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Appendix C Lynch Syndrome Topic Brief Marc Williams, M.D. Intermountain Healthcare Clinical Genetics Institute LDS Hospital CLINICAL SCENARIO Tumor screening and genetic testing for Lynch syndrome, i.e., mismatch repair (MMR) gene mutations (changes), in individuals newly diagnosed with colorectal cancer in order to identify patients with Lynch syndrome and to reduce morbidity and mortality from Lynch syndrome in relatives (EGAPP, 2009; Palomaki et al., 2009). PUBLIC HEALTH IMPORTANCE Individuals with Lynch syndrome, sometimes referred to as hereditary non-polyposis colorectal cancer (HNPCC), have a high risk of developing colorectal cancer as well as other cancers, particularly endometrial. The increased risk is due to mutations in mismatch repair genes which reduce the ability of cells to repair DNA damage. Approximately 20 to 65 percent of individuals with Lynch syndrome develop colorectal cancer during their lifetimes, whereas lifetime risk in the general population is approximately 5.0 percent. Of the approximately 142,000 new cases of colorectal cancer diagnosed each year, approximately 4,250 (about 3 percent of all patients) are attributable to Lynch syndrome. In addition, about half of the close bio- logical relatives of those colorectal cancer patients with Lynch syndrome, about 8,000 relatives, also have Lynch syndrome and are at high risk. Screening for colorectal cancer substantially reduces the risk of developing colorectal cancer and is recommended for the general population begin- ning at age 50. Annual or biennial screening colonoscopy at an early age in 

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 ThE VALuE Of GENETIC AND GENOMIC TEChNOLOGIES individuals at high risk of Lynch has been found to reduce risk of colorectal cancer by about 60 percent. Genetic testing for MMR gene mutations can identify individuals with Lynch syndrome. Identifying Lynch syndrome in newly diagnosed colorectal patients and offering testing to relatives of patients with Lynch could identify relatives with Lynch syndrome before they develop cancer and allow them to reduce their risk through screening. Potentially, more than 2,500 cases of colorectal cancer could be prevented each year if all individuals with Lynch were identified and screened early (Baglietto et al., 2009; EGAPP, 2009; Horner et al., 2009; Palomaki et al., 2009; Stoffel et al., 2009; U.S. Cancer, 2009; U.S. Preventive Services Task Force, 2008). Test Purpose Screening: a test to identify patients with colorectal cancer who should be offered confirmatory molecular testing. Diagnostic: a test to confirm that the person has a specific genetic condition. Test Description DNA analysis of 4 major MMR genes (MLh, MSh, MSh, and PMS) is the standard test for Lynch (Bonis et al., 2007; EGAPP, 2009; Palomaki et al., 2009). Because of the cost of MMR testing, 3 preliminary tests on tumors may be considered in patients with colorectal cancer in order to determine whom to test for MMR mutations. Microsatellite insta- bility (MSI) testing identifies tumors demonstrating abnormalities of DNA mismatch repair. Patients with a high instability score can be offered DNA sequencing of the 4 MMR genes. Immunohistochemical (IHC) staining tests of tumors identify proteins produced by MMR genes. Patients with no stain- ing of a specific protein can be offered DNA analysis of the MMR gene identified by IHC. About 30 percent of tumors that lack staining for the MLH1 protein have a somatic mutation in BRAf (V600E) or MLh pro- moter hypermethylation, neither of which is associated with Lynch syndrome. BRAf gene testing and MLh promoter hypermethylation may be done for patients who have no IHC staining for MLH1. Patients who do not have the BRAf mutation or MLh promoter hypermethylation can be offered DNA analysis of MLh. MLh promoter hypermethylation was not considered in the published evidence reviews. Other test combinations are sometimes used (Bonis et al., 2007; EGAPP, 2009; Palomaki et al., 2009).

