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1
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de Freitas Junior JCM, Morgado-Díaz JA. The role of N-glycans in colorectal cancer progression: potential biomarkers and therapeutic applications. Oncotarget 2017; 7:19395-413. [PMID: 26539643 PMCID: PMC4991391 DOI: 10.18632/oncotarget.6283] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 10/22/2015] [Indexed: 12/12/2022] Open
Abstract
Changes in glycosylation, which is one of the most common protein post-translational modifications, are considered to be a hallmark of cancer. N-glycans can modulate cell migration, cell-cell adhesion, cell signaling, growth and metastasis. The colorectal cancer (CRC) is a leading cause of cancer-related mortality and the correlation between CRC progression and changes in the pattern of expression of N-glycans is being considered in the search for new biomarkers. Here, we review the role of N-glycans in CRC cell biology. The perspectives on emerging N-glycan-related anticancer therapies, along with new insights and challenges, are also discussed.
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Affiliation(s)
| | - José Andrés Morgado-Díaz
- Cellular Biology Program, Structural Biology Group, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
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2
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Galas A, Miszczyk J. Aberrations Involving Chromosome 1 as a Possible Predictor of Odds Ratio for Colon Cancer--Results from the Krakow Case-Control Study. PLoS One 2016; 11:e0147658. [PMID: 26824604 PMCID: PMC4732693 DOI: 10.1371/journal.pone.0147658] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Accepted: 01/06/2016] [Indexed: 12/16/2022] Open
Abstract
Background There is still an open question how to predict colorectal cancer risk before any morphological changes appear in the colon. Objective The purpose was to investigate aberrations in chromosomes 1, 2 and 4 in peripheral blood lymphocytes analyzed by fluorescence in situ hybridization technique as a tool to assess the likelihood of colorectal cancer. Methods A hospital-based case-control study included 20 colon cancer patients and 18 hospital-based controls. Information about potential covariates was collected by interview. The frequency of stable and unstable chromosome aberrations in chromosome 1, 2 and 4 was assessed by fluorescence in situ hybridization technique. Results Colorectal cancer patients, as compared to controls, had a relatively higher frequency of chromosome 1 translocations (median: 3.5 versus 1.0 /1000 cells, p = 0.006), stable aberrations (3.8 versus 1.0 /1000 cells, p = 0.007) and total aberrations (p = 0.009). There were no differences observed for chromosomes 2 and 4. Our results showed an increase in the odds of having colon cancer by about 50–80% associated with an increase by 1/1000 cells in the number of chromosome 1 aberrations. Conclusions The results revealed that the frequency of chromosomal aberrations, especially translocations in chromosome 1, seems to be a promising method to show a colon cancer risk. Additionally, our study suggests the reasonableness of use of biomarkers such as chromosome 1 aberrations in peripheral blood lymphocytes in screening prevention programs for individuals at higher colon cancer risk to identify those who are at increased risk and require more frequent investigations, e.g. by sigmoidoscopy.
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Affiliation(s)
- Aleksander Galas
- Department of Epidemiology, Jagiellonian University–Medical College, Krakow, Poland
- * E-mail: ;
| | - Justyna Miszczyk
- Department of Experimental Physics of Complex Systems, Institute of Nuclear Physics, Polish Academy of Sciences, Krakow, Poland
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Sandouk F, Al Jerf F, Al-Halabi MHDB. Precancerous lesions in colorectal cancer. Gastroenterol Res Pract 2013; 2013:457901. [PMID: 23737765 PMCID: PMC3666221 DOI: 10.1155/2013/457901] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2012] [Accepted: 04/04/2013] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cause of cancer death in the world. The incidence rate (ASR) and age distribution of this disease differ between most of African-Middle-Eastern (AMAGE) and North America and Europe for many reasons. However, in all areas, "CRC" is considered as one of the most preventable cancers, because it might develop from variant processes like polyps and IBD in addition to the genetic pathogenesis which became very well known in this disease. We tried in this paper to review all the possible reasons of the differences in incidence and age between the west and AMAGE. Also we reviewed all the mutations that lead to the hereditary and familiar clustering of this disease with the correlations with the surrounding food and environment of different areas. Then, we focused on the precancerous pathology of this disease with special focusing on early detection depending on new endoscopy technology and most important genetic studies. We lastly reviewed the evidence of some of the surveillance and put suggestions about future surveillance programs and how important those programs are on the psychological aspect of the patients and their families.
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Affiliation(s)
| | - Feras Al Jerf
- Syrian National Cancer Registry, Office in Charge, Damascus, Syria
| | - M. H. D. Bassel Al-Halabi
- Lab of Human Genetics, Molecular Biology and Biotechnology Department, Atomic Energy Commission of Syria (AECS), Damascus, Syria
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4
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Abstract
Genetic susceptibility testing for common complex disease is a practice that is currently in clinical use. There are two types of gene mutations, and therefore, two varieties of genotype testing: deterministic and susceptibility. As the term suggests, deterministic genes determine whether or not a person will develop a given trait in mendelian fashion, such as Huntington's disease. Genotype screening for such deterministic mutations has existed for decades, and is commonly used in routine medical practice. In recent years, the sequencing of the human genome has identified several 'susceptibility genes' or genes with incomplete penetrance. Mutations in these genes may increase disease susceptibility, but are not causative for disease. Genetic susceptibility testing allows unaffected individuals to obtain risk information for a variety of common complex diseases and health conditions including Alzheimer's disease (AD), CVD, cancer and diabetes. The availability of genetic susceptibility testing has increased over the past decade, and several studies are now focusing on the impact that genetic testing has on health and other lifestyle behaviours related to nutrition. The aim of this paper is to review the literature and evaluate what, if any, impact genetic risk assessment has on behaviours related to nutrition and physical activity. This paper summarises seven clinical studies that evaluated the impact of disclosing genetic risk information for disease on nutrition-related health behaviour changes. Of these seven studies, only three studies reported that health behaviour change was influenced by genotype disclosure.
