigen-anticor interaction methods. Comparing the frequencies of the two separate population control groups, the APC I1307K allele is associated with an estimated relative risk of 1.9 for colorectal neoplasia. Furthermore, APC I1307K carriers had greater numbers of adenomas and colorectal cancers per patient than noncarriers. The conclusion is that the APC I1307K variant leads to increased adenoma formation and colorectal cancer. The estimated relative risk for carriers may justify specific clinical screening for Turkish people expected to harbor this allele, and genetic testing in the long term may significantly promote colorectal cancer prevention in this population.
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Affiliation(s)
- Munis Dundar
- Department of Medical Genetics, Medical Faculty, Erciyes University, Talas Caddesi, 38039, Kayseri, Turkey.
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Young J, Jass JR. The case for a genetic predisposition to serrated neoplasia in the colorectum: hypothesis and review of the literature. Cancer Epidemiol Biomarkers Prev 2007; 15:1778-84. [PMID: 17035382 DOI: 10.1158/1055-9965.epi-06-0164] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
In recent years, an alternative pathway of colorectal cancer development has been described in which serrated polyps replace the traditional adenoma as the precursor lesion. Importantly, serrated polyps and a subset of colorectal cancer show largely nonoverlapping mutation profiles to those found in adenomas and the majority of colorectal cancer. These genetic alterations include activating mutation of the BRAF proto-oncogene and widespread gene promoter hypermethylation (CpG island methylator phenotype or CIMP). Up to 15% of colorectal cancer is likely to develop on the basis of a strong genetic predisposition. The two most well-characterized syndromes, familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer (Lynch syndrome), both develop via the adenoma-carcinoma pathway and together account for approximately one third of familial colorectal cancer. We have recently described 11 families in which there is evidence that the genetic predisposition to autosomal dominant colorectal cancer is linked to the serrated pathway. This condition, serrated pathway syndrome, and the related condition, hyperplastic polyposis, the presentation of which suggests a recessive mode of inheritance, represent two syndromes in which BRAF mutation and methylation co-occur within serrated precursor lesions. Further, CIMP is observed in the normal colonic mucosa of individuals with hyperplastic polyposis consistent with a field defect in epigenetic regulation. The spectrum of serrated neoplasia may also implicate the apparently sporadic and later onset subset of colorectal cancer with high levels of microsatellite instability. The tendency for these lesions to be multiple, associated with smoking, and to show frequent BRAF mutation and CIMP points to a defect that may result from interactions between the environment and a weakly penetrant genetic alteration.
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Affiliation(s)
- Joanne Young
- Molecular Cancer Epidemiology Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, Queensland 4006, Australia.
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Stormorken AT, Clark N, Grindedal E, Maehle L, Møller P. Prevention of colorectal cancer by colonoscopic surveillance in families with hereditary colorectal cancer. Scand J Gastroenterol 2007; 42:611-7. [PMID: 17454882 DOI: 10.1080/00365520601010230] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE In recent years persons at risk for colorectal cancers (CRC) have been subjected to follow-up with colonoscopy in many centres. There is, however, limited knowledge about the effect of such interventions. The objective of this study was to report the results of our observations during the past 15 years. MATERIAL AND METHODS Healthy persons were included in the study according to their family history of CRCs, and prospectively followed with colonoscopies. RESULTS Altogether, 1133 individuals were included and observed for a total of 3474 follow-up years from the first to the last colonoscopy initiated by our activity. Mismatch repair (MMR) mutations were detected in 6.5% of cases. A total of 1383 polyps were removed, 72% were less than 5 mm in diameter. Findings were scored as hyperplastic polyps (n=887), adenomas with mild to moderate dysplasia (n=460), adenomas with high-grade dysplasia (n=30) and cancers (n=6). Two cancers were observed after the first colonoscopy, compared with 2.6 expected by chance and more than 20 expected under the hypothesis of predominant inherited diseases in the families. Observed annual incidence rates for adenomas were similar in all groups, while in the mutation carriers there was a higher frequency of progression to severe dysplasia or infiltrating cancer. CONCLUSIONS A simple explanation for the combined findings may be that all selected families had a similar tendency to produce adenomas, while mutation carriers more frequently demonstrated dysplasia/cancer in the adenomas. The low annual incidence rates for CRC indicated that the removal of adenomas may have prevented cancers.
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Affiliation(s)
- Astrid T Stormorken
- Section of Genetic Counselling, Department of Cancer Genetics, Rikshospitalet-Radiumhospitalet Medical Centre, Oslo, Norway
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Brinkman H, Barwell J, Rose S, Tinworth L, Sodha N, Langman C, Brooks L, Payne S, Fisher S, Rowan A, Tomlinson I, Hodgson S. Evidence against a major genetic basis for combined breast and colorectal cancer susceptibility. Clin Genet 2007; 70:526-9. [PMID: 17100999 DOI: 10.1111/j.1399-0004.2006.00711.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Abstract
Cancer affects more people than any other disease. About one-third of the world's population is likely to get this diagnosis during their lifetime. Currently, the diagnostic methods for cancer detection are based on visual inspection. The lack of high analytical and clinical specificity and sensitivity makes these methods in many cases inferior to recently developed molecular methods. The increased clinical specificity and sensitivity of these new molecular approaches have great benefits, such as the possibility of implementing the molecular methods in miniaturized systems and enabling easier and faster point-of-care or bedside diagnostics. This chapter provides an introduction to performing clinical trials, screening, and molecular diagnostics against cancer-related markers. In addition, an example of molecular diagnosis of cervical cancer within a microsystem concept will be presented.
