EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome
2009; Elsevier BV; Volume: 11; Issue: 1 Linguagem: Inglês
10.1097/gim.0b013e31818fa2db
ISSN1530-0366
AutoresGlenn E. Palomaki, Monica R. McClain, Stephanie Melillo, Heather L. Hampel, Stephen N. Thibodeau,
Tópico(s)Cancer Genomics and Diagnostics
ResumoAn original evidence review examined screening and diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) and the subsequent outcomes in a population of newly diagnosed cases of colorectal cancer (CRC). This supplementary evidence review focuses on five issues of further interest to the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG), as summarized below. 1.Clarifying how to define the clinical disorder—Lynch syndrome. In this supplementary review, Lynch syndrome refers to individuals with a predisposition to CRC and certain other malignancies as a result of a germline mismatch repair (MMR) gene mutation—including those with an existing cancer and those who have not yet developed cancer. This definition allows planned analyses of clinical validity and utility to be more straightforward. Several recent editorials and publications recommend that the ambiguous term HNPCC be abandoned and that this clarified definition of Lynch syndrome should be used instead.2.Removing family history from consideration as a preliminary test. A previous evidence review showed that screening performance of both the Amsterdam and the Bethesda criteria to identify individuals with Lynch syndrome were highly heterogeneous, possibly due to differences among the populations tested. In a general population, Amsterdam criteria are associated with relatively low sensitivity (28–45%), but high specificity (99%), whereas Bethesda criteria are associated with higher sensitivity (73–91%), but at the cost of lower specificity (82–77%). Neither provides the necessary high sensitivity/specificity in a reliable and consistent manner. There are also gaps in knowledge relating to the time required to collect family history, the consistency with which it is collected, and the accuracy of the information. These shortcomings have led us to remove family history from consideration as a preliminary test in individuals newly diagnosed with CRC. However, family history may still be an important component of CRC risk assessment in the general population.3.Documenting the clinical validity of DNA-based preliminary tests. Because of rapid advances in knowledge and technology regarding molecular testing and Lynch syndrome, we generally limited this review to publications from 2003 and later. Although not formally studied, this is a likely reason why several of our estimates differ from those provided in an earlier evidence report. There was “Adequate” (a formal EWG term) evidence showing the sensitivity of microsatellite instability (MSI) testing to be about 89% (for mutations in the MMR genes MLH1 and MSH2), with a lower sensitivity of about 77% for MSH6 mutations. Sensitivity was higher when three or more mononucleotide markers were included in the panel. Specificity was estimated to be 90.2%, with an adequate level of evidence. There was also good evidence showing the sensitivity of immunohistochemical (IHC) testing to be 83%, regardless of the underlying MMR gene involved. Specificity was more variable with a central estimate of 88.8%, and an adequate level of evidence. Inadequate evidence was available to determine the distribution of mutations in the MMR genes, but the limited data suggest 32% will be in MLH1, 38% in MSH2, 14% in MSH6, and 15% in PMS2. Adequate evidence was available to estimate sensitivity (69%) and specificity (point estimate of 100%) for identifying Lynch syndrome using a specific mutation in the BRAF gene among those with absent IHC staining for MLH1. An alternative to BRAF mutation testing might be direct testing of MLH1 methylation status, but this was not evaluated.4.Benefits and harms to probands and relatives with Lynch syndrome. Between 2 and 12 first-degree relatives of probands (newly diagnosed CRC cases with Lynch syndrome, or index cases) can be contacted, based on resources and methodology. There was adequate evidence to document uptake of counseling among these first-degree relatives who were contacted (52%) and subsequently targeted for MMR gene mutation testing (95%). Adequate evidence was found showing the risk of CRC by age 70 to be approximately 45% for men and 35% for women among relatives with Lynch syndrome. This is lower than earlier estimates, because of the more severe family histories included in earlier studies. Among relatives with Lynch syndrome, risks for endometrial cancer by 70 years of age are variable and range from as low as 31% to as high as 64%. Some of the higher estimates, however, may be subject to family history bias. The U.S. Multisociety Task Force on