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5
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Saunders IW, Ross J, Macrae F, Young GP, Blanco I, Brohede J, Brown G, Brookes D, Lockett T, Molloy PL, Moreno V, Capella G, Hannan GN. Evidence of linkage to chromosomes 10p15.3-p15.1, 14q24.3-q31.1 and 9q33.3-q34.3 in non-syndromic colorectal cancer families. Eur J Hum Genet 2011; 20:91-6. [PMID: 21829229 DOI: 10.1038/ejhg.2011.149] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Up to 25% of colorectal cancer (CRC) may be caused by inherited genetic variants that have yet to be identified. Previous genome-wide linkage studies (GWLSs) have identified a new loci postulated to contain novel CRC risk genes amongst affected families carrying no identifiable mutations in any of the known susceptibility genes for familial CRC syndromes. To undertake a new GWLS, we recruited members from 54 non-syndromic families from Australia and Spain where at least two first-degree relatives were affected by CRC. We used single-nucleotide polymorphism arrays to genotype 98 concordant affected relative pairs that were informative for linkage analyses. We tested for genome-wide significance (GWS) for linkage to CRC using a quantile statistic method, and we found that GWS was achieved at the 5% level. Independently, using the PSEUDO gene-dropping algorithm, we also found that GWS for linkage to CRC was achieved (P=0.02). Merlin non-parametric linkage analysis revealed significant linkage to CRC for chromosomal region 10p15.3-p15.1 and suggestive linkage to CRC for regions on 14q and 9q. The 10p15.3-p15.1 has not been reported to be linked to hereditary CRC in previous linkage studies, but this region does harbour the Kruppel-like factor 6 (KLF6) gene that is known to be altered in common CRC. Further studies aimed at localising the responsible genes, and characterising their function will give insight into the factors responsible for susceptibility in such families, and perhaps shed further light on the mechanisms of CRC development.
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Affiliation(s)
- Ian W Saunders
- CSIRO Preventative Health Flagship, North Ryde, New South Wales, Australia
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Ho SMY, Ho JWC, Bonanno GA, Chu ATW, Chan EMS. Hopefulness predicts resilience after hereditary colorectal cancer genetic testing: a prospective outcome trajectories study. BMC Cancer 2010; 10:279. [PMID: 20537192 PMCID: PMC2891641 DOI: 10.1186/1471-2407-10-279] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2009] [Accepted: 06/11/2010] [Indexed: 11/25/2022] Open
Abstract
Background - Genetic testing for hereditary colorectal cancer (HCRC) had significant psychological consequences for test recipients. This prospective longitudinal study investigated the factors that predict psychological resilience in adults undergoing genetic testing for HCRC. Methods - A longitudinal study was carried out from April 2003 to August 2006 on Hong Kong Chinese HCRC family members who were recruited and offered genetic testing by the Hereditary Gastrointestinal Cancer Registry to determine psychological outcomes after genetic testing. Self-completed questionnaires were administered immediately before (pre-disclosure baseline) and 2 weeks, 4 months and 1 year after result disclosure. Using validated psychological inventories, the cognitive style of hope was measured at baseline, and the psychological distress of depression and anxiety was measured at all time points. Results - Of the 76 participating subjects, 71 individuals (43 men and 28 women; mean age 38.9 ± 9.2 years) from nine FAP and 24 HNPCC families completed the study, including 39 mutated gene carriers. Four patterns of outcome trajectories were created using established norms for the specified outcome measures of depression and anxiety. These included chronic dysfunction (13% and 8.7%), recovery (0% and 4.3%), delayed dysfunction (13% and 15.9%) and resilience (76.8% and 66.7%). Two logistic regression analyses were conducted using hope at baseline to predict resilience, with depression and anxiety employed as outcome indicators. Because of the small number of participants, the chronic dysfunction and delayed dysfunction groups were combined into a non-resilient group for comparison with the resilient group in all subsequent analysis. Because of low frequencies, participants exhibiting a recovery trajectory (n = 3 for anxiety and n = 0 for depression) were excluded from further analysis. Both regression equations were significant. Baseline hope was a significant predictor of a resilience outcome trajectory for depression (B = -0.24, p < 0.01 for depression); and anxiety (B = -0.11, p = 0.05 for anxiety). Conclusions - The current findings suggest that hopefulness may predict resilience after HCRC genetic testing in Hong Kong Chinese. Interventions to increase the level of hope may be beneficial to the psychological adjustment of CRC genetic testing recipients.
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Affiliation(s)
- Samuel M Y Ho
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
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Brown AC, Roy M. Does evidence exist to include dietary therapy in the treatment of Crohn's disease? Expert Rev Gastroenterol Hepatol 2010; 4:191-215. [PMID: 20350266 DOI: 10.1586/egh.10.11] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Prescription drugs and surgery are two common medical therapies for Crohn's disease (CD), an inflammatory bowel disease that affects the GI tract. Unfortunately, certain drugs can cause serious side effects, and surgeries must often be repeated. No diet has been established to alleviate the pain and suffering of CD patients. This is curious given the fact that a higher prevalence of food sensitivities exist in this population of patients, and enteral nutrition is not only the first-line of therapy in Japan, but a known research method used to place the majority of CD patients into remission. Although not all patients respond equally to diet, many simply remove symptom-provoking foods, such as dairy, wheat, corn and certain fruits and vegetables. We suggest assisting these patients in their self-assessment of irritating and symptom-provoking foods by educating them in the use of a food-symptom diary followed by a customized elimination diet trialed for 2-4 weeks to determine if there is any benefit to the individual patient.
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Affiliation(s)
- Amy C Brown
- Department of Complementary and Alternative Medicine, John A Burns School of Medicine, University of Hawaii, 651 Ilalo Street, MEB 223, Honolulu, HI 96813, USA.
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PELLEGRINI M, ARGIBAY P, GOMEZ D. Dietary factors, genetic and epigenetic influences in colorectal cancer. Exp Ther Med 2010; 1:241-250. [PMID: 22993535 PMCID: PMC3445943 DOI: 10.3892/etm_00000038] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2009] [Accepted: 11/10/2009] [Indexed: 01/05/2023] Open
Abstract
Genetic influences, together with epigenetic components and dietary factors, play a fundamental role in the initiation and progression of cancer by causing a number of deregulations. Colorectal cancer (CRC) is a disease influenced by dietary factors, for which established genetic and epigenetic alterations have been identified. Within CRC, there are hereditary syndromes that present mutations in the germ-line hMLH1, and also alterations in the methylation of the promoters. Epigenetics has also been established as a pathway of carcinogenesis. In the present review, we analyzed studies conducted to discern the different pathways leading to established CRC, stressing the importance of identifying factors that may predict CRC at an early stage, since it is mostly a silent disease observed at the clinical level in advanced stages.