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Kemp ZE, Carvajal-Carmona LG, Barclay E, Gorman M, Martin L, Wood W, Rowan A, Donohue C, Spain S, Jaeger E, Evans DG, Maher ER, Bishop T, Thomas H, Houlston R, Tomlinson I. Evidence of linkage to chromosome 9q22.33 in colorectal cancer kindreds from the United Kingdom. Cancer Res 2006; 66:5003-6. [PMID: 16707420 DOI: 10.1158/0008-5472.can-05-4074] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
About 30% of all colorectal cancers are thought to have a genetic basis and the known predisposing genes can only account for a small fraction of cases. A previous report suggested that a colorectal cancer candidate gene, explaining at least 20% of colorectal cancer cases with family history, was located within a 25 cM region on chromosome 9q22.2-q31.3. We typed 16 polymorphic markers encompassing the region of putative linkage in 57 colorectal tumor families from the United Kingdom. Known Mendelian syndromes had been excluded. We found suggestive evidence of linkage, as positive parametric (HLOD = 1.23) and nonparametric (NPL = 1.21, P = 0.11) LOD scores were obtained by analysis of the whole family set. Enrichment for cases with a priori genetic etiology by analyzing families with at least one person affected at <45 years of age (n = 39 families) gave a maximum multipoint NPL score of 2.65 (P = 0.007). In this group, significant NPL scores >1.67 (P < 0.05) were found in a 6.5 cM region between D9S1851 and D9S277. With a more stringent threshold (NPL>2.4, P < 0.01), the linked region was 1.7 cM between D9S971 and D9S272/D9S173. Exclusion from the analysis of kindreds with a phenotype of multiple polyposis also found evidence of linkage in the same region (NPL = 2.47 at close to D9S277, P = 0.009). The type I transforming growth factor-beta receptor, a prime candidate gene, was excluded as a cause of disease. The results presented here further support the existence of a colorectal cancer susceptibility gene on chromosome 9q and refine its likely location.
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Affiliation(s)
- Zoe E Kemp
- Molecular and Population Genetics Laboratory, Cancer Research UK, London, United Kingdom
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Hadjisavvas A, Papasavva T, Loizidou M, Malas S, Potamitis G, Christodoulou C, Pavlides G, Papamichael D, Klonis C, Nasioulas G, Anastasiadou V, Kyriacou K. Novel germline mutations in the APC gene of Cypriot patients with familial and sporadic adenomatous polyposis. Clin Genet 2006; 69:404-9. [PMID: 16650078 DOI: 10.1111/j.1399-0004.2006.00617.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Familial adenomatous polyposis (FAP) is one of the two commonest familial syndromes that predispose to colorectal cancer. FAP is caused by mutations in the adenomatous polyposis coli (APC) tumour suppressor gene that has a high penetrance. The disease is characterized by the occurrence of hundreds to thousands of colorectal polyps, which if left untreated give rise to colorectal cancer. In Cyprus, there are no molecular data available as yet on families with FAP. This work presents the results of APC analysis in our population for the first time. The APC gene was analyzed in 33 DNA samples from 20 individuals belonging to four FAP families and 13 patients with sporadic polyposis. We identified three truncating mutations, four missense mutations and 11 polymorphisms. It is of interest that two of the three truncating mutations, 2307delA and Q1242X, are novel, which supports the existence of a unique genetic pool in the Cypriot population. This ethnic molecular study in addition to highlighting population heterogeneity also contributes to phenotype-genotype associations that are essential for the clinical management of FAP families in Cyprus.
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Affiliation(s)
- A Hadjisavvas
- The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
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Mao X, Hamoudi RA, Talbot IC, Baudis M. Allele-specific loss of heterozygosity in multiple colorectal adenomas: toward an integrated molecular cytogenetic map II. ACTA ACUST UNITED AC 2006; 167:1-14. [PMID: 16682279 DOI: 10.1016/j.cancergencyto.2005.08.030] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2005] [Accepted: 08/25/2005] [Indexed: 12/22/2022]
Abstract
Colorectal cancer (CRC) remains a significant public health challenge despite our increased understanding of the genetic defects underlying the pathogenesis of this common disease. It has been thought that multiple mechanisms lead to the malignant phenotype, with familial predisposition syndromes accounting for only a small proportion of all CRC cases. To identify additional loci likely involved in CRC and to test the hypothesis of allele-specific loss of heterozygosity (LOH) for the localization of CRC susceptibility genes, we initially conducted a genome-wide allelotyping analysis of 48 adenomas from a patient with familial adenomatous polyposis coli (FAP) and 63 adenomas from 7 patients with sporadic CRC using 79 fluorescently tagged oligonucleotide primers amplifying microsatellite loci covering the human genome. Frequent allelic losses were identified at D17S802 (41%), D7S518 (40%), D18S53 (38%), D10S249 (32%), D2S391 (29%), D16S419 (27%), D15S1005 and D15S120 (24%), D9S274 and D11S1318 (23%), D14S65 (20%), D14S274 and D17S953 (19%), D19S424 (18%), D5S346 and D1S397 (15%), and D6S468 (13%) in multiple FAP adenomas. Common LOH was also detected at D4S1584 (42%), D11S968 (31%), D17S953 (28%), D5S394, D9S286 and D10S249 (24%), D8S511 (23%), D13S158 (21%), D7S669 (20%), D18S58 (19%), D2S162 and D16S432 (16%), D2S206 (15%), D7S496 and D17S946 (14%), D6S292 (13%), D4S1586 and D8S283 (11%), and D1S2766 (10%) in multiple CRC adenomas. In addition, allele-specific LOH at D5S346, D15S1005, and D15S120 was observed in multiple FAP adenomas (P < 0.01) and at D2S206 and D16S423 in multiple CRC (P < 0.05). To compare our data to previous reports, we determined the band-specific frequency of chromosomal imbalances in CRC karyotypes reported in the Mitelman database, and from the CGH results of cases accessible through the PROGENETIX website. Furthermore, published genome-wide allelotyping analysis of CRC and other allele-specific LOH studies were compiled and collated with our LOH data. The combined results not only provide a comprehensive view of genetic losses in CRC, indicating the comparability of these different techniques, but they also reveal different novel loci in multiple adenomas from FAP and sporadic CRC patients, suggesting that they represent a distinct subtype of CRC in terms of allelic losses. Allele-specific LOH is an alternative approach for cancer gene mapping.
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Affiliation(s)
- Xin Mao
- Skin Tumour Unit, St. John's Institute of Dermatology, St. Thomas' Hospital, 4th Floor, South Wing, Block 7, Lambeth Palace Road, London SE1 7EH, UK.