Colorectal Cancer recommends colonoscopy every 1 or 2 years for first-degree relatives of individuals diagnosed with Lynch syndrome, and uptake among this group is about 80%. The most serious adverse events associated with colonoscopy in the general population are bleeding (1.1/1000 individuals), perforation (3.3/1000), and death (0.08/1000). Adequate evidence on the effectiveness of routine colonoscopy in relatives with Lynch syndrome is available from a controlled trial in Finland and from an observational cohort study in the Netherlands. Evidence, overall, was rated as Level IIb. By using an intention to treat analysis, the Finnish study reported that CRC incidence was reduced by 62%, with no deaths among those undergoing surveillance, compared with nine in the control group. Other less direct studies suggest efficacy of periodic colonoscopy. Adequate evidence exists that 63% of women will adhere to endometrial cancer surveillance. Inadequate data are available to document that transvaginal ultrasound and endometrial biopsy can reduce the incidence of endometrial cancer. Hysterectomy and bilateral salpingo-oophorectomy are effective in reducing the risk for endometrial cancer, but uptake is low (19%) and it has not been the standard of care to recommend this procedure.5.Economic modeling of programmatic costs and costs per Lynch syndrome detected using four different testing strategies. Data from this supplementary review, along with other published information, were used to perform a cost-consequences analysis. Rather than looking at health outcomes, this type of analysis focuses on the direct consequences of testing. In this analysis, the costs per Lynch syndrome case detected were determined for four strategies that represent a wide range of possible testing/diagnostic scenarios. The list of strategies is not intended to be exhaustive but to provide examples. It is assumed that the initial test in each of the four strategies described below would have 67% uptake so that detection rates for Lynch syndrome can be compared between strategies. Subsequent actions are modeled at rates found in the literature (e.g., uptake of counseling and testing among their relatives). Total program costs (preliminary testing, counseling, diagnostic testing, contacting relatives and targeted testing) are computed assuming a cohort of 150,000 newly diagnosed CRC cases with a 3% prevalence of Lynch syndrome. a.Strategy 1. Individuals with newly diagnosed CRC (probands) would have MMR gene sequencing/deletion testing for MLH1, MSH2, and MSH6. This strategy will have the highest sensitivity for Lynch syndrome (about 85% or 2537 of the 3000 cases), and cost about $111,000 (90% CI, $83,000–$148,000) per proband with Lynch syndrome detected. If relatives of the proband are included in the analysis as well, the cost per adult with Lynch detected is reduced to about $72,000 (90% CI, $49,000–$101,000). Costs are reduced when relatives are included because they require only counseling and targeted testing for the family mutation. Total program costs for this strategy are about $281 million.b.Strategy 2. All probands would have quality MSI testing; those with high instability would have sequencing/deletion testing for the three MMR genes. This strategy will have a lower overall detection rate (73% or 2198 cases) because the MSI is not high in all individuals with Lynch syndrome. The cost per proband with Lynch syndrome detected is $47,000 (90% CI, $33,000–$64,000). When relatives are included, the cost per case detected is reduced to $31,000 (90% CI, $20,000–$44,000). Total program costs are about $104 million.c.Strategy 3. All probands would have quality IHC testing; those with negative staining would have sequencing/deletion testing for the some of the three MMR genes. This strategy will have a slightly lower overall detection rate (70% or 2105 cases), compared with Strategy 2, because IHC testing seems to be slightly less reliable when identifying probands with Lynch syndrome. The cost per Lynch syndrome proband detected is $21,000 (90% CI, $14,000–$29,000). When relatives are included, the cost per case detected is reduced to $14,000 (90% CI, $9,000–$20,000). The lower costs are because IHC testing provides information about which MMR gene(s) are likely to contain the mutation, thereby reducing testing costs for the probands. Total program costs are about $46 million.d.Strategy 4. Strategy 3 is modified so that probands with an IHC MLH1 negative stain are all tested for the specific BRAF mutation. If that mutation is not found, the individual continues on for MMR gene(s) testing. If the mutation is found, no further testing (sequencing) is required as the chance of having Lynch syndrome is very low. The overall detection rate remains at about 70% (or 2097 cases), as the sensitivity of BRAF mutation testing is close to 100%. The cost per Lynch syndrome proband detected is $19,000 (90% CI, $13,000–$26,000). When relatives are included, the cost per case detected is reduced to $13,000 (90% CI, $8,000–$18,000). Total program costs are about $41 million. •What is the clinical validity of sequentially applied screening tests (e.g., MSI, then IHC testing)?