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• W3168979825 abstract "In the era of precision medicine, universal genomic testing in cancer is becoming routine. In colorectal cancer (CRC), universal tumor testing for mismatch repair deficiency by immunohistochemistry (IHC) or polymerase chain reaction is recommended by multiple professional organizations.1Evaluation of Genomic Applications in Practice and Prevention (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 (550) Google Scholar, 2Giardiello F.M. Allen J.I. Axilbund J.E. et al.US Multi-Society Task Force on Colorectal Cancer. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer.Gastroenterology. 2014; 147: 502-526Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar, 3National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Colorectal (Version 1.2021). Available at: https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf. Accessed May 22, 2021.Google Scholar In addition to potential identification of Lynch syndrome, mismatch repair deficiency status has prognostic and therapeutic implications. Systematic sequencing of tumors or circulating cell-free DNA by next-generation sequencing (NGS) offers the promise of therapeutic actionability specific to an individual’s cancer including for mismatch repair deficiency assessment.4Niu B. Ye K. Zhang Q. et al.MSIsensor: microsatellite instability detection using paired tumor-normal sequence data.Bioinformatics. 2014; 30: 1015-1016Crossref PubMed Scopus (333) Google Scholar, 5Stadler Z.K. Battaglin F. Middha S. et al.Reliable detection of mismatch repair deficiency in colorectal cancers using mutational load in next-generation sequencing panels.J Clin Oncol. 2016; 34: 2141-2147Crossref PubMed Scopus (163) Google Scholar, 6Hampel H. Pearlman R. Beightol M. et al.Ohio Colorectal Cancer Prevention Initiative Study Group. Assessment of tumor sequencing as a replacement for lynch syndrome screening and current molecular tests for patients with colorectal cancer.JAMA Oncol. 2018; 4: 806-813Crossref PubMed Scopus (84) Google Scholar, 7Ratovomanana T. Cohen R. Svrcek M. et al.Performance of next generation sequencing for the detection of microsatellite instability in colorectal cancer with deficient DNA mismatch repair.Gastroenterology. 2021 May 13; ([Epub ahead of print])Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar NGS is also applied to sequence multiple genes simultaneously in the germline, and multigene panel tests are now routinely used for clinical genetic testing and recommended for all patients with CRC under age 50.8Heald B. Hampel H. Church J. et al.Collaborative Group of the Americas on Inherited Gastrointestinal Cancer. Collaborative Group of the Americas on Inherited Gastrointestinal Cancer Position statement on multigene panel testing for patients with colorectal cancer and/or polyposis.Fam Cancer. 2020; 19: 223-239Crossref PubMed Scopus (19) Google Scholar Combined NGS tumor and germline sequencing is currently performed in some centers for patients with CRC with advanced disease.9Mandelker D. Zhang L. Kemel Y. et al.Mutation detection in patients with advanced cancer by universal sequencing of cancer-related genes in tumor and normal DNA vs guideline-based germline testing.JAMA. 2017; 318: 825-835Crossref PubMed Scopus (241) Google Scholar In this issue of Clinical Gastroenterology and Hepatology, we add to our understanding of universal tumor and/or germline testing outcomes in CRC. In the systematic review and meta-analysis of IHC for Lynch syndrome, Eikenboom et al identified 56 studies of tumor testing in 58,580 CRCs.10Eikenboom E.L. van der Werf-’t Lam A.S. Rodriguez-Girondo M. et al.Universal immunohistochemistry for Lynch syndrome: a systematic review and meta-analysis of 58,580 colorectal carcinomas.Clin Gastroenterol Hepatol. 2022; 20: e496-e507Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Abnormal IHC was found in 10% of tumors overall, although results were unknown in more than 1 of 10 tumors. BRAF mutation or MLH1 promoter methylation was found in 3.6% overall. Among patients with abnormal IHC without MLH1 methylation, 76% underwent genetic testing, with an overall prevalence of Lynch syndrome of about 2%. Double somatic variants were identified in 0.24% of all tumors; whereas in 4% of tumors, the abnormal IHC testing was not explained. Importantly, in cases where somatic testing was complete, the prevalence of Lynch syndrome was 3% (7% and 5% for individuals under age 50 and 70, respectively), 3.7% of tumors had MLH1 methylation, 1.75% had double somatic variants, and only 0.8% of abnormal IHC results were unexplained. In the study by Uson et al,11Uson Jr., P.L.S. Riegert-Johnson D. Boardman L. et al.Germline cancer susceptibility gene testing in unselected patients with colorectal adenocarcinoma: a multicenter prospective study.Clin Gastroenterol Hepatol. 