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Dove-Edwin I, de Jong AE, Adams J, Mesher D, Lipton L, Sasieni P, Vasen HFA, Thomas HJW. Prospective results of surveillance colonoscopy in dominant familial colorectal cancer with and without Lynch syndrome. Gastroenterology 2006; 130:1995-2000. [PMID: 16762622 DOI: 10.1053/j.gastro.2006.03.018] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2005] [Accepted: 03/09/2006] [Indexed: 01/20/2023]
Abstract
BACKGROUND & AIMS Lynch syndrome is an autosomal dominant predisposition to colorectal cancer caused by mutations in DNA mismatch repair genes; colorectal cancer risk is high. Few studies have addressed colorectal cancer risk in individuals from dominant families without mismatch repair deficiency. We sought to establish whether these individuals are also at increased risk by examining the incidence of advanced neoplasia during surveillance. METHODS In this prospective cohort study, BAT26 testing of tumors was carried out at 2 tertiary centers on 125 individuals from 97 families (with a dominant colorectal cancer history) to classify families as Lynch syndrome (microsatellite unstable) or non-Lynch syndrome (microsatellite stable). Colonoscopy results in 288 at-risk family members were compared. RESULTS Twenty-nine families were classified as Lynch syndrome and 68 as non-Lynch syndrome. Seven hundred seventy-six colonoscopies were undertaken. High-risk adenomas occurred in 7 of 91 (7.7%) Lynch syndrome individuals and 15 of 197 (7.6%) non-Lynch syndrome individuals, adjusted relative risk 1.15 (95% CI: 0.6-2.3). Cancer was observed only in Lynch syndrome individuals (4/91; 4.4%), Fisher exact test, P = .010. Multiple adenomas were only seen in non-Lynch syndrome individuals (13/197; 6.6%), Fisher exact text, P = .06. CONCLUSIONS Individuals with an autosomal dominant family history of colorectal cancer with and without evidence of Lynch syndrome are at equal risk of high-risk adenomas during surveillance, but colorectal cancer was only seen in Lynch syndrome. Therefore non-Lynch syndrome individuals do require colonoscopic surveillance, but the interval could be lengthened because risk of (interval) cancer is low. Lynch syndrome individuals require short surveillance intervals as is the recommended practice.
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Affiliation(s)
- Isis Dove-Edwin
- Family Cancer Group, Cancer Research, UK Colorectal Cancer Unit, St. Mark's Hospital, Watford Road, Harrow, Middlesex, United Kingdom
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Kim H, Kim HJ, Chi SG, Lee SK, Joo GR, Dong SH, Kim BH, Chang YW, Lee JI, Chang R. Absence of MutY homologue mutation in patients with multiple sporadic adenomatous polyps in Korea. World J Gastroenterol 2006; 12:951-5. [PMID: 16521226 PMCID: PMC4066163 DOI: 10.3748/wjg.v12.i6.951] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Recently, germ-line mutation in the base excision repair gene MYH has been identified to cause a novel autosomal recessive form of familial adenomatous polyposis (FAP). Interestingly, a striking evidence for MYH mutations within different ethnic groups has been demonstrated. In this study, we screened 30 patients with multiple adenomatous polyps for MYH mutations to assess its prevalence and ethnic specificity in Korea.
METHODS: Thirty patients (21 men and 9 women; mean age 62.3 years) with multiple adenomatous polyps were examined for MYH mutations. The mean number of adenomas per patient was 10.0. Sixteen exonic regions and their intronic sequences were amplified by PCR and subjected to SSCP and DNA sequencing analyses.
RESULTS: None of the patients was identified to carry any truncating or sequence alterations in MYH. Our screening for the mutational regions, which were recognized from Caucasian patients or affected Indian families, also failed to detect sequence substitutions.
CONCLUSION: Mutation in MYH may be rarely involved in the pathogenesis of multiple sporadic colorectal adenomas in Korean population, although a large-scale analysis will be required to clarify the presence of specific MYH variants in a subset of patients and their role in the predisposition of multiple colorectal adenomas in Korean population.
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Affiliation(s)
- Hansoo Kim
- Department of Medicine, Kyung Hee University School of Medicine, #1 Hoegi-Dong, Dongdaemun-Gu, Seoul 130-702, Korea
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Woods MO, Hyde AJ, Curtis FK, Stuckless S, Green JS, Pollett AF, Robb JD, Green RC, Croitoru ME, Careen A, Chaulk JAW, Jegathesan J, McLaughlin JR, Gallinger SS, Younghusband HB, Bapat BV, Parfrey PS. High frequency of hereditary colorectal cancer in Newfoundland likely involves novel susceptibility genes. Clin Cancer Res 2006; 11:6853-61. [PMID: 16203774 DOI: 10.1158/1078-0432.ccr-05-0726] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Newfoundland has one of the highest rates of colorectal cancer in North America. The most common hereditary form of colorectal cancer is hereditary nonpolyposis colorectal cancer caused by mutations in genes involved in mismatch repair. Our purpose was to determine the proportion of hereditary colorectal cancer and to determine the genetic basis of disease in both population and clinically referred cohorts from Newfoundland. EXPERIMENTAL DESIGN Seventy-eight colorectal cancer patients were accrued over a 2-year period from the Avalon Peninsula of Newfoundland. We also examined 31 hereditary nonpolyposis colorectal cancer-like families, which had been referred to the Provincial Medical Genetics Program. Tumors from probands were tested by immunohistochemistry for deficiencies in MLH1, MSH2, and MSH6 proteins and tested for DNA microsatellite instability. Mutation analyses of MLH1, MSH2, and MSH6 were undertaken by direct sequencing and an assay to detect deletions, amplifications, and rearrangements in MSH2 and MLH1. RESULTS We identified eight population-based families that fulfill the Amsterdam I or II criteria, 4 (50%) of which seem to have hereditary cancer not attributable to the most commonly mutated mismatch repair genes. In addition, in 16 of 21 (76%) referred families fulfilling Amsterdam I or II criteria, no mutations were found in the three most commonly altered mismatch repair genes, and tumor analyses corroborated these findings. CONCLUSIONS It seems that strong and novel genetic causes of hereditary colorectal cancer are responsible for a high proportion of colorectal cancer in this population. Conditions are suitable for the identification of these genes by linkage studies of large Newfoundland cancer families.