•Is methylation testing useful as part of preliminary testing for Lynch syndrome?•Additional information needs to be collected regarding the methods of identifying, approaching, educating, counseling, and testing relatives of probands with Lynch syndrome.•Although randomized trials are unlikely, observational studies could provide additional information on whether systematic surveillance is effective in reducing Lynch syndrome–related morbidity and mortality for both CRC and other related cancers.•Should the clinical care of CRC patients with Lynch syndrome be altered?•Among females with Lynch syndrome, is endometrial cancer surveillance effective?•A comprehensive cost-effectiveness analysis (CEA) should be performed as a way to help inform policymakers about which strategy(s) might be recommended. The aims of this supplementary evidence review are to reconsider aspects of the evidence regarding: (1) a clarified DNA-based definition of the clinical disorder; (2) performance characteristics of preliminary, laboratory-based tests, taking into account the technical laboratory issues and new markers; (3) an updated and expanded exploration of implications for other family members (psychosocial, as well as other benefits and harms); (4) the usefulness of considering family history as a preliminary test; and (5) an economic model for detecting Lynch syndrome that includes both probands and their first-degree relatives. Recently, an evidence report was released1.Bonis PA, Trikalinos TA, Chung M, et al. Hereditary nonpolyposis colorectal cancer: accuracy of diagnostic strategies and implications to patients with colorectal cancer and their families. Evidence report/technology assessment No. 07-E008. Rockville, MD: Agency for Healthcare Research and Quality, 2007.Google Scholar regarding the use of gene-based tests in the diagnosis and treatment of HNPCC. Its purpose was to inform the EGAPP Working Group (EWG) in making recommendations. Because these tests are rapidly evolving and the evidence report highlighted important gaps in knowledge, the EWG requested a supplementary report to provide updated information and an expanded evidence base upon which to build its recommendations.2.EGAPP Working Group 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 in relatives.Genet Med. 2009; 11: 35-41Abstract Full Text Full Text PDF PubMed Scopus (577) Google Scholar The updated information relies on the original evidence report as its basis, but adds to and extends those findings. This supplemental evidence was targeted at five specific areas after discussions with a Technical Evaluation Panel consisting of EWG members, Centers for Disease Control and Prevention (CDC) consultants and staff, and experts in the field of identifying Lynch syndrome (H. Hampel) and laboratory testing for Lynch syndrome (S. Thibodeau). These five areas are summarized below and the first four are reviewed in detail in the remainder of this document. Defining Lynch syndrome (sometimes referred to as HNPCC) clinically, using family and personal history of cancer, is problematic. The original Amsterdam criteria were designed to identify a suitable group for further study of an inherited form of CRC; not to define a specific clinical disorder. Subsequent modifications to these criteria (e.g., Bethesda criteria) were interpreted as a more sensitive test for identifying inherited forms of CRC. However, such a group is heterogeneous, with some cancers caused by MMR gene mutations, others by inactivated MMR genes, and many others of unknown etiology. This has led to confusion in the literature. As a result, specifications for the primary, evidence-based review were difficult to shape, and it was determined that interpretation of data from that review would require supplementary information. The initial review helped the EWG realize that the clinical scenario needed to be refined. Consequently, the present document replaces a family history–based definition with a molecular definition that has recently been promulgated in the research community—individuals with an identifiable MMR gene mutation are defined as having Lynch syndrome, whether or not an existing CRC or other cancer is present. On the basis of the original evidence report, the EWG Technical Evaluation Panel members decided against using the family history as the initial screening test (e.g., Bethesda criteria) in this population. This was based on the difficulty and the costs of obtaining reliable family history, and the overall