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Affiliation(s)
- M.L. PELLEGRINI
- Instituto de Ciencias Básicas y Medicina Experimental, Hospital Italiano de Buenos Aires
| | - P. ARGIBAY
- Instituto de Ciencias Básicas y Medicina Experimental, Hospital Italiano de Buenos Aires
| | - D.E. GOMEZ
- Laboratorio de Oncología Molecular, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, Buenos Aires,
Argentina
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Wang CW, Hui EC. Ethical, legal and social implications of prenatal and preimplantation genetic testing for cancer susceptibility. Reprod Biomed Online 2010; 19 Suppl 2:23-33. [PMID: 19891845 DOI: 10.1016/s1472-6483(10)60274-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
With the progress in cancer genetics and assisted reproductive technologies, it is now possible for cancer gene mutation carriers not only to reduce cancer mortality through the targeting of surveillance and preventive therapies, but also to avoid the birth of at-risk babies through the choice of different means of reproduction. Thus, the incidence of hereditary cancer syndromes may be decreased in the future. The integration of cancer genetic testing and assisted reproductive technologies raises certain ethical, legal and social issues beyond either genetic testing or assisted reproductive technology itself. In this paper, the reproductive decisions/choices of at-risk young couples and the ethical, legal and social concerns of prenatal genetic testing and preimplantation genetic diagnosis for susceptibility to hereditary cancer syndromes are discussed. Specifically, three ethical principles related to the integration of cancer genetic testing and assisted reproductive technologies, i.e. informed choice, beneficence to children and social justice, and their implications for the responsible translation of these medical techniques into common practice of preventive medicine are highlighted.
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Affiliation(s)
- C-W Wang
- Medical Ethics Unit, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong
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10
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Tranø G, Wasmuth HH, Sjursen W, Hofsli E, Vatten LJ. Awareness of heredity in colorectal cancer patients is insufficient among clinicians: a Norwegian population-based study. Colorectal Dis 2009; 11:456-61. [PMID: 19508550 DOI: 10.1111/j.1463-1318.2009.01830.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVE The assessment of family history and medical data is crucial in identifying families with Lynch syndrome (LS). Among consecutive colorectal cancer (CRC) patients, we aimed at identifying all patients with a hereditary predisposition, and to study a possible discrepancy with assessments made by the responsible clinicians. METHOD All consecutively diagnosed patients with CRC from two Norwegian hospitals were included, and information on family history was collected in a detailed interview. We assessed information in medical records, and tumours were examined for LS-associated histopathological features. RESULTS Among 562 patients, there was no documentation of family history in 388 (69.0%) medical records, and in 174 (31.0%) patients, there was no clinical assessment of the information that was collected on family history. Based on detailed interviews and extended pathological examination, we found that 137 (24.4%) of the 562 patients could be classified as possible LS according to the Revised Bethesda Guidelines (RBG); and that 46 (33.6%) of these patients could be identified by family history alone. CONCLUSION Family history and relevant information in patient records can identify patients with possible LS. However, clinicians often fail to include information on hereditary factors and to assess relevant data in medical records. Familial CRC is therefore not acknowledged, and genetic counselling is not offered.
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Affiliation(s)
- G Tranø
- Department of Gastrointestinal Surgery, Hamar Hospital, Sykehuset Innlandet Hospital Trust, Hamar, Norway.
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11
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Mitchell RJ, Ferguson RK, Macdonald A, Dunlop MG, Campbell H, Porteous ME. Cascade genetic testing for mismatch repair gene mutations. Fam Cancer 2008; 7:293-301. [PMID: 18389387 DOI: 10.1007/s10689-008-9192-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2007] [Accepted: 03/21/2008] [Indexed: 11/29/2022]
Abstract
Mismatch repair gene mutation carriers have a high risk of developing colorectal cancer, and can benefit from appropriate surveillance. A combined population based ascertainment cascade genetic testing approach provides a systematic and potentially effective strategy for identifying such carriers. We have developed a Markov Chain computer model system which simulates various factors influencing cascade genetic testing; including demographics, uptake, genetic epidemiology and family size. This was used to evaluate cascade genetic testing for mismatch repair gene mutations in theory and practice. Simulations focussed on the population of Scotland by way of illustration, and were based on a 20-year programme in which index cases were ascertained from colorectal cancer cases aged<55 years at onset. Results indicated that without practical barriers to cascade genetic testing, 545 (95% CI=522, 568) carriers could be identified; 42% of the population total. This comprised approximately 140 index cases, 302 asymptomatic relatives and 104 previously affected relatives. However, when realistic ascertainment and acceptance rates were used to inform simulations, only 257 (95% CI=246, 268) carriers, about 20% of the carrier population, were identifiable. Of these approximately 112 were index cases, 108 were asymptomatic relatives, and 37 were previously affected relatives. This contrast emphasises the importance of ascertainment and acceptance rates. Likewise the low number of index cases shows that case identification is a limiting factor. In the absence of robust data from epidemiological studies, these findings can inform decisions about the use of cascade genetic testing for mismatch repair gene mutations.
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Affiliation(s)
- R J Mitchell
- Public Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, EH89AG, UK.
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A systematic review of perceived risks, psychological and behavioral impacts of genetic testing. Genet Med 2008; 10:19-32. [PMID: 18197053 DOI: 10.1097/gim.0b013e31815f524f] [Citation(s) in RCA: 240] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Genetic testing may enable early disease detection, targeted surveillance, and result in effective prevention strategies. Knowledge of genetic risk may also enable behavioral change. However, the impact of carrier status from the psychological, behavior, and perceived risk perspectives is not well understood. We conducted a systematic review to summarize the available literature on these elements. An extensive literature review was performed to identify studies that measured the perceived risk, psychological, and/or behavioral impacts of genetic testing on individuals. The search was not limited to specific diseases but excluded the impacts of testing for single gene disorders. A total of 35 articles and 30 studies were included. The studies evaluated hereditary nonpolyposis colorectal carcinoma, hereditary breast and ovarian cancer, and Alzheimer disease. For affective outcomes, the majority of the studies reported negative effects on carriers but these were short-lived. For behavioral outcomes, an increase in screening behavior of varying rates was demonstrated in carriers but the change in behaviors was less than expected. With respect to perceived risk, there were generally no differences between carriers and noncarriers by 12 months after genetic testing and over time risk perception decreased. Overall, predispositional genetic testing has no significant impact on psychological outcomes, little effect on behavior, and did not change perceived risk. It seems as though better patient education strategies are required. Our data would suggest better knowledge among carriers would not have significant psychological impacts and therefore, it is worth pursuing improved educational strategies.