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 APPENDIX C Systematic Evidence Reviews Agency for Healthcare Research and Quality, Evidence Report/Technology Assessment (Bonis et al., 2007). Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Supplemental Evidence Review (Palomaki et al., 2009). Recommendations by an Independent Group The EGAPP Working Group recommended offering genetic testing for Lynch syndrome in individuals newly diagnosed with colorectal cancer in order to reduce morbidity and mortality in relatives (EGAPP, 2009). Guidelines by Professional Groups American Society of Clinical Oncology (Locker et al., 2006). National Comprehensive Cancer Network (National Cancer Center, 2010). EVIDENCE OVERVIEW Analytic Validity The accuracy and reliability of the tests in detecting the genetic changes of interest. Based on evidence reviews, the EGAPP Working Group reported that, overall, the analytic validity of the tests is high, although there were gaps in research on analytic validity and proficiency testing, as described below (Bonis et al., 2007; EGAPP, 2009; Palomaki et al., 2009). MMR: DNA sequencing of 4 MMR genes (MLh, MSh, MSh, and PMS) is the practice standard, but actual performance is difficult to esti- mate and it is not known if laboratory proficiency testing will be an ade- quate validity measure. In addition, research may identify additional MMR genes (Yu et al., 2010). MSI: Testing is offered by many laboratories that participate in proficiency testing programs, and performance in such testing programs is high, so adherence to best practices may provide valid testing. 1 Independent groups include the Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children, the Evaluation of Genomic Applications in Practice and Prevention (EGAPPP) Working Group, the United Kingdom’s National Institute for Health and Clinical Excellence, and the U.S. Preventive Services Task Force (USPSTF).

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4 ThE VALuE Of GENETIC AND GENOMIC TEChNOLOGIES IHC: IHC proficiency testing is offered for other proteins but not specifi- cally for MMR gene proteins. BRAF: Given that the goal of this test is to identify a single mutation and that proficiency testing for some other single-mutation tests has been high, analytic validity is likely to be high. Clinical Validity The accuracy and reliability of the test in identifying patients with the disorder. Based on the evidence reviews, the EGAPP Working Group reported that there is adequate evidence of clinical validity for the preliminary tests, although the evidence varied and research gaps were identified for the issues of which tests and which combinations perform best and the use of family history with tests, as described below (Baglietto et al., 2009; Bonis et al., 2007; EGAPP, 2009; Palomaki et al., 2009; Stoffel et al., 2009). MMR: DNA sequencing of 4 MMR genes (MLh, MSh, MSh, and PMS) is the current standard for defining patients with Lynch syndrome. The lifetime risk of colorectal cancer among individuals with Lynch syn- drome is approximately 20 to 65 percent. MSI: Studies enrolling a total of 150 patients with Lynch syndrome and using a variety of MSI methods found that high MSI score test results are adequately sensitive and specific in identifying individuals who had tested positive for some MMR genes. IHC: Studies with a total of 149 patients found that IHC testing is ade- quately sensitive and specific in identifying individuals who test positive for some MMR genes. BRAF: A few studies found BRAf mutation tests are adequately sensitive and specific in identifying individuals with abnormal MLH1 staining. Clinical utility The possibility that using the test will lead to improved health. Based on the evidence reviews, the EGAPP Working Group reported that there is adequate evidence from research that more than 90 percent of relatives of patients with Lynch would consent to genetic testing and that more than half of those who were identified as having Lynch syndrome began screening with colonoscopy, beginning at age 20–25. A single study

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 APPENDIX C of relatives at high risk provides evidence that screening colonoscopy results in an approximately 60 percent reduction in the incidence of colorectal cancer. Harms appear to be minimal in comparison with benefits. However, additional research is needed on the overall strategy, or each step from offering genetic testing to patients through studying the long-term health benefits to relatives. Additional cost–benefit analyses are also needed (Bonis et al., 2007; EGAPP, 2009; Palomaki et al., 2009). Screening or prophylac- tic surgery for prevention of other Lynch-syndrome-associated cancers (par- ticularly endometrial) have not been assessed for utility. A cost-effectiveness analysis has reported an incremental cost-effectiveness ratio of less than $45,000 per quality-adjusted life-year saved for a Lynch syndrome testing strategy using tumor screening and genetic testing for all individuals newly diagnosed with colorectal cancer (Mvundura et al., 2010). Contextual Issues Including clinical alternatives to genetic testing and practice; ethical, legal, and social issues. The EGAPP Working Group found that, based on the evidence reviews, methods using family history to identify patients with Lynch produce inconsistent results and identify a lower percentage of patients with Lynch than do tumor-based screening protocols. However, MMR testing of patients based on family history was not excluded. The work- ing group also recommended informed consent for preliminary testing of patients and noted that studies suggest adverse psychosocial outcomes should be minimal and that resource requirements appear to be justified by the willingness of relatives to participate in health benefits for relatives (Bonis et al., 2007; EGAPP, 2009; Palomaki et al., 2009). A recent report suggests that more research is needed on psychosocial issues because of evidence that some subgroups are more vulnerable to testing-related stress (Landsbergen et al., 2009). Overall, there is limited research on how to effectively implement testing. REFERENCES Baglietto, L., N. M. Lindor, J. G. Dowty, D. M. White, A. Wagner, E. B. Gomez Garcia, A. H. J. T. Vriends, et al. 2009. Risk for Lynch syndrome cancers for MSh mutation carriers. J Natl Cancer Inst 102:1–9. Bonis, P. A., T. A. Trikalinos, M. Chung, P. Chew, S. Ip, D. A. Devine, J. Lau. 2007. Hereditary nonpolyposis colorectal cancer: Accuracy of diagnostic strategies and implications to pa- tients with colorectal cancer and their families. Evidence Report/Technology Assessment No. 07-E008. Rockville, MD: Agency for Healthcare Research and Quality. http://www. ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=erta150 (accessed August 24, 2010).