poor sensitivity and specificity. Significant new information is available in the literature, and we also reviewed whether any information in the original evidence review had become outdated. For example, older reports containing results for MMR gene testing used less sensitive technologies (e.g., denaturing gradient gel electrophoresis or single strand conformation polymorphism analyses) and did not check for large deletions. In addition, older tests for MSI relied on only a few repeated sequences, compared with more recent expanded testing panels that utilize three or more mononucleotide repeats. Given the rapid advances in both knowledge and technology, we also restricted literature searches to more recent dates and stratified results by technology to determine the impact of newer test panels. For example, we stratified the analysis of MSI testing by factors known to improve sensitivity (e.g., number of mononucleotide repeats). The original evidence report (www.ahrq.gov/downloads/pub/evidence/pdf/hnpcc/hnpcc.pdf) addressed anxiety and psychosocial issues, but did not address the medical harms related to screening and diagnosis in probands and relatives (e.g., additional colonoscopies) or the benefits in probands and relatives (e.g., avoidable CRC and endometrial cancer). In addition, neither uptake rates for subsequent screening nor effectiveness of screening tests were addressed. This type of information is necessary when balancing the benefits and harms of testing and diagnosis, and also to inform decision analysis/economic models. Data from the original evidence report were reanalyzed to determine whether more data from the breast cancer literature could be included to inform the review. A more comprehensive set of models using updated information was requested in order that the EWG might create broad recommendations. For example, the model in the original evidence review did not consider the benefits that IHC testing provided in directing which MMR gene to sequence, nor did it include relatives of probands. Although it was not possible to perform a comprehensive CEA, it was possible to conduct a cost-consequences analysis to help inform recommendations. The EWG has explicit methods for both identifying published and gray data, and for ranking the quality of data sources (1 being the highest quality and 4 being the lowest) and quality of evidence (convincing being the highest, adequate and inadequate being the lowest).2.EGAPP Working Group 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 in relatives.Genet Med. 2009; 11: 35-41Abstract Full Text Full Text PDF PubMed Scopus (577) Google Scholar Criteria for both the quality of data sources and quality of evidence differ for analytic validity, clinical validity, and clinical utility. Specific details regarding the identification of data are contained within each section. In general, data identification was based on explicit search strategies for each question of interest, with occasional use of gray data, referral to the original evidence report,2.EGAPP Working Group 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 in relatives.Genet Med. 2009; 11: 35-41Abstract Full Text Full Text PDF PubMed Scopus (577) Google Scholar and in some instances, existing structured reviews. Although the analytic framework used for the original evidence review remains relevant, the present review does not address all aspects of the overarching question. For example, we did not systematically collect additional data regarding the analytic validity of preliminary DNA-based tests. An interpretation of the data are also provided for each question of interest that includes an assessment of quality of data and quality of evidence and identification of possible biases and gaps in knowledge. In this supplementary review, we will use the terminology and definitions as proposed by Jass3.Jass J.R. Hereditary non-polyposis colorectal cancer: the rise and fall of a confusing term.1:CAS:528:DC%2BD28XhtVehtrbL169374884087395World J Gastroenterol. 2006; 12: 4943-4950Google Scholar and Lindor et al.4.Lindor N.M. Rabe K. Petersen G.M. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X.1:CAS:528:DC%2BD2MXjsleitrs%3D158554312933042JAMA. 2005; 293: 1979-1985Google Scholar Lynch syndrome will refer to an individual with a germline MMR gene mutation who has a predisposition to CRC and to certain other malignancies, or is diagnosed with one of these cancers. The term HNPCC will generally not be used except in direct reference to a publication. The following sections provide the rationale for this definition. The term HNPCC is problematic and has multiple definitions (e.g., defined by family history, clinical, and/or pathologic features). In a 2005 editorial, Terdiman5.Terdiman J.P. It is time to get serious about diagnosing Lynch syndrome (hereditary nonpolyposis colorectal cancer with defective DNA mismatch repair) in the general population.16083727Gastroenterology. 