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Affiliation(s)
- Michael O Woods
- Discipline of Genetics, Department of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
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Stormorken AT, Bowitz-Lothe IM, Norèn T, Kure E, Aase S, Wijnen J, Apold J, Heimdal K, Møller P. Immunohistochemistry identifies carriers of mismatch repair gene defects causing hereditary nonpolyposis colorectal cancer. J Clin Oncol 2005; 23:4705-12. [PMID: 16034045 DOI: 10.1200/jco.2005.05.180] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
PURPOSE Hereditary nonpolyposis colorectal cancer (HNPCC) may be caused by mutations in mismatch repair (MMR) genes. The aim of this study was to validate immunohistochemistry and family history as prescreening tools to predict germline mutations in MLH1, MSH2, and MSH6. PATIENTS AND METHODS Pedigrees from 250 families were extended, cancer diagnoses were verified, and families were classified according to the Amsterdam and the Bethesda criteria. Tumor specimens were examined with immunohistochemistry for the presence of MLH1, MSH2, and MSH6 proteins. Mutation analyses were performed in blood samples from the same patients. RESULTS Blood samples from affected index persons in 181 families and tumor specimens from 127 of the affected index persons were obtained. Thirty tumors lacked one or more gene products. Sensitivity of immunohistochemistry to detect mutation carriers was 100%, specificity was 82%, and positive predictive value was 85%. Sensitivities, specificities, and positive predictive values for the Amsterdam criteria were 82%, 8%, and 45%, respectively, and for the Bethesda criteria were 100%, 0%, and 48%, respectively. Distribution of mutations was MLH1 = 4, MSH2 = 11, and MSH6 = 4. CONCLUSION Wide clinical criteria to select HNPCC kindreds, followed by immunohistochemistry of tumor material from one affected person in each family, had high sensitivity and specificity to predict MMR mutations.
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Affiliation(s)
- Astrid T Stormorken
- Section of Genetic Counselling, Department of Cancer Genetics, The Norwegian Radium Hospital, N-0310 Oslo, Norway
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Schimanski CC, Schmitz G, Kashyap A, Bosserhoff AK, Bataille F, Schäfer SC, Lehr HA, Berger MR, Galle PR, Strand S, Strand D. Reduced expression of Hugl-1, the human homologue of Drosophila tumour suppressor gene lgl, contributes to progression of colorectal cancer. Oncogene 2005; 24:3100-9. [PMID: 15735678 DOI: 10.1038/sj.onc.1208520] [Citation(s) in RCA: 114] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The human gene, human giant larvae (Hugl-1/Llg1/Lgl1) has significant homology to the Drosophila tumour suppressor gene lethal(2)giant larvae (lgl). The lgl gene codes for a cortical cytoskeleton protein, Lgl, that binds Myosin II and is involved in maintaining cell polarity and epithelial integrity. The human protein, Hugl-1 contains several conserved functional domains found in Lgl, suggesting that these proteins may have closely related functions. Whether loss of Hugl expression plays a role in human tumorigenesis has so far not been extensively investigated. Thus, we evaluated tumour tissues from 94 patients undergoing surgery for colorectal cancer (CRC) for loss of Hugl-1 transcription and compared our findings with the clinical data from each of these patients. We found that Hugl-1 was lost in 75% of tumour samples and these losses were associated with advanced stage and particularly with lymph node metastases. Reduced Hugl-1 expression during the adenoma-carcinoma sequence occurring as early as in colorectal adenomas was detected by both immunohistochemical and reverse transcription-polymerase chain reaction analysis. Functional assays with ecdysone-inducible cell lines revealed that Hugl-1 expression increased cell adhesion and decreased cell migration. Our studies thus indicate that downregulation of Hugl-1 contributes to CRC progression.
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Affiliation(s)
- Carl C Schimanski
- First Department of Internal Medicine, Johannes Gutenberg University, 55101 Mainz, Germany
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30
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Abstract
The observed increased incidence of colorectal cancer in Ashkenazi Jews compared to other populations is unexplained but likely has a genetic component. The I1307K APC polymorphism/mutation is carried by 6-8% of Ashkenazim and increases the risk of colorectal cancer 1.5-2 fold. There are few differences between the phenotype of colorectal cancer in I1307K carriers and sporadic cases. It is estimated that the mutation accounts for 6% of cases of colorectal cancer in Jews of Eastern European heritage. It should not be the subject of mass screening in Ashkenazi Jews, although it may be important in cases of familial colorectal cancer. Even rarer is the 1906G-->C MSH2 mutation carried by less than 1% of Ashkenazim, but as with other HNPCC mutations likely associated with a high risk of malignancy. Mutations at 15q13-14 are associated with the colorectal adenoma and carcinoma syndrome (CRAC) described in Ashkenazi families. The prevalence of the mutation is not known, nor its significance as a cause of colorectal cancer. Despite the paucity of genetic explanations for the high risk of colorectal cancer in Ashkenazim, that risk warrants aggressive colorectal cancer screening and particular attention to family history of malignancy in all Jews of Ashkenazi descent.
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Ramsey SD, Burke W, Clarke L. An economic viewpoint on alternative strategies for identifying persons with hereditary nonpolyposis colorectal cancer. Genet Med 2004; 5:353-63. [PMID: 14501830 PMCID: PMC2692576 DOI: 10.1097/01.gim.0000086626.03082.b5] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
PURPOSE There is uncertainty regarding the optimal strategy for identifying mutation carriers among those with hereditary nonpolyposis colorectal cancer (HNPCC). METHODS We used decision analysis to compare the cost-effectiveness of 4 strategies among those with newly diagnosed colon cancer: (1) clinical and family history followed by microsatellite instability testing and germline testing (Bethesda guidelines); (2) universal microsatellite instability testing; (3) germline testing of those who meet clinical and family history criteria; and (4) universal germline testing. RESULTS The added cost per year of life saved (YLS) for each strategy was as follows: (1) 11,865 US dollars/YLS, (2) 35,617 US dollars/YLS, (3) 49,702 US dollars/YLS, and (4) 267,548 US dollars/YLS. CONCLUSIONS The Bethesda guidelines are the most cost-effectiveness approach to screen persons for HNPCC.