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Stuckless S, Parfrey PS, Woods MO, Cox J, Fitzgerald GW, Green JS, Green RC. The phenotypic expression of three MSH2 mutations in large Newfoundland families with Lynch syndrome. Fam Cancer 2006; 6:1-12. [PMID: 17039271 DOI: 10.1007/s10689-006-0014-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2006] [Accepted: 06/19/2006] [Indexed: 01/29/2023]
Abstract
To compare the phenotypic expression of three different MSH2 mutations causing Lynch syndrome, 290 family members at 50% risk of inheriting a mutation were studied. Two truncating mutations of the MSH2 gene have been identified in Newfoundland: an exon 8 deletion in five families (N=74 carriers) and an exon 4-16 deletion in one family (N=65 carriers). The third mutation was an intron 5 splice site mutation resulting in deletion of exon 5 in RNA and occurred in 12 families (N=151 carriers). Age to onset of first cancer, first colorectal cancer (CRC), first extracolonic cancers and death were compared. By age 60, 89% of family members with the intron 5 mutation, 81% with the exon 8 deletion, and 85% with the exon 4-16 deletion had developed cancer. For all three mutations males had a higher age-related risk of CRC and death compared to females. In the intron 5 splice site mutation carriers, the number of transitional cell cancers of the urinary tract was significantly lower and time to first ovarian cancer was significantly higher than in the carriers of the genomic deletions. The incidence of CRC in MSH2 mutation carriers, exposed to the same environment, is not modified by the specific mutation, although there is a suggestion that type of mutation may influence development of some extracolonic cancers.
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Affiliation(s)
- Susan Stuckless
- Department of Clinical Epidemiology, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada
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Satia JA, McRitchie S, Kupper LL, Halbert CH. Genetic testing for colon cancer among African-Americans in North Carolina. Prev Med 2006; 42:51-9. [PMID: 16297974 DOI: 10.1016/j.ypmed.2005.10.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2005] [Revised: 10/06/2005] [Accepted: 10/07/2005] [Indexed: 10/25/2022]
Abstract
OBJECTIVE To describe attitudes and correlates of intention to take a genetic test for colon cancer in a population-based sample of African-Americans. METHODS African-Americans (n = 658), age 18-70, in North Carolina completed an 11-page questionnaire between June-October 2003 that assessed attitudes (familiarity, perceived benefits and risks, anxiety, and confidentiality) and intention to take a genetic test for colon cancer and various participant characteristics. RESULTS Respondents expressed favorable attitudes and high intention regarding genetic testing for colon cancer: 87% would definitely/probably take a genetic test, although only 42% had read/heard a lot or some about genetic testing. Most agreed that genetic test results should be available to healthcare providers (79%) but not to health insurers (62%) or employers (82%). About a third were concerned that genetic testing could lead to discrimination. Correlates of intention differed by sex. Perceived benefits were significantly positively associated with intention among all respondents. However, being married (OR = 2.1, 95% CI: 1.2, 3.7), doctor as the main source of health information (OR = 2.4, 95% CI: 1.4, 3.9), and colon cancer family history (OR = 4.3, 95% CI: 1.6, 11.6) were significant only for women; some college education (OR = 4.1, 95% CI: 1.7, 9.7), importance of sharing test results with relatives (OR = 5.5, 95% CI: 1.6, 18.7), and colon cancer screening history (OR = 3.4, 95% CI: 1.6, 7.5) were only significant for men. CONCLUSIONS Respondents expressed high interest in genetic testing for colon cancer risk, although confidentiality of test results is a concern. Guidelines and policies for genetic testing specific to African-Americans should be established and future research should examine the prevalence of genetic testing.
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Affiliation(s)
- Jessie A Satia
- Department of Nutrition, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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15
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Abstract
Heredity plays an important causative role in a large percentage of colorectal cancers. Clinical recognition of the hereditary polyposis syndromes, hereditary nonpolyposis colorectal cancer, and common familial colorectal cancer is essential because screening, surveillance, and treatment among affected individuals and their family members differs from that recommended for the general population. More intensive cancer screening and surveillance is required if premature death is to be avoided. Genetic testing is commercially available for most of the hereditary colorectal cancer syndromes and can greatly facilitate the management of patients if properly undertaken.
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Affiliation(s)
- Yuki Young
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, 94115, USA
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Silva RVE, Garicochea B, Cotti G, Maranho IC, Cutait R. Hereditary nonpolyposis colorectal cancer identification and surveillance of high-risk families. Clinics (Sao Paulo) 2005; 60:251-6. [PMID: 15962087 DOI: 10.1590/s1807-59322005000300011] [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: 11/22/2022] Open
Abstract
Hereditary nonpolyposis colorectal cancer is an autosomal dominant condition caused by highly penetrant gene mutations. It is characterized by increased susceptibility for a specific group of cancer, mainly colorectal cancer. The syndrome originates from the inheritance of mutations in DNA mismatch repair genes. The most commonly affected genes in hereditary nonpolyposis colorectal cancer are hMLH1 and hMSH2. Their deficient expression renders the cell susceptible to the accumulation of many molecular defects, a condition which can be evaluated by the instability in sections of base repeats in the genoma known as microsatellite instability. The molecular detection of hereditary nonpolyposis colorectal cancer is possible in most of the highly suspicious cases. Genetic tests for hereditary nonpolyposis colorectal cancer also allow characterization of the individual that bears the mutation within a family. The high cost and restricted availability of these tests hamper their use for every person presenting colorectal cancer. Due to this fact, some clinical criteria have been developed by a hereditary nonpolyposis colorectal cancer international organization to select families with a high probability of carrying the mutation. Once families at risk are identified, they are encouraged to join a screening program that aims at early detection of hereditary nonpolyposis colorectal cancer-related cancers, increasing the possibility of its prevention and early detection.