2022; 20: e508-e528Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar 361 consecutive patients with CRC of all stages (38% metastatic) seen at 3 Mayo Clinic sites were enrolled to undergo an 80+ gene germline panel test. Patients were overall younger, more female, predominantly white, and had a higher proportion of metastatic disease than average patients with CRC in the United States. Overall, 15.5% of patients were found to have germline pathogenic or likely pathogenic variants, of which 78.6% were in moderate- to high-penetrant genes. Nearly one-half of the patients were found to have variants of uncertain significance. No survival difference was identified by variant status, although follow-up time was limited. One-half of the patients would not have been detected by standard criteria, and 10% had a modification in their treatment based on their variant status. Strikingly, only 16% of family members of patients with positive variants had genetic testing, despite it being free of charge. Both studies add important new knowledge about outcomes, opportunities, and barriers in CRC universal testing approaches. One theme common to both studies is the importance of comprehensive approaches to ensure benefits are truly “universal” and cost-effective. For tumor testing, nearly one-quarter of patients with abnormal testing did not undergo genetic testing, a missed opportunity to identify Lynch syndrome in families. Indeed, the cost-effectiveness of tumor testing for Lynch syndrome was only realized when cascade testing among at-risk family members was performed.12Ladabaum U. Wang G. Terdiman J. et al.Strategies to identify the Lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis.Ann Intern Med. 2011; 155: 69-79Crossref PubMed Scopus (277) Google Scholar We previously found low rates of recommendation and genetic testing in patients who had abnormal tumor testing, especially among African Americans and Hispanics, highlighting how universal approaches can potentially widen health inequities if not addressed.13Muller C. Lee S.M. Barge W. et al.Low referral rate for genetic testing in racially and ethnically diverse patients despite universal colorectal cancer screening.Clin Gastroenterol Hepatol. 2018; 16: 1911-1918.e2Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar Among studies with complete somatic testing in the meta-analysis, genetic testing rates and identification of Lynch syndrome were highest, underscoring the importance of systematic approaches. For germline testing, there was low uptake (16%) of genetic testing among at-risk family members (so-called cascade testing) that did not appear to be related to cost. Low rates of genetic testing among family members has been previously described, with most estimates under 50%.14Sharaf R.N. Myer P. Stave C.D. et al.Uptake of genetic testing by relatives of lynch syndrome probands: a systematic review.Clin Gastroenterol Hepatol. 2013; 11: 1093-1100Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar As Uson et al point out, reasons for the lack of uptake are multifactorial, and include difficulties with understanding or interpretation of results, family dynamics and communication, lack of access to genetics professionals, fear of discrimination and/or fear of learning the results, and cancer risk.11Uson Jr., P.L.S. Riegert-Johnson D. Boardman L. et al.Germline cancer susceptibility gene testing in unselected patients with colorectal adenocarcinoma: a multicenter prospective study.Clin Gastroenterol Hepatol. 2022; 20: e508-e528Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Improved efforts to facilitate communication of results and uptake of genetic testing among at-risk family members are needed, given that identification of an individual before they develop cancer is one of the benefits of universal genetic testing. As with tumor testing, the cost-effectiveness of germline testing relies on cascade testing and uptake of cancer preventive strategies among family members.15Gallego C.J. Shirts B.H. Bennette C.S. et al.Next-generation sequencing panels for the diagnosis of colorectal cancer and polyposis syndromes: a cost-effectiveness analysis.J Clin Oncol. 