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Affiliation(s)
- Scott D Ramsey
- Fred Hutchinson Cancer Research Center, and Department of Medicine, University of Washington, Seattle, Washington, USA
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32
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Reilly JJ, McDowell ZC. Physical activity interventions in the prevention and treatment of paediatric obesity: systematic review and critical appraisal. Proc Nutr Soc 2004; 62:611-9. [PMID: 14692597 DOI: 10.1079/pns2003265] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Interventions for prevention and treatment of childhood obesity typically target increases in physical activity and, more recently, reductions in physical inactivity (sedentary behaviour such as television viewing). However, the evidence base for such strategies is extremely limited. The main aim of the present review was to update the systematic review and critical appraisal of evidence in the light of the recent rapid expansion of research in this area. Randomised controlled trials (RCT) that targeted activity or inactivity, that followed up children or adolescents for at least 1 year and that included an objective weight-related outcome measure were included. Trials were appraised using previously published criteria (Harbour & Miller, 2001), and literature search strategies described previously (Reilly et al. 2002) were updated to May 2002. A total of four new RCT, two new systematic reviews and one meta-analysis were identified. The evidence base has increased markedly since the completion of earlier reviews, although high-quality evidence is still lacking. The evidence on childhood obesity prevention is not encouraging, although promising targets for prevention are now clear, notably reduction in sedentary behaviour. There is stronger evidence that targeting activity and/or inactivity might be effective in paediatric obesity treatment, but doubts as to the generalisability of existing interventions, and the clinical relevance of the interventions is unclear. Further research in settings outside the USA is urgently needed, and two ongoing RCT in Scotland are summarised.
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Affiliation(s)
- John J Reilly
- University of Glasgow Department of Human Nutrition, Royal Hospital for Sick Children, Yorkhill, Glasgow G3 8SJ, UK.
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Marcelis CL, van der Putten HW, Tops C, Lutgens LC, Moog U. Chemotherapy resistant ovarian cancer in carriers of an hMSH2 mutation? Fam Cancer 2003; 1:107-9. [PMID: 14574006 DOI: 10.1023/a:1013865323890] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Hereditary Non-Polyposis Colorectal Cancer (HNPCC, Lynch syndrome) is an autosomal dominant condition of cancer susceptibility with high penetrance, characterised by early onset of colon tumours as well as a variety of extracolonic tumours including ovarian cancer and, in particular, cancer of the endometrium. Germline mutations in one of five DNA-mismatch repair (MMR) genes (hMLH1, hMSH2, hMSH6, PMS1, PMS2) are known to cause HNPCC. To date, mutations in two of these genes (hMSH2 and hMLH1) are found in the majority of mutation positive families. Recent literature suggests that especially hMSH2 mutations are associated with extracolonic tumours. We describe two women from an HNPCC family carrying an hMSH2 mutation (deletion of exon 6 of this gene) who developed ovarian cancer. In these patients (full cousins) the ovarian cancers were noted for their aggressive development and rapid recurrence after surgical debulking and during regular multichemotherapy including Cisplatin. This report strengthens recent in vitro studies suggesting an involvement of MMR-gene mutations in ovarian cancer cell biology with decreased susceptibility to Cisplatin therapy. The possible implications for the therapy of ovarian cancer, the screening and genetic counselling of family members are discussed.
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Affiliation(s)
- C L Marcelis
- Department of Clinical Genetics, University Hospital Maastricht, P.O. Box 1475, 6201 BL Maastricht, The Netherlands.
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Enholm S, Hienonen T, Suomalainen A, Lipton L, Tomlinson I, Kärjä V, Eskelinen M, Mecklin JP, Karhu A, Järvinen HJ, Aaltonen LA. Proportion and phenotype of MYH-associated colorectal neoplasia in a population-based series of Finnish colorectal cancer patients. THE AMERICAN JOURNAL OF PATHOLOGY 2003; 163:827-32. [PMID: 12937124 PMCID: PMC1868242 DOI: 10.1016/s0002-9440(10)63443-8] [Citation(s) in RCA: 106] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Recessively inherited mutations in the base excision repair gene MYH have recently been associated with predisposition to colorectal adenomas and cancer in materials selected for occurrence of multiple adenomas. In particular, variants Y165C and G382D have been shown to play a role in Caucasian patients. To evaluate the contribution of MYH mutations to colorectal cancer burden on the population level, and to examine the MYH-associated phenotype in an unselected series of colorectal cancer patients, we determined the frequencies of Y165C and G382D MYH mutations in a population-based series of 1042 Finnish colorectal cancer patients. Four (0.4%) patients had both MYH alleles mutated. Although all these patients had multiple adenomatous polyps, the phenotypes tended to be less extreme than in previous studies on selected cases. The lowest number of colorectal adenomas at the time of cancer diagnosis was five. Cases with one mutant MYH allele were subjected to sequencing of all exons to detect possible Finnish founder mutations, but no additional changes were detected. The Y165C and G382D variants were not present in 424 Finnish cancer-free controls showing that MYH mutations are not enriched in the population. As evaluated against national Finnish Polyposis Registry data MYH-associated colorectal cancer appears to be as common as colorectal cancer associated with familial adenomatous polyposis.