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18
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Tischkowitz M, Rosser E. Inherited cancer in children: practical/ethical problems and challenges. Eur J Cancer 2004; 40:2459-70. [PMID: 15519520 DOI: 10.1016/j.ejca.2004.06.005] [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: 12/12/2003] [Revised: 04/30/2004] [Accepted: 06/02/2004] [Indexed: 11/22/2022]
Abstract
Over recent years significant molecular advances have led to a better understanding of the genetics of both syndromic and non-syndromic paediatric cancers. In addition many hereditary cancer predisposition syndromes are now recognised, some of which have implications for children in affected families. Improvements in gene mutation screening will increase the sensitivity, accuracy and therefore the applicability of genetic testing in these conditions. This review will deal with four main areas pertaining to paediatric cancer genetics (i) genetic aspects of some non-syndromic paediatric cancers (ii) paediatric cancer predisposition syndromes, (iii) the management of children in families with predominantly adult- onset cancer predisposition syndromes and (iv) special ethical, legal, social and psychological considerations in the management of children, with actual or possible genetic cancer predisposition. Current concepts and controversies in the rapidly changing field of paediatric cancer genetics will be examined in detail and the application of existing guidelines and their limitations will be discussed.
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Affiliation(s)
- Marc Tischkowitz
- North East Thames Regional Genetics Service, Clinical and Molecular Genetics Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
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Satheshkumar T, Saklani AP, Nagbhushan JS, Delicata RJ. Documenting family history in colorectal cancer patients - a retrospective audit. THE JOURNAL OF SURGERY 2004; 2:22-23. [DOI: 10.1016/s1743-9191(06)60021-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Annie Yu HJ, Lin KM, Ota DM, Lynch HT. Hereditary nonpolyposis colorectal cancer: preventive management. Cancer Treat Rev 2003; 29:461-70. [PMID: 14585257 DOI: 10.1016/s0305-7372(03)00084-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common form of hereditary colorectal cancer. Inherited mutations in the mismatch repair genes associated with this syndrome have an approximate 80% lifetime risk of colorectal cancer. Since there are no premonitory signs of susceptibility to HNPCC, family history is the initial method for identifying those at increased risk. At risk individuals should undergo genetic counseling and testing. Although an algorithmic indication for genetic testing in at risk HNPCC patients is yet to be determined, many advocate initial screening for microsatellite instability (MSI) of the cancer specimen in individuals suspected of carrying HNPCC mutations. Those who test positive for MSI can then undergo further testing for mutations in the associated germline mismatch repair genes. Techniques for detecting these mutations currently include in vitro synthesized-protein assay, single-strand conformational polymorphism, and DNA sequencing. Given the aggressive nature of HNPCC adenomas, individuals who test positive for HNPCC mutations are recommended to undergo yearly colonoscopic surveillance starting at the age of 25. A reasonable alternative to lifetime colonoscopic surveillance for the prevention of colorectal cancer in these individuals is prophylactic colectomy. The prevention of colorectal cancer through pharmacological means is under investigation as another option in the management of HNPCC patients. Specifically, chemoprevention trials are currently ongoing to evaluate the efficacy of COX-2 inhibitors in the prevention of colorectal cancer in HNPCC and familial adenomatous polyposis patients.
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Affiliation(s)
- Hwei-Ju Annie Yu
- Department of Internal Medicine, Southern California Permanente Medical Center, Los Angeles, CA 90027, USA.
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21
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Affiliation(s)
- John DeFrancisco
- Department of Medicine/Division of Gastroenterology, Vanderbilt University Medical School, Nashville, Tennessee 37232-2279, USA
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22
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Abstract
Colorectal cancer is the third leading cause of cancer-related deaths in both men and women in the United States and is estimated to have affected 148,000 people in 2002. The cumulative lifetime risk for colon cancer is approximately 5%-6%, and this risk is influenced by hereditary and lifestyle factors. In fact, 20%-30% of all colon cancer cases have a potentially definable inherited cause, and 3%-5% of colon cancers occur in genetically defined high-risk colon cancer family syndromes. Although the genes responsible for the cases of moderate-risk colon cancer remain to be characterized, many of the genes responsible for the high-risk colon cancer cases have already been determined. These genetic discoveries have been translated into clinical practice and have led to improved risk assessment through the use of genetic testing. The introduction into clinical practice of genetic testing for the assessment of colon cancer risk has led to more effective management strategies for patients with potentially high-risk colon cancer and has presented new challenges to the clinician because of the unique issues involved with genetic testing. In this review, an overview of the colon cancer high-risk syndromes, with a focus on the availability and indications for genetic testing, is presented.
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Affiliation(s)
- William M Grady
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2279, USA.
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23
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Allen BA, Terdiman JP. Hereditary polyposis syndromes and hereditary non-polyposis colorectal cancer. Best Pract Res Clin Gastroenterol 2003; 17:237-58. [PMID: 12676117 DOI: 10.1016/s1521-6918(02)00149-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Colorectal cancer due to hereditary syndromes comprises approximately 5% of the overall colorectal cancer burden. Conditions fall into two distinct categories, the polyposis syndromes and hereditary non-polyposis colorectal cancer. It is important for the clinician to have a working knowledge of both as screening and surveillance recommendations differ significantly from those applicable to the general population. The polyposis syndromes include familial adenomatous polyposis, Peutz-Jeghers syndrome, juvenile polyposis, and Cowden syndrome. For each condition, a review of both the intestinal and extra-intestinal clinical findings is presented as well as the genetic basis, genetic testing, screening, surveillance and treatment options. As genetic testing for several of these conditions has recently become both commercially available and standard practice, special attention is given to indications and strategies for genetic testing in hereditary colorectal cancer syndromes.
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Affiliation(s)
- Brian A Allen
- University of California, San Francisco, 1600 Divisadero Street Box 1623, San Francisco, CA 94143, USA
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24
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Kim KE. Risk assessment and screening for colorectal cancer. CANCER CHEMOTHERAPY AND BIOLOGICAL RESPONSE MODIFIERS ANNUAL 2003; 21:747-57. [PMID: 15338772 DOI: 10.1016/s0921-4410(03)21035-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Karen E Kim
- Section of Gastroenterology, University of Chicago, IL 60637, USA.