2015; 33: 2084-2091Crossref PubMed Scopus (97) Google Scholar Approaches that enable communication of genetic test results directly with family members could augment current cascade testing efforts, although privacy concerns remain a barrier.16Pande M. Peterson S. Lynch P.M. Development and evaluation of an online, patient-driven, family outreach intervention to facilitate sharing of genetic risk information in families with Lynch syndrome.J Med Genet. 2021 May 18; ([Epub ahead of print])Crossref PubMed Scopus (1) Google Scholar Another theme in both studies is the likelihood of uncertain results. In universal tumor testing, unexplained abnormal IHC was noted in up to 4% of cases. As discussed by the authors, unexplained IHC has been referred to as “Lynch-like syndrome,” a term that leads to considerable confusion and should be avoided. Unresolved IHC can lead to inappropriate management of an individual or family as Lynch syndrome. In fact, most abnormal results can be explained by double somatic variants, and additional surveillance is not indicated unless warranted by family history. In a recent statewide study of comprehensive tumor testing of 3310 CRCs in Ohio, Pearlman et al reported that nearly 90% of unresolved IHC was explained by double somatic variants (0.5% of the total tumors),17Pearlman R. Frankel W.L. Swanson B.J. et al.Prospective statewide study of universal screening for hereditary colorectal cancer: the Ohio Colorectal Cancer Prevention Initiative.JCO Precision Oncology. 2021; : 779-791Crossref Scopus (11) Google Scholar in line with the findings from the meta-analysis in cases of complete somatic testing (0.8%). For universal germline testing, a substantial proportion of patients were found to have a variant of uncertain significance, meaning that the DNA change cannot be determined to be benign or disease-causing based on current evidence and should not change medical management. In clinical practice, these uncertain results can lead to increased patient anxiety or confusion, as well as inappropriate management recommendations by providers.18Mighton C. Shickh S. Uleryk E. et al.Clinical and psychological outcomes of receiving a variant of uncertain significance from multigene panel testing or genomic sequencing: a systematic review and meta-analysis.Genet Med. 2021; 23: 22-33Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar The prevalence of variants of uncertain significance increases with the number of genes on the panel, with previous estimates between 31% and 40%.19LaDuca H. Polley E.C. Yussuf A. et al.A clinical guide to hereditary cancer panel testing: evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients.Genet Med. 2020; 22: 407-415Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Prevalence is higher among non-European populations with the highest rates in African Americans.20Ricker C. Culver J.O. Lowstuter K. et al.Increased yield of actionable mutations using multi-gene panels to assess hereditary cancer susceptibility in an ethnically diverse clinical cohort.Cancer Genet. 2016; 209: 130-137Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar In addition, larger gene panels, as were used in the Uson study, include genes with low or uncertain cancer risks for which surveillance might not be recommended or available. Pathogenic variants in high-penetrance genes are also found that are not proven to be causally linked to CRC but for which medical management exists (eg, BRCA). Finally, there is a low rate of potential targeted therapies based on germline testing (10% in this study); thus, realistic expectations need to be set for patients with cancer regarding therapeutic implications of germline testing. In sum, there is a critical need for informed and accurate counseling by a provider educated in cancer genetics to help patients and families understand uncertain, unanticipated, or uninformative results. A number of recent studies also have investigated the outcomes of universal CRC testing. The statewide study from Ohio of universal tumor and germline testing demonstrated that tumor-only mismatch repair deficiency testing is important for immunotherapy eligibility but not for evaluation of hereditary cancer syndromes, in that nearly 40% of patients with pathogenic variants were missed by tumor-only testing including Lynch syndrome.17Pearlman R. Frankel W.L. Swanson B.J. et al.Prospective statewide study of universal screening for hereditary colorectal cancer: the Ohio Colorectal Cancer Prevention Initiative.JCO Precision Oncology. 2021; : 779-791Crossref Scopus (11) Google Scholar A study by Yurgelun et al performed germline testing using a 25-gene panel in consecutive patients with CRC unselected for age, stage, or family history and found 10% prevalence of pathogenic variants.21Yurgelun M.B. Kulke M.H. Fuchs C.S. et al.Cancer susceptibility gene mutations in individuals with colorectal cancer.J Clin Oncol. 