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Affiliation(s)
- Susa Enholm
- From the Department of Medical Genetics,*Programme of Neurosciences, and the Department of Neurology,†Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; the Molecular and Population Genetics Laboratory,‡Cancer Research UK, London, United Kingdom; the Departments of Pathology§and Surgery,¶Kuopio University Central Hospital, Kuopio, Finland; the Department of Surgery,∥Jyväskylä Central Hospital, Jyväskylä, Finland; the Second Department of Surgery,**Helsinki University Central Hospital, Helsinki, Finland
| | - Tuija Hienonen
- From the Department of Medical Genetics,*Programme of Neurosciences, and the Department of Neurology,†Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; the Molecular and Population Genetics Laboratory,‡Cancer Research UK, London, United Kingdom; the Departments of Pathology§and Surgery,¶Kuopio University Central Hospital, Kuopio, Finland; the Department of Surgery,∥Jyväskylä Central Hospital, Jyväskylä, Finland; the Second Department of Surgery,**Helsinki University Central Hospital, Helsinki, Finland
| | - Anu Suomalainen
- From the Department of Medical Genetics,*Programme of Neurosciences, and the Department of Neurology,†Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; the Molecular and Population Genetics Laboratory,‡Cancer Research UK, London, United Kingdom; the Departments of Pathology§and Surgery,¶Kuopio University Central Hospital, Kuopio, Finland; the Department of Surgery,∥Jyväskylä Central Hospital, Jyväskylä, Finland; the Second Department of Surgery,**Helsinki University Central Hospital, Helsinki, Finland
| | - Lara Lipton
- From the Department of Medical Genetics,*Programme of Neurosciences, and the Department of Neurology,†Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; the Molecular and Population Genetics Laboratory,‡Cancer Research UK, London, United Kingdom; the Departments of Pathology§and Surgery,¶Kuopio University Central Hospital, Kuopio, Finland; the Department of Surgery,∥Jyväskylä Central Hospital, Jyväskylä, Finland; the Second Department of Surgery,**Helsinki University Central Hospital, Helsinki, Finland
| | - Ian Tomlinson
- From the Department of Medical Genetics,*Programme of Neurosciences, and the Department of Neurology,†Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; the Molecular and Population Genetics Laboratory,‡Cancer Research UK, London, United Kingdom; the Departments of Pathology§and Surgery,¶Kuopio University Central Hospital, Kuopio, Finland; the Department of Surgery,∥Jyväskylä Central Hospital, Jyväskylä, Finland; the Second Department of Surgery,**Helsinki University Central Hospital, Helsinki, Finland
| | - Vesa Kärjä
- From the Department of Medical Genetics,*Programme of Neurosciences, and the Department of Neurology,†Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; the Molecular and Population Genetics Laboratory,‡Cancer Research UK, London, United Kingdom; the Departments of Pathology§and Surgery,¶Kuopio University Central Hospital, Kuopio, Finland; the Department of Surgery,∥Jyväskylä Central Hospital, Jyväskylä, Finland; the Second Department of Surgery,**Helsinki University Central Hospital, Helsinki, Finland
| | - Matti Eskelinen
- From the Department of Medical Genetics,*Programme of Neurosciences, and the Department of Neurology,†Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; the Molecular and Population Genetics Laboratory,‡Cancer Research UK, London, United Kingdom; the Departments of Pathology§and Surgery,¶Kuopio University Central Hospital, Kuopio, Finland; the Department of Surgery,∥Jyväskylä Central Hospital, Jyväskylä, Finland; the Second Department of Surgery,**Helsinki University Central Hospital, Helsinki, Finland
| | - Jukka-Pekka Mecklin
- From the Department of Medical Genetics,*Programme of Neurosciences, and the Department of Neurology,†Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; the Molecular and Population Genetics Laboratory,‡Cancer Research UK, London, United Kingdom; the Departments of Pathology§and Surgery,¶Kuopio University Central Hospital, Kuopio, Finland; the Department of Surgery,∥Jyväskylä Central Hospital, Jyväskylä, Finland; the Second Department of Surgery,**Helsinki University Central Hospital, Helsinki, Finland
| | - Auli Karhu
- From the Department of Medical Genetics,*Programme of Neurosciences, and the Department of Neurology,†Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; the Molecular and Population Genetics Laboratory,‡Cancer Research UK, London, United Kingdom; the Departments of Pathology§and Surgery,¶Kuopio University Central Hospital, Kuopio, Finland; the Department of Surgery,∥Jyväskylä Central Hospital, Jyväskylä, Finland; the Second Department of Surgery,**Helsinki University Central Hospital, Helsinki, Finland
| | - Heikki J. Järvinen
- From the Department of Medical Genetics,*Programme of Neurosciences, and the Department of Neurology,†Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; the Molecular and Population Genetics Laboratory,‡Cancer Research UK, London, United Kingdom; the Departments of Pathology§and Surgery,¶Kuopio University Central Hospital, Kuopio, Finland; the Department of Surgery,∥Jyväskylä Central Hospital, Jyväskylä, Finland; the Second Department of Surgery,**Helsinki University Central Hospital, Helsinki, Finland
| | - Lauri A. Aaltonen
- From the Department of Medical Genetics,*Programme of Neurosciences, and the Department of Neurology,†Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; the Molecular and Population Genetics Laboratory,‡Cancer Research UK, London, United Kingdom; the Departments of Pathology§and Surgery,¶Kuopio University Central Hospital, Kuopio, Finland; the Department of Surgery,∥Jyväskylä Central Hospital, Jyväskylä, Finland; the Second Department of Surgery,**Helsinki University Central Hospital, Helsinki, Finland
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Laiho P, Hienonen T, Karhu A, Lipton L, Aalto Y, Thomas HJW, Birkenkamp-Demtroder K, Hodgson S, Salovaara R, Mecklin JP, Järvinen H, Knuutila S, Halford S, Ørntoft TF, Tomlinson I, Launonen V, Houlston R, Aaltonen LA. Genome-wide allelotyping of 104 Finnish colorectal cancers reveals an excess of allelic imbalance in chromosome 20q in familial cases. Oncogene 2003; 22:2206-14. [PMID: 12687022 DOI: 10.1038/sj.onc.1206294] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
We have allelotyped a series of 104 Finnish colorectal cancers (CRCs) using 372 polymorphic markers spaced, on average, at 10 cM intervals, and have made a comparison of the differences in the frequency of allelic imbalance (AI) between familial and sporadic cases. Differences in the frequency of allelic imbalance (loss of heterozygosity or amplification) at a number of loci were detected and these were evaluated through analysis of additional series of cancers using specific markers. The most consistent difference was observed at chromosome 20q13.1-13.3 characterized by a two fold difference between familial and nonfamilial disease in a total of 99 familial and 186 sporadic Finnish cases. This difference was not observed in a UK set of 67 familial and 96 sporadic CRCs. The genome-wide effort resulted in a large data set giving clues to the location of putative CRC predisposition genes in the genome. The approach provides an alternative strategy for detecting cancer predisposition genes solely reliant on the molecular analysis of single cases obviating the requirement to collect multiple samples from families.
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Affiliation(s)
- Päivi Laiho
- Department of Medical Genetics, Biomedicum Helsinki, Haartmanikatu, University of Helsinki, Finland
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Sarroca C, Peltomäki P, Alfano N, Tedesco G, Della Valle A, Dominguez A, Lynch HT. Three new mutations in hereditary nonpolyposis colorectal cancer (Lynch syndrome II) in Uruguay. CANCER GENETICS AND CYTOGENETICS 2003; 142:13-20. [PMID: 12660027 DOI: 10.1016/s0165-4608(02)00766-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common hereditary form of colorectal cancer (CRC). Our purpose is to describe three extended HNPCC families, each of which manifests novel germline mutations in Uruguay, a small country that is a study model for cancer investigation given its high cancer incidence and mortality rate. This is a study of three extended HNPCC families in which extensive genealogic information, medical history, and pathology findings are critically reviewed. DNA testing was performed for evidence of HNPCC mutations. The findings reveal three novel germline mutations, namely MLH1, with a deletion resulting in a frameshift and a premature stop codon (codon 228) in one of the families; in the second family, MSH2 exon 1, codon 61 at nucleotide 181, which results in immediate stop of translation; and in the third family, a mutation in MSH2 at exon 3: the amino acid at nucleotide 530, codon 117, causing a frameshift and a premature stop codon eight base pairs later. We conclude that it is important to study HNPCC mismatch repair genes because of emerging evidence for genotypic and phenotypic heterogeneity, which will harbor the potential to eventually translate this knowledge into specific screening and management protocols. Future projections for such mutations could even contribute to the emergence of molecular-based designer drugs developed through advances in genomics, proteomics, high-throughput screening, and bioinformatics, which would be effective therapeutically for these high-cancer risk patients.