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25
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Spolidoro JV, Kay M, Ament M, Cadranel S, Fujimoto T, Gilger M, Kato S, Olives JP, Goncalves MEP, Wyllie R. New endoscopic and diagnostic techniques: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition: management of GI bleeding, dysplasia screening, and endoscopic training--issues for the new millennium. J Pediatr Gastroenterol Nutr 2002; 35 Suppl 2:S196-204. [PMID: 12192189 DOI: 10.1097/00005176-200208002-00018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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26
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McGrath DR, Spigelman AD. Hereditary colorectal cancer: keeping it in the family--the bowel cancer story. Intern Med J 2002; 32:325-30. [PMID: 12088352 DOI: 10.1046/j.1445-5994.2002.00224.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Up to 20% of colorectal cancers are thought to have a genetic component. Several familial syndromes are known to confer an increased risk for colorectal cancer. Advances in our understanding of these syndromes has improved the care delivered to, and the overall survival of, these patients. Genetic testing has great potential to further improve detection and direct subsequent preventative measures. The diagnosis, management and surveillance issues relating to some of the more commonly encountered syndromes - in particular Familial Adenomatous Polyposis and Hereditary Non-Polyposis Colorectal Cancer - are reviewed.
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Affiliation(s)
- D R McGrath
- Discipline of Surgical Science, Faculty of Health, The University of Newcastle, New South Wales, Australia
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27
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Solano AR, Dourisboure RJ, Weitzel J, Podesta EJ. A cautionary note: false homozygosity for BRCA2 6174delT mutation resulting from a single nucleotide polymorphism masking the wt allele. Eur J Hum Genet 2002; 10:395-7. [PMID: 12080393 DOI: 10.1038/sj.ejhg.5200821] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2001] [Revised: 04/15/2002] [Accepted: 04/16/2002] [Indexed: 11/08/2022] Open
Abstract
Sequencing an amplification product of the terminal segment of BRCA2 exon 11 showed apparent homozygosity for the 6174delT mutation in two healthy sisters. Subsequent sequencing of an alternate overlapping amplicon revealed the presence of the 5972C >T polymorphism, which is within the standard upstream amplification primer. This mismatch was responsible for the failure to amplify the normal (5972T) allele in both sisters who were heterozygous for the 6174delT mutation. Though the unexpected finding of apparent homozygosity for the 6174delT mutation prompted re-evaluation of the assay, the potential for false negative results due to masking of a mutation-bearing allele by such a circumstance should be a cautionary note for the testing and also in the interpretation of the results published under such assay conditions.
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Affiliation(s)
- Angela R Solano
- Laboratory ACDM-Instituto Alexander Fleming, Buenos Aires, Argentina.
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28
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Easson AM, Cotterchio M, Crosby JA, Sutherland H, Dale D, Aronson M, Holowaty E, Gallinger S. A population-based study of the extent of surgical resection of potentially curable colon cancer. Ann Surg Oncol 2002; 9:380-7. [PMID: 11986190 DOI: 10.1007/bf02573873] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND We attempted to determine factors contributing to the extent of initial curative resection for colon cancer in a population-based cohort. Total abdominal colectomy with ileorectal anastomosis (TAC-IR) may be considered for young patients or those with a colorectal cancer family history to prevent metachronous lesions and facilitate surveillance. METHODS All Ontario patients newly diagnosed with colon cancer over 12 months beginning in July 1997 were staged at the time of surgery. The extent of resection was compared with variables, including familial risk obtained from the Ontario Familial Colon Cancer Registry. RESULTS Complete staging was possible for 86% of patients. A total of 1223 patients had a potentially curative resection: 17%, 46%, and 36% were stage I, II, and III, respectively. Patients were more likely to receive a TAC-IR if they were < or = 50 years old (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.8-6.6), if they had a synchronous lesion (OR, 28.37; 95% CI, 12.2-61.2), or if they were at a teaching hospital (OR, 2.8; 95% CI, 1.6-4.7), but not if they had a family history (OR,.7; 95% CI,.3- 1.5). CONCLUSIONS Young age, teaching hospital, and multiple cancers but not family history were important factors for performing a TAC-IR.
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Affiliation(s)
- Alexandra M Easson
- Department of Surgical Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada.
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29
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Abstract
Screening for colorectal cancer is commanding increasing attention. Other cancer screening programmes have been a part of public consciousness for some time, but, until recently, colorectal cancer screening has remained in the background. Fuelled by new research, market opportunities and increased recognition of individual risk, screening for colorectal cancer is becoming a recommended procedure, but controversy about how best to implement widespread screening remains.
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Affiliation(s)
- Robert E Schoen
- Division of Gastroenterology, Pennsylvania University Hospital, Pittsburgh 15213-2582, USA.
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30
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Cai Q, Sun MH, Lu HF, Zhang TM, Mo SJ, Xu Y, Cai SJ, Zhu XZ, Shi DR. Clinicopathological and molecular genetic analysis of 4 typical Chinese HNPCC families. World J Gastroenterol 2001; 7:805-10. [PMID: 11854906 PMCID: PMC4695599 DOI: 10.3748/wjg.v7.i6.805] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [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: To study the clinicopathological and mole cular genetic characteristics of typical Chinese hereditary nonpolyposis cotorectal cancer (HNPCC) families.
METHODS: Four typical Chinese HNPCC families were analyzed using microdissection, microsatellite instability analysis, immunostaining of hMSH2 and hMLH1 proteins and direct DNA sequencing of hMSH2 and hMLH1 genes.
RESULTS: All five tumor tissues of 4 probands from the 4 typical Chinese HNPCC families showed microsatellite instability at more than two loci (MSI-H or RER+ phenotype). Three out of the 4 cases lost hMSH2 protein expression and the other case showed no hMLH1 protein expression. Three pathological germline mutations (2 in hMSH2 and 1 in hMLH1), which had not been reported previously, were identified. The same mutations were also found in other affected members of two HNPCC families, respectively.
CONCLUSION: Typical Chinese HNPCC families showed relatively frequent germline mutation of mismatch repair genes. High-level microsatellite instability and loss of expression of mismatch repair genes correlated closely with germline mutation of mismatch repair genes. Microsatellite instability analysis and immunostaining of mismatch repair gene might serve as effective screening methods before direct DNA sequencing. It is necessary to establish clinical criteria and molecular diagnostic strategies more suitable for Chinese HNPCC families.