2017; 35: 1086-1095Crossref PubMed Scopus (225) Google Scholar Although the overall prevalence of pathogenic variants was higher in the Uson et al study, the rates of pathogenic variants in mismatch repair genes, polyposis genes, hereditary breast and ovarian cancer genes, and moderate-penetrant CRC genes were fairly similar to those reported in the Yurgelun and Pearlman studies. Thus, higher prevalence was due to other genes on the larger panels that, arguably, do not all have clear “actionability” in terms of medical management, raising questions about incremental benefits of larger panels. A recent position statement provides guidance on selection of genes for NGS panel testing in CRC and/or polyposis.8Heald B. Hampel H. Church J. et al.Collaborative Group of the Americas on Inherited Gastrointestinal Cancer. Collaborative Group of the Americas on Inherited Gastrointestinal Cancer Position statement on multigene panel testing for patients with colorectal cancer and/or polyposis.Fam Cancer. 2020; 19: 223-239Crossref PubMed Scopus (19) Google Scholar With any universal testing approach, benefits must be weighed against risks and costs. Benefits of universal testing include identification of inherited cancer syndromes for which effective preventive and early detection strategies exist as well as the potential for targeted therapies in patients with cancer. Importantly, universal approaches identify pathogenic variants in individuals who would not have been picked up by traditional family history- or age-based criteria. Current guidelines endorse universal germline testing for all patients with ovarian, pancreatic, and metastatic prostate cancer where the prevalence of germline pathogenic variants (~10%) is similar to CRC. Given that CRC is one of the most common cancers in both men and women, we must be cognizant of the systems, cost, and personnel requirements to appropriately and equitably implement universal testing. As was reinforced in the 2 studies in this issue, comprehensive systems approaches are critical. Cascade testing is essential to realize the individual benefits of surveillance as well as cost-effectiveness. Given that uncertain results are anticipated, especially with larger gene panels, patients must be appropriately counseled by knowledgeable professionals. However, current numbers of genetics professionals, especially genetic counselors, are not sufficient to provide traditional counseling to all patients with CRC, and hybrid or alternative approaches need to be optimized and deployed. As the cost of sequencing continues to drop, we will likely see clinical implementation of NGS somatic and germline sequencing for many patients with cancer in the near future. Lessons learned from studies of universal CRC testing to date teach us what is needed to ensure benefits are realized universally by patients, families, and society. Germline Cancer Susceptibility Gene Testing in Unselected Patients With Colorectal Adenocarcinoma: A Multicenter Prospective StudyClinical Gastroenterology and HepatologyVol. 20Issue 3PreviewHereditary factors play a role in the development of colorectal cancer (CRC). Identification of germline predisposition can have implications on treatment and cancer prevention. This study aimed to determine the prevalence of pathogenic germline variants (PGVs) in CRC patients using a universal testing approach, association with clinical outcomes, and the uptake of family variant testing. Full-Text PDF Open AccessUniversal Immunohistochemistry for Lynch Syndrome: A Systematic Review and Meta-analysis of 58,580 Colorectal CarcinomasClinical Gastroenterology and HepatologyVol. 20Issue 3PreviewLynch syndrome is a form of hereditary colorectal cancer (CRC) caused by pathogenic germline variants (PV) in DNA mismatch repair (MMR) genes. Currently, many Western countries perform universal immunohistochemistry testing on CRC to increase the identification of Lynch syndrome patients and their relatives. For a clear understanding of health benefits and costs, data on its outcomes are required: proportions of Lynch syndrome, sporadic MMR-deficient (MMRd) cases, and unexplained MMRd cases. Full-Text PDF Open Access" @default.
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• W3168979825 title "Block, Blood, or Both? Outcomes, Opportunities, and Barriers in Colorectal Cancer Universal Testing" @default.
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