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Affiliation(s)
- Carlos Sarroca
- Uruguayan Collaborative Group: Survey of Hereditary Oncologic Disorders, Hospital Central de las Fuerzas Armadas, 11600 Montevideo, Uruguay
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Abstract
The DNA mismatch repair (MMR) system is necessary for the maintenance of genomic stability. In a broad sense, all main functions of the MMR system, including the correction of biosynthetic errors, DNA damage surveillance, and prevention of recombination between nonidentical sequences serve this important purpose. Failure to accomplish these functions may lead to cancer. It is therefore not surprising that inherited defects in the MMR system underlie one of the most prevalent cancer syndromes in humans, hereditary nonpolyposis colon cancer (HNPCC). In addition, acquired defects of the same system may account for 15% to 25%, or even a higher percentage, of sporadic cancers of different organs of the "HNPCC spectrum," including the colon and rectum, uterine endometrium, stomach, and ovaries. Recent studies indicate that the MMR genes may be involved in the pathogenesis of even a broader spectrum of tumors in one way or another. An updated review of the different features of the human MMR system will be provided, with the emphasis on their implications in cancer development.
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Affiliation(s)
- Päivi Peltomäki
- Department of Medical Genetics, University of Helsinki, Finland.
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Affiliation(s)
- Henry T Lynch
- Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, Nebr 68178, USA.
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39
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Hereditary Non-polyposis Colorectal Cancer (Lynch Syndrome). COLORECTAL CANCER 2002. [DOI: 10.1007/978-3-642-56008-8_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Abstract
Rare highly penetrant genes cannot account for much of the familial risk for most common cancers, and there is increasing evidence that a high proportion of cancers arise in a susceptible minority who carry low-penetrance genes or gene combinations. The evidence for the existence of such genes and the prospects for identifying them are reviewed.
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Affiliation(s)
- J Peto
- Section of Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
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Samowitz WS, Curtin K, Lin HH, Robertson MA, Schaffer D, Nichols M, Gruenthal K, Leppert MF, Slattery ML. The colon cancer burden of genetically defined hereditary nonpolyposis colon cancer. Gastroenterology 2001; 121:830-8. [PMID: 11606497 DOI: 10.1053/gast.2001.27996] [Citation(s) in RCA: 184] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Estimates of the frequency of hereditary nonpolyposis colon cancer (HNPCC) based on clinical criteria have varied widely. Recent studies of germline mismatch repair gene mutations have suggested that HNPCC accounts for close to 3% of all colon cancer, but this estimate may have been inflated by inclusion of founder effects peculiar to Finland. We therefore determined by genetic criteria the colon cancer burden associated with HNPCC in a population-based study of 1066 individuals from Utah and California. METHODS The coding regions of mismatch repair genes hMSH2 and hMLH1 were sequenced from the germline of those individuals whose tumors exhibited microsatellite instability. RESULTS Microsatellite instability was present in 16% (171/1066) of tumors. Pathogenic germline mismatch repair gene mutations were identified in 7 individuals, and missense amino acid changes of uncertain significance were identified in another 6 individuals. After adjusting for the availability of sufficient germline DNA for sequencing, the 7 clearly pathogenic mutations accounted for 0.86% of colon cancer at the population level. Individuals with these mutations were significantly younger, more likely to have a family history of colon and endometrial cancer, and more likely to have first-degree relatives with a young-age onset of colon cancer than individuals with unstable tumors but without germline mutations (P < 0.01). CONCLUSIONS We conclude that genetically defined HNPCC accounts for a very small percentage of colon cancer at the population level, a percentage less than that estimated by most previous clinical studies.
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Affiliation(s)
- W S Samowitz
- Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA.
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Kong S, Wei Q, Amos CI, Lynch PM, Levin B, Zong J, Frazier ML. Cyclin D1 polymorphism and increased risk of colorectal cancer at young age. J Natl Cancer Inst 2001; 93:1106-8. [PMID: 11459873 DOI: 10.1093/jnci/93.14.1106] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Affiliation(s)
- S Kong
- Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA
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Abstract
Colorectal cancer is a leading cause of cancer mortality in the industrialized world. Survival remains poor because most cases are diagnosed at an advanced stage. It is a preventable disease as colorectal cancers usually develop slowly from an identifiable precursor lesion, the adenoma. The existing strategies for colorectal cancer prevention include dietary prevention, chemoprevention and endoscopic intervention. The exact relationship between diet, particularly fibre, and colorectal cancer remains unclear, with the most recent studies suggesting that dietary fibre may not decrease colorectal cancer risk as previously thought. Non-steroidal anti-inflammatory drugs have been shown to have a protective effect against colorectal cancer, but the adverse effect profile of the non COX-2 selective drugs, particularly the risk of gastrointestinal haemorrhage, precludes their widespread use. There is increasing evidence that colorectal cancer incidence and mortality can be decreased from endoscopic polypectomy and early detection of cancer. Faecal occult blood testing in the general population ('average-risk') has been shown in randomized trials to decrease mortality from colorectal cancer by 15--33%. Long-term results of randomized trials of the effectiveness of flexible sigmoidoscopy and colonoscopy screening in the general population are awaited. Targeting high risk individuals may also be an effective and efficient way to decrease the colorectal cancer burden. As many as 15--30% of colorectal cases may be due to hereditary factors. Individuals with one or two direct relatives affected are at moderate risk for colorectal cancer (empirical lifetime mortality from colorectal cancer approximately 10%) and approximately 2--3% of cases arise in individuals harbouring highly penetrant autosomal dominant mutations, which puts them at high-risk for colorectal cancer. Surveillance colonoscopy is offered to individuals at moderate and high risk for colorectal cancer.