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Affiliation(s)
- Q Cai
- Department of Pathology, Cancer Hospital/Cancer Institute, Fudan University, Shanghai 200032, China
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31
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Povey AC, Hall CN, Badawi AF, Cooper DP, Guppy MJ, Jackson PE, O'Connor PJ, Margison GP. Host determinants of DNA alkylation and DNA repair activity in human colorectal tissue: O(6)-methylguanine levels are associated with GSTT1 genotype and O(6)-alkylguanine-DNA alkyltransferase activity with CYP2D6 genotype. Mutat Res 2001; 495:103-15. [PMID: 11448648 DOI: 10.1016/s1383-5718(01)00203-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
There is increasing evidence that alkylating agent exposure may increase large bowel cancer risk and factors which either alter such exposure or its effects may modify risk. Hence, in a cross-sectional study of 78 patients with colorectal disease, we have examined whether (i) metabolic genotypes (GSTT1, GSTM1, CYP2D6, CYP2E1) are associated with O(6)-methyldeoxyguanosine (O(6)-MedG) levels, O(6)-alkylguanine-DNA alkyltransferase (ATase) activity or K-ras mutations, and (ii) there was an association between ATase activity and O(6)-MedG levels. Patients with colon tumours and who were homozygous GSTT1(*)2 genotype carriers were more likely than patients who expressed GSTT1 to have their DNA alkylated (83 versus 32%, P=0.03) and to have higher O(6)-MedG levels (0.178+/-0.374 versus 0.016+/-0.023 micromol O(6)-MedG/mol dG, P=0.04) in normal, but not tumour, DNA. No such association was observed between the GSTT1 genotype and the frequency of DNA alkylation or O(6)-MedG levels in patients with benign colon disease or rectal tumours. Patients with colon tumours or benign colon disease who were CYP2D6-poor metabolisers had higher ATase activity in normal tissue than patients who were CYP2D6 extensive metabolisers or CYP2D6 heterozygotes. Patients with the CYP2E1 Dra cd genotype were less likely to have a K-ras mutation: of 55 patients with the wild-type CYP2E1 genotype (dd), 23 had K-ras mutations, whereas none of the 7 individuals with cd genotype had a K-ras mutation (P=0.04). No other associations were observed between GSTT1, GSTM1, CYP2D6 and CYP2E1 Pst genotypes and adduct levels, ATase activity or mutational status. O(6)-MedG levels were not associated with ATase activity in either normal or tumour tissue. However, in 15 patients for whom both normal and tumour DNA contained detectable O(6)-MedG levels, there was a strong positive association between the normal DNA/tumour DNA adduct ratio and the normal tissue/tumour tissue ATase ratio (r(2)=0.66, P=0.001). These results indicate that host factors can affect levels both of the biologically effective dose arising from methylating agent exposure and of a susceptibility factor, the DNA repair phenotype.
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Affiliation(s)
- A C Povey
- Cancer Research Campaign Carcinogenesis Group, Paterson Institute for Cancer Research, Manchester M20 9BX, UK.
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32
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Abstract
Colorectal cancer remains a leading cause of cancer-related mortality in the United States. Recently, colorectal cancer screening and colorectal cancer prevention have gained national attention. In response, the American Gastroenterological Association, the American College of Gastroenterology and the Agency for Healthcare Policy and Research have published recommendations for colorectal cancer screening and surveillance in patients with sporadic as well as hereditary forms of colorectal cancer. This review will focus on the basic molecular differences underlying the formation of carcinoma in patients with sporadic colorectal cancer, and the heritable syndromes of familial adenomatous polyposis (FAP), hereditary non-polyposis colorectal cancer (HNPCC), and juvenile polyposis (JPS). By appreciating the molecular mechanisms underlying these four types of polyp cancer syndromes, the differences in clinical time course for progression from polyp to carcinoma and in current screening recommendations for patients with sporadic adenomas, FAP, HNPCC and JPS can be better understood.
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Affiliation(s)
- R F Souza
- Department of Medicine, Dallas VA Medical Center and University of Texas-Southwestern Medical Center at Dallas, TX, USA.
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33
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Abstract
OBJECTIVE To review the advances in clinically useful molecular biological techniques and their applications in clinical practice as presented at the Ninth Annual William Beaumont Hospital DNA Symposium. DATA SOURCES The 10 manuscripts submitted were reviewed and their major findings were compared with literature on the same topic. STUDY SELECTION One manuscript reviewed the development of pharmacogenetics, 3 described analytic approaches to detect aneuploidy or cancer, 1 described transcription factor E2F-1 increase during apoptosis, 2 reported on genetic and pharmacologic factors that influence platelet aggregation, 2 described molecular methods for detecting long QT syndrome or mycobacteria, and 1 reported a modification in collection of buccal DNA. DATA SYNTHESIS Genomic and proteomic approaches to develop clinically useful assays have been successful. Aneuploidy can be easily detected by comparative genomic hybridization, which does not require cell culture like cytogenetics. Mutations have been characterized for a variety of hereditary cancer syndromes, 2 inherited long QT syndromes, and thromboembolism. PlA1 and PlA2 polymorphisms in platelets are associated with a difference in aggregation inhibition by estrogen, another example of genotypic pharmacogenetics. Protein expression differences may define colorectal cancer stage and explain apoptotic signal transduction. Mycobacterial detection by nucleic acid amplification and simplified buccal DNA collection demonstrate cost-effective strategies. CONCLUSION The working draft of the Human Genome Project is completed and the number of clinically useful molecular pathologic techniques and assays will expand as additional disease-associated mutations are defined. Expanded use of database software for genomic and proteomic screening should increase the efficiency of clinical useful assay development.
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Affiliation(s)
- F L Kiechle
- Department of Clinical Pathology, William Beaumont Hospital, Royal Oak, Mich 48073-6769, USA.