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 ThE VALuE Of GENETIC AND GENOMIC TEChNOLOGIES Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. 2009. Recommendations from the EGAPP Working Group: Genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med 11(1):35–41. Horner, M. J., L. A. G. Ries, M. Krapcho, N. Neyman, R. Aminou, N. Howlader, S. F. Altekruse, et al. (eds). 2009. SEER Cancer Statistics Review, 1975–2006. National Cancer Institute. Bethesda, MD. http://seer.cancer.gov/csr/1975_2006/ (accessed August 24, 2010). Landsbergen, K. M., J. B. Prins, H. G. Brunner, F. W. Kraaimaat, and N. Hoogerbrugge. 2009. Genetic testing for Lynch syndrome in the first year of colorectal cancer: A review of the psychological impact. familial Cancer 8:325–337. Locker, G. Y., S. Hamilton, J. Harris, J. M. Jessup, N. Kemeny, J. S. Macdonald, M. R. Somerfield, et al. 2006. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Oncol Pract 24:5313–5327. Mvundura, J., S. D. Grosse, H. Hampel, and G. E. Palomaki. 2010. The cost-effectiveness of genetic testing strategies for Lynch syndrome among newly diagnosed patients with colorectal cancer. Genet Med. 12(2):93–104. National Cancer Center Network Guidelines. 2010. NCCN Practice Guidelines in Oncology. Screening for Colorectal Cancer. www.nccn.org/professionals/physician_gls/f_guidelines. asp#detection (accessed January 13, 2010). Palomaki, G. E., M. R. McClain, S. Melillo, H. L. Hampel, and S. N. Thibodeau. 2009. EGAPP supplementary evidence review: DNA testing strategies aimed at reducing mor- bidity and mortality from Lynch syndrome. Genet Med 11(1):42–65. Stoffel, E., B. Mukhergee, B. M. Raymond, N. Tayob, F. Kastrinos, J. Sparr, F. Wang, et al. 2009. Calculation of risk of colorectal cancer and endometrial cancer among patients with Lynch syndrome. Gastroenterology 137:1621–1627. U.S. Cancer Statistics Working Group. 2009. United States Cancer Statistics: 1999–2005 Incidence and Mortality Web-based Report. Atlanta: U.S. Department of Health and Hu- man Services, Centers for Disease Control and Prevention and National Cancer Institute. www.cdc.gov/uscs (accessed August 24, 2010). U.S. Preventive Services Task Force. 2008. Screening for colorectal cancer: Statement of the U.S. Preventive Services Task Force. Ann Intern Med 149(9):627–637. Yu, W., M. Clyne, M. J. Khoury, and M. Gwinn. 2010. Phenopedia and Genopedia: Disease- centered and Gene-centered Views of the Evolving Knowledge of Human Genetic Asso- ciations. Bioinformatics, search term “Lynch Syndrome.” http://www.hugenavigator.net/ HuGENavigator/phenoPedia .do?firstQuery=LynchSyndromeII&cuiID=C1333991&type Submit=GO&check=y&which=2&pubOrderType=pubD (accessed January 12, 2010).