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Affiliation(s)
- I Dove-Edwin
- ICRF Family Cancer Clinic, St Mark's Hospital, Harrow, Middlesex, UK
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45
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Genetics of Cancer. Surgery 2001. [DOI: 10.1007/978-3-642-57282-1_73] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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Lamlum H, Al Tassan N, Jaeger E, Frayling I, Sieber O, Reza FB, Eckert M, Rowan A, Barclay E, Atkin W, Williams C, Gilbert J, Cheadle J, Bell J, Houlston R, Bodmer W, Sampson J, Tomlinson I. Germline APC variants in patients with multiple colorectal adenomas, with evidence for the particular importance of E1317Q. Hum Mol Genet 2000; 9:2215-21. [PMID: 11001924 DOI: 10.1093/oxfordjournals.hmg.a018912] [Citation(s) in RCA: 86] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Mendelian tumour syndromes are caused by rare mutations, which usually lead to protein inactivation. Few studies have determined whether or not the same genes harbour other, more common variants, which might have a lower penetrance and/or cause mild disease, perhaps indistinguishable from sporadic disease and accounting for a considerable proportion of the unexplained inherited risk of tumours in the general population. Germline variants at the APC locus are excellent candidates for explaining why some individuals are predisposed to colorectal adenomas, but do not have the florid phenotype of familial adenomatous polyposis. We have screened 164 unrelated patients with 'multiple' (3-100) colorectal adenomas for germline variants throughout the APC gene, including promoter mutations. In addition to three Ashkenazi patients with I1307K, we found seven patients with the E1317Q variant. E1317Q is significantly associated with multiple colorectal adenomas (OR = 11. 17, 95% CI = 2.30-54.3, p < 0.001), accounting for approximately 4% of all patients with multiple colorectal adenomas. In addition, four patients with truncating APC variants in exon 9 or in the 3' part of the gene were identified. Germline APC variants account for approximately 10% of patients with multiple adenomas. Unidentified predisposition genes almost certainly exist. We argue that it is worthwhile to screen multiple adenoma patients for a restricted number of germline APC variants, namely the missense changes E1317Q and I1307K (if of Ashkenazi descent), and, if there is a family history of colorectal tumours, for truncating mutations 5' to exon 5, in exon 9 and 3' to codon 1580.
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Affiliation(s)
- H Lamlum
- Molecular and Population Genetics Laboratory, Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
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Planck M, Anderson H, Bladstr�m A, M�ller T, Wenngren E, Olsson H. Increased cancer risk in offspring of women with colorectal carcinoma. Cancer 2000. [DOI: 10.1002/1097-0142(20000815)89:4<741::aid-cncr4>3.0.co;2-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Abstract
Mechanisms involved in hereditary intestinal cancer are likely to play a role in sporadic tumorigenesis as well. Studies focusing on the molecular biology underlying these syndromes has contributed considerably to our knowledge on molecular bases of malignant transformation. It can be concluded, that there are two aspects to the importance of studies on intestinal cancer predisposition. First, the families suffering from cancer proneness need help which can, to some extent, be provided through molecular genetic studies. Second, the resources appointed to such research have produced scientific advances with outstanding importance to our understanding of common malignant diseases.
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Affiliation(s)
- L A Aaltonen
- Department of Medical Genetics, University of Helsinki, P.O. Box 21, FIN-00014, Finland
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49
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Abstract
Hereditary nonpolyposis colorectal cancer (HNPCC) is inherited as a dominant disorder caused by germline defects in one of at least four mismatch repair (MMR) genes. Two of these genes, hMSH2 and hMLH1, account for the vast majority of the germline mutations in HNPCC kindreds, whereas hPMS1 and hPMS2 are mutated in only few families. MMR genes also are susceptible to somatic mutations in sporadic tumors. The mutational spectrum of the MMR genes shows no predominant type of mutation. Furthermore, the mutations are spread throughout the length of the genes, with no significant hot spots. Identification of MMR genes as the cause of HNPCC made presymptomatic diagnosis a reality. However, the presence of multiple genes and the heterogeneity of mutations present challenges to the development of diagnostic tests for this disease.
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Affiliation(s)
- N Papadopoulos
- Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA
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50
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Lynch HT, de la Chapelle A. Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet 2000. [PMID: 10544223 DOI: 10.1136/jmg.36.11.801] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Familial colorectal cancer (CRC) is a major public health problem by virtue of its relatively high frequency. Some 15-20% of all CRCs are familial. Among these, familial adenomatous polyposis (FAP), caused by germline mutations in the APC gene, accounts for less than 1%. Hereditary non-polyposis colorectal cancer (HNPCC), also called Lynch syndrome, accounts for approximately 5-8% of all CRC patients. Among these, some 3% are mutation positive, that is, caused by germline mutations in the DNA mismatch repair genes that have so far been implicated (MLH1, MSH2, MSH6, PMS1, and PMS2). Most of the remaining patients belonging to HNPCC or HNPCC-like families are still molecularly unexplained. Among the remaining familial CRCs, a large proportion is probably caused by gene mutations and polymorphisms of low penetrance, of which the I1307K polymorphism in the APC gene is a prime example. Molecular genetic findings have enabled hereditary CRC to be divided into two groups: (1) tumours that show microsatellite instability (MSI), occur more frequently in the right colon, have diploid DNA, harbour characteristic mutations such as transforming growth factor beta type II receptor and BAX, and behave indolently, of which HNPCC is an example; and (2) tumours with chromosomal instability (CIN), which tend to be left sided, show aneuploid DNA, harbour characteristic mutations such as K-ras, APC, and p53, and behave aggressively, of which FAP is an example. This review focuses most heavily on the clinical features, pathology, molecular genetics, surveillance, and management including prophylactic surgery in HNPCC. Because of the difficulty in diagnosing HNPCC, a detailed differential diagnosis of the several hereditary CRC variants is provided. The extant genetic and phenotypic heterogeneity in CRC leads to the conclusion that it is no longer appropriate to discuss the genetics of CRC without defining the specific hereditary CRC syndrome of concern. Therefore, it is important to ascertain cancer of all anatomical sites, as well as non-cancer phenotypic stigmata (such as the perioral and mucosal pigmentations in Peutz-Jeghers syndrome), when taking a family cancer history.
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Affiliation(s)
- H T Lynch
- Department of Preventive Medicine and Public Health, Creighton University School of Medicine, 2500 California Plaza, Omaha, Nebraska 68178, USA
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