2005; 129: 741-744Google Scholar provides an example of how the terms Lynch syndrome and HNPCC have multiple and overlapping definitions which can cause confusion. HNPCC, also called Lynch syndrome after Henry T. Lynch, MD, a pioneer in the field, is an autosomal dominant hereditary cancer syndrome which accounts for upwards of 3% of all CRC, and is associated with an increased risk of endometrial, ovarian, and other extra-colonic cancers. The syndrome originally was defined in clinical terms by the stringent Amsterdam criteria, although over time, more relaxed clinical definitions have been suggested, culminating in the recently published revised Bethesda guidelines. Many cases of clinically defined Lynch syndrome are caused by a germline mutation in one of a set of genes responsible for DNA mismatch repair. A solution to the confusion of terms is best summarized by Jass.3.Jass J.R. Hereditary non-polyposis colorectal cancer: the rise and fall of a confusing term.1:CAS:528:DC%2BD28XhtVehtrbL169374884087395World J Gastroenterol. 2006; 12: 4943-4950Google Scholar The term HNPCC is a poor descriptor of the syndrome described by Lynch. Over the last decade, the term has been applied to heterogeneous groups of families meeting limited clinical criteria, for example, the Amsterdam criteria. It is now apparent that not all Amsterdam criteria–positive families have the Lynch syndrome. The term HNPCC has also been applied to clinical scenarios in which CRCs with DNA microsatellite instability are diagnosed but in which there is no vertical transmission of an altered DNA mismatch repair gene. A term that has multiple, mutually incompatible meanings is highly problematic, particularly when it may influence the management of an individual family. The Lynch syndrome is best understood as a hereditary predisposition to malignancy that is explained by a germline mutation in a DNA MMR gene. The diagnosis does not depend in an absolute sense on any particular family pedigree structure or age of onset of malignancy. These definitions were extended by Lindor et al.4.Lindor N.M. Rabe K. Petersen G.M. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X.1:CAS:528:DC%2BD2MXjsleitrs%3D158554312933042JAMA. 2005; 293: 1979-1985Google Scholar who suggest using the term Familial CRC Type X to describe individuals in families satisfying stringent family history criteria (e.g., Amsterdam) who have no evidence of a MMR gene mutation. The use of HNPCC as a label needs to be refined or made obsolete. The term HNPCC encompasses considerable heterogeneity and has come to mean different entities to different people. We prefer the term “Lynch syndrome” or “HNPCC Lynch syndrome” to specify those individuals or families with germline mutations in the DNA MMR genes. It may be reasonable to introduce a term for families similar to our group B families, who have a clustering of CRC but in whose tumors no DNA MMR gene defect is evident. We suggest the term “familial colorectal cancer type X.” This term does not define these groups as having hereditary CRC (which usually implies single-gene etiology), and it acknowledges our lack of understanding of the etiology (thus the “X”). Regardless of what term is eventually adopted, it is essential that the term HNPCC not be used without clearly defining it, to acknowledge that families with Lynch syndrome (hereditary DNA MMR deficiency) and those with familial colorectal cancer type X are not equivalent entities. This is not to say that all experts in the field are consistently using this terminology at this point in time. In a 2007 article by Lynch et al.,6.Lynch H.T. Lynch J.F. Lynch P.M. Toward a consensus in molecular diagnosis of hereditary nonpolyposis colorectal cancer (Lynch syndrome).1:CAS:528:DC%2BD2sXjsVeitro%3D17312298J Natl Cancer Inst. 2007; 99: 261-263Google Scholar the terms HNPCC and Lynch syndrome are still, apparently, used interchangeably. Before molecular genetic diagnosis came of age in the 1990s, a comprehensive family history was the only basis on which familial risk of CRC could be estimated. In the case of HNPCC, also known as Lynch syndrome, the historic perspective offered by Warthin in 1895 has not changed appreciably. The optimal study design for this purpose would be population based, enrolling a large group of individuals consecutively diagnosed with CRC. Initially, MMR gene mutation testing, accounting for as many major mutations as possible, would be performed on all of these cases. MSI testing would then be performed on samples from all cases with a mutation. Testing (both for MSI and MMR mutations) would utilize the technology currently in use. We restricted the search to articles published in 2003 and later, to help ensure that retrieved studies utilized current testing technologies. By that time, testing laboratories often would have (1) incorporated the basic National Cancer Institute (NCI) panel7.Boland C.R. Thibodeau S.N. Hamilton S.R. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer.1:CAS:528:DyaK1cXnsFSmtbk%3D9823339Cancer Res. 1998; 58: 5248-5257Google Scholar for MSI testing; (2) included additional mononucleotide markers to improve performance8.Bacher J.W. Flanagan L.A. Smalley R.L. Development of a fluorescent multiplex assay for detection of MSI-High tumors.155287893839403Dis Markers. 2004; 20: 237-250Google Scholar,9.Buhard O. Suraweera N. Lectard A. Duval A. Hamelin R. Quasimonomorphic mononucleotide repeats for high-level microsatellite instability analysis.155287903888729Dis Markers. 2004; 20: 251-257Google Scholar; (3) routinely tested for mutations in MSH6 and, possibly, PMS2; and (4) routinely tested for large deletions in MMR genes using multiplex ligation-dependent probe amplification. We searched PubMed from 2003 through June 2007, using the MeSH terms “(Colorectal Neoplasms or Hereditary Nonpolyposis) and (MSI or microsatellite instability),” restricted to humans and the English language. Overall, 212 articles were identified. Two of us (G.E.P. and S.M.) reviewed the 212 abstracts and agreed that 28 full articles should be reviewed for appropriateness. Of these 28 articles, 11 met the following inclusion criteria.10.Barnetson R.A. Tenesa A. Farrington S.M. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer.1:CAS:528:DC%2BD28XmsVKrur8%3D16807412N Engl J Med. 2006; 354: 2751-2763Google Scholar, 11.Hendriks Y. Franken P. Dierssen J.W. Conventional and tissue microarray immunohistochemical expression analysis of mismatch repair in hereditary colorectal tumors.1:CAS:528:DC%2BD3sXhtlKrurY%3D125477051851154Am J Pathol. 2003; 162: 469-477Google Scholar, 12.Hendriks Y.M. Wagner A. Morreau H. Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance.1:CAS:528:DC%2BD2cXmsVShsr8%3D15236168Gastroenterology. 2004; 127: 17-25Google Scholar, 13.Hoedema R. Monroe T. Bos C. Genetic testing for hereditary nonpolyposis colorectal cancer.12769209Am Surg. 2003; 69: 387-391Google Scholar, 14.Lee S.C. Guo J.Y. Lim R. Clinical and molecular characteristics of hereditary non-polyposis colorectal cancer families in Southeast Asia.15996210Clin Genet. 2005; 68: 137-145Google Scholar, 15.Niessen R.C. Berends M.J. Wu Y. Identification of mismatch repair gene mutations in young patients with colorectal cancer and in patients with multiple tumours associated with hereditary non-polyposis colorectal cancer.1:CAS:528:DC%2BD2sXkvFOjtg%3D%3D166360191856475Gut. 2006; 55: 1781-1788Google Scholar, 16.Wolf B. Henglmueller S. Janschek E. Spectrum of germ-line MLH1 and MSH2 mutations in Austrian patients with hereditary nonpolyposis colorectal cancer.1:CAS:528:DC%2BD2MXhtVegsL3J15926618Wien Klin Wochenschr. 2005; 117: 269-277Google Scholar, 17.Plaschke J. Engel C. Kruger S. Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium.1:CAS:528:DC%2BD2cXhtFWqt7%2FM15483016J Clin Oncol. 2004; 22: 4486-4494Google Scholar, 18.Plevova P. Krepelova A. Papezova M. Immunohistochemical detection of the hMLH1 and hMSH2 proteins in hereditary non-polyposis colon cancer and sporadic colon cancer.1:CAS:528:DC%2BD2cXms1Gqs7g%3D15254659Neoplasma. 2004; 51: 275-284Google Scholar, 19.Southey M.C. Jenkins M.A. Mead L. Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer.1:CAS:528:DC%2BD2MXhtFWqsLnP16116158J Clin Oncol. 2005; 23: 6524-6532Google Scholar, 20.Spaepen M. Vankeirsbilck B. Van Opstal S. Germline mutations of the hMLH1 and hMSH2 mismatch repair genes in Belgian hereditary nonpolyposis colon cancer (HNPCC) patients.1:CAS:528:DC%2BD28XltFWktrg%3D16736289Fam Cancer. 2006; 5: 179-189Google Scholar (1) MMR gene mutations were identified without knowledge of MSI status (in at least an identifiable subset of the data); (2) MSI testing was attempted on all patients with Lynch syndrome; (3) the MSI testing methodology was described in sufficient detail to rate test quality; and (4) the MMR gene with the mutation was identifiable. The analysis was restricted to individuals with CRC (a few excluded studies included only patients with endometrial or breast cancer). In some studies, a few individuals had multiple CRC tumors tested. We chose the earliest sample with complete test results (i.e., MSI and IHC), to best simulate what might happen as part of routine evaluation in the future. In some studies, there were a few instances of multiple family members being tested. We chose to use the family member with the youngest age of onset for a CRC who had complete test results. Assessment of MSI test quality was defined before reviewing the articles and consisted of four questions: (1) did the authors di
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