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34
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Terdiman JP, Gum JR, Conrad PG, Miller GA, Weinberg V, Crawley SC, Levin TR, Reeves C, Schmitt A, Hepburn M, Sleisenger MH, Kim YS. Efficient detection of hereditary nonpolyposis colorectal cancer gene carriers by screening for tumor microsatellite instability before germline genetic testing. Gastroenterology 2001; 120:21-30. [PMID: 11208710 DOI: 10.1053/gast.2001.20874] [Citation(s) in RCA: 103] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS The optimal strategy for the detection of hereditary nonpolyposis colorectal cancer (HNPCC) gene carriers remains uncertain. We evaluated whether microsatellite instability (MSI) analysis or MSH2 and MLH1 protein immunostaining of tumors will screen individuals efficiently for germline MSH2 and MLH1 testing. METHODS We performed a case-series study of 114 eligible families enrolled in our high-risk colorectal cancer (CRC) registry. Medical history data were collected on probands and relatives. MSI analysis was performed on proband tumors, and MSH2 and MLH1 protein immunostaining was assessed. Denaturing gradient gel electrophoresis was used to identify germline MSH2 or MLH1 mutations in probands found to have tumors with high-frequency MSI. RESULTS Tumor tissue and adequate clinical data were available in 109 of the 114 families. Amsterdam criteria and Bethesda guidelines were met by 23% and 70% of the families, respectively. High-frequency MSI was identified in the proband tumors in 47 of the 109 families (43%). Germline MSH2 and MLH1 gene testing was carried out in the probands of 32 of 47 families with MSI-H tumors. Mutations were detected in 16 families (9 in MSH2 and 7 in MLH1) and sequence variants of uncertain significance in 5 families (1 in MSH2 and 4 in MLH1). Germline mutations or sequence variants of uncertain significance were detected in 15 of 19 (79%) of our Amsterdam families and in 6 of 13 (46%) of our non-Amsterdam families with MSI-H tumors. MSH2 and MLH1 protein immunostaining was assessed in 38 of the 47 MSI-H tumors. Unequivocal loss of hMLH1 expression was found in 20 tumors and loss of MSH2 expression in 9 tumors. Corresponding loss of protein expression was seen in 17 of 18 (94%) of tumors from probands with germline mutations or variants. CONCLUSIONS The detection of high-frequency MSI or the loss of MSH2 or MLH1 immunostaining in CRCs are both useful criteria for selecting high-risk patients who should be tested for germline mutations in MSH2 or MLH1.
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Affiliation(s)
- J P Terdiman
- Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
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35
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Kinney AY, DeVellis BM, Skrzynia C, Millikan R. Genetic testing for colorectal carcinoma susceptibility: focus group responses of individuals with colorectal carcinoma and first-degree relatives. Cancer 2001; 91:57-65. [PMID: 11148560 DOI: 10.1002/1097-0142(20010101)91:1<57::aid-cncr8>3.0.co;2-u] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Colorectal carcinoma (CRC) may be the most frequent form of hereditary cancer. Genetic counseling and testing for heritable CRC is a promising approach for reducing the high incidence and mortality rates associated with the disease. Patients with CRC or those with at least one family member with the disease are the most likely persons to request or be offered genetic testing in the clinical or research setting. Currently, however, little is known about the behavioral, psychosocial, ethical, legal, and economic outcomes of CRC genetic counseling and testing. METHODS Eight focus group interviews, four for CRC patients (n = 28) and four for first-degree relatives (n = 33), were conducted to obtain insights into attitudes, beliefs, and informational needs about genetic testing for hereditary CRC. RESULTS Focus group interviews revealed a general lack of knowledge about cancer genetics and genetic testing; worry about confidentiality issues; strong concern for family members, particularly children; and a need for primary care providers to be informed about these issues. Major perceived advantages of genetic testing included improving health-related decisions, guiding physicians in making recommendations for surveillance, and informing relatives about risk potential. Disadvantages included potential discrimination, adverse psychologic effects, and financial costs associated with testing. CONCLUSIONS As knowledge and media coverage of genetics continue to expand, it becomes increasingly important to continue efforts on behalf of, and in partnership with, those individuals most affected by genetic testing for hereditary cancer syndromes. These findings provide data needed to develop and implement informational, educational, counseling, and research-oriented programs that are sensitive to individuals' concerns and preferences.
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Affiliation(s)
- A Y Kinney
- University of Utah College of Nursing, Salt Lake City, Utah 84112, USA.
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36
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Abstract
As befits a common cancer, a family history of colorectal cancer (CRC) is reported by about 10% of individuals. The discovery of the genetic basis of hereditary nonpolyposis CRC and familial adenomatous polyposis has opened up the possibility for determining genetic predisposition to CRC in asymptomatic family members of affected cases. This article reviews the information needed for accurate risk assessment for those with a family history of CRC. Screening recommendations and the current status of genetic testing, including review of available tests such as microsatellite instability, immunohistochemistry for hMSH2 and hMLH1, testing for I1307K, and gene testing for germline mutations in hMSH2 and hMLH1 are discussed. At the current time, reliable, informative genetic testing, capable of application to broad segments of the population, is an unrealized goal. But as the methodology for testing improves and as better appreciation of the significance and meaning of a positive or negative test result ensues conditions for increased use of genetic testing could emerge.
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Affiliation(s)
- R E Schoen
- Department of Medicine, University of Pittsburgh Medical Center, Pennsylvania, USA
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37
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Affiliation(s)
- R W Burt
- Division of Gastroenterology, Department of Medicine, University of Utah, Salt Lake City, Utah 84132, USA.
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38
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Abstract
Familial adenomatous polyposis (FAP) is a dominantly inherited familial cancer syndrome characterized by an increased predisposition to colorectal cancer and other benign and malignant extra-colonic lesions. FAP has been linked to germline mutations of the adenomatous polyposis coli (APC) gene that encodes a protein with 2,843 amino acids that has important functions in the regulation of cell growth. A genotype-phenotype correlation has also been observed between mutations in the APC gene and polyp phenotype. We review the clinical and genetic features of this disorder and provide information on the diagnostic approaches and treatment options available for this disease.
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Affiliation(s)
- G Lal
- Department of Surgery, University of Toronto, The Division of General Surgery, Toronto, Ontario, Canada
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39
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Barcus ME, Ferreira-Gonzalez A, Buller AM, Wilkinson DS, Garrett CT. Genetic changes in solid tumors. SEMINARS IN SURGICAL ONCOLOGY 2000; 18:358-70. [PMID: 10805958 DOI: 10.1002/(sici)1098-2388(200006)18:4<358::aid-ssu11>3.0.co;2-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Although most solid tumors are treated surgically, determining the genetic changes present in the tumor of an individual patient is becoming increasingly important for managing the oncology patient. Our knowledge of the genetic alterations that characterize and predispose to solid tumors continues to expand. Concurrently, the advent of newer technologies such as DNA chips has the potential to enable a more rapid and comprehensive assessment of these changes. The ultimate goal of this new information and technology is to provide sensitive and specific tests that reduce unnecessary procedures and optimize therapy. This review addresses the utility of molecular testing in evaluating cancer. A review of the current technology and hereditary cancer syndromes is also presented.
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Affiliation(s)
- M E Barcus
- Department of Pathology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia, USA
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