Abstract
BRAF and MLH1 promoter methylation testings have been proven effective prescreens for Lynch Syndrome. We aimed to compare different screening strategies for Lynch Syndrome in patients with MLH1(−) CRC. Patients with MLH1(−) CRC who had been tested for BRAF mutation and germline variants of DNA mismatch repair genes were included. We compared the sensitivities and specificities for identifying Lynch Syndrome and the cost-effectiveness of four screening approaches that used the following tests as prescreens: BRAF testing, MLH1 methylation testing, MLH1 methylation & BRAF testing, and MLH1 methylation testing & Revised Bethesda Criteria. Of 109 patients included, 23 (21.1%) were Lynch Syndrome patients. BRAF mutation and MLH1 methylation occurred in 6 (5.5%) and 40 (36.7%) patients, respectively. The sensitivity for identifying Lynch syndrome of BRAF testing was 100%, but the specificity was only 7%. MLH1 methylation testing had a lower sensitivity than BRAF testing (97.5% vs 100%), but had a markedly higher specificity (45.3% vs 7%). The combination of the two testings had a slightly higher specificity than MLH1 methylation testing alone (47.7% vs 45.3%). The MLH1 methylation testing approach had a 10% lower cost of identifying MLH1(−) Lynch syndrome carriers per case than universal genetic testing, but it missed 4.5% of patients. BRAF and MLH1 promoter methylation testings as prescreens for Lynch syndrome are less effective in Chinese patients with MLH1(−) CRC than in their Western counterparts. Universal genetic testing could be considered an up-front option for this population.
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References
Bonadona V, Bonaïti B, Olschwang S, Grandjouan S, Huiart L, Longy M, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305:2304–10.
Moreira L, Balaguer F, Lindor N, de la Chapelle A, Hampel H, Aaltonen LA, et al. Identification of Lynch syndrome among patients with colorectal cancer. JAMA. 2012;308:1555–65.
Pérez-Carbonell L, Ruiz-Ponte C, Guarinos C, Alenda C, Payá A, Brea A, et al. Comparison between universal molecular screening for Lynch syndrome and revised Bethesda guidelines in a large population-based cohort of patients with colorectal cancer. Gut. 2012;61:865–72.
Ward RL, Hicks S, Hawkins NJ. Population-based molecular screening for Lynch syndrome: Implications for personalized medicine. J Clin Oncol. 2013;31:2554–62.
Palomaki GE, McClain MR, Melillo S, Hampel HL, Thibodeau SN. EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med. 2009;11:42–65.
Sourrouille I, Coulet F, Lefevre JH, Colas C, Eyries M, Svrcek M, et al. Somatic mosaicism and double somatic hits can lead to MSI colorectal tumors. Fam Cancer. 2013;12:27–33.
Giardiello FM, Allen JI, Axilbund JE, Boland CR, Burke CA, Burt RW, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer. Am J Gastroenterol. 2014;109:1159–79.
Stoffel EM, Mangu PB, Gruber SB, Hamilton SR, Kalady MF, Lau MWY, et al. Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. J Clin Oncol. 2015;33:209–17.
Rubenstein JH, Enns R, Heidelbaugh J, Barkun A, Adams MA, Dorn SD, et al. American Gastroenterological Association Institute Guideline on the diagnosis and management of lynch syndrome. Gastroenterology. 2015;149:777–82.
Kidambi TD, Blanco A, Myers M, Conrad P, Loranger K, Terdiman JP. Selective versus universal screening for lynch syndrome: a six-year clinical experience. Dig Dis Sci. 2015;60:2463–9.
Toon CW, Walsh MD, Chou A, Capper D, Clarkson A, Sioson L, et al. BRAFV600E immunohistochemistry facilitates universal screening of colorectal cancers for Lynch syndrome. Am J Surg Pathol. 2013;37:1592–602.
Yoon HH, Shi Q, Alberts SR, Goldberg RM, Thibodeau SN, Sargent DJ et al. Racial Differences in BRAF/KRAS Mutation Rates and Survival in Stage III Colon Cancer Patients. J Natl Cancer Inst. 2015; 107.
Guo T-A, Wu Y-C, Tan C, Jin Y-T, Sheng W-Q, Cai S-J, et al. Clinicopathologic features and prognostic value of KRAS, NRAS and BRAF mutations and DNA mismatch repair status: a single-center retrospective study of 1,834 Chinese patients with Stage I-IV colorectal cancer. Int J Cancer. 2019;145:1625–34.
Vilkin A, Niv Y, Nagasaka T, Morgenstern S, Levi Z, Fireman Z, et al. Microsatellite instability, MLH1 promoter methylation, and BRAF mutation analysis in sporadic colorectal cancers of different ethnic groups in Israel. Cancer. 2009;115:760–9.
Jiang W, Cai M-Y, Li S-Y, Bei J-X, Wang F, Hampel H, et al. Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: high prevalence and unique molecular features: Universal screening for LS in Chinese CRC patients. Int J Cancer. 2019;144:2161–8.
Adar T, Rodgers LH, Shannon KM, Yoshida M, Ma T, Mattia A, et al. A tailored approach to BRAF and MLH1 methylation testing in a universal screening program for Lynch syndrome. Mod Pathol. 2017;30:440–7.
Moreira L, Muñoz J, Cuatrecasas M, Quintanilla I, Leoz ML, Carballal S, et al. Prevalence of somatic mutl homolog 1 promoter hypermethylation in Lynch syndrome colorectal cancer: MLH1 Methylation in Lynch Syndrome CRC. Cancer. 2015;121:1395–404.
Bessa X, Ballesté B, Andreu M, Castells A, Bellosillo B, Balaguer F, et al. A prospective, multicenter, population-based study of BRAF mutational analysis for Lynch syndrome screening. Clin Gastroenterol Hepatol. 2008;6:206–14.
Pérez-Carbonell L, Alenda C, Payá A, Castillejo A, Barberá VM, Guillén C, et al. Methylation analysis of MLH1 improves the selection of patients for genetic testing in Lynch syndrome. J Mol Diagn. 2010;12:498–504.
Chen J, Guo F, Shi X, Zhang L, Zhang A, Jin H, et al. BRAF V600E mutation and KRAS codon 13 mutations predict poor survival in Chinese colorectal cancer patients. BMC Cancer. 2014;14:802.
Ye J-X, Liu Y, Qin Y, Zhong H-H, Yi W-N, Shi X-Y. KRAS and BRAF gene mutations and DNA mismatch repair status in Chinese colorectal carcinoma patients. World J Gastroenterol. 2015;21:1595–605.
Parsons MT, Buchanan DD, Thompson B, Young JP, Spurdle AB. Correlation of tumour BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) gene mutation status: a literature review assessing utility of tumour features for MMR variant classification. J Med Genet. 2012;49:151–7.
Wang VW, Koh PK, Chow WL, Lim JFY. Predictive genetic testing of first degree relatives of mutation carriers is a cost-effective strategy in preventing hereditary non-polyposis colorectal cancer in Singapore. Fam Cancer. 2012;11:279–89.
Acknowledgements
This study was funded by the National Natural Science Foundation of China (No. 81871971 to PD), the Science and Technology Planning Project of Guangzhou City of China (No. 201803010117 to PD), and Science and Technology Program Project of Guangzhou (No. 201802020030 to LM). We also thank the Research Data Deposit public platform (www.researchdata.org.cn) for validating the authenticity of the data of this article (the approval number RDDA2020001429).
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Conceptualization: P-RD and WJ; Methodology: JL, BX and LM; Formal analysis and investigation: JL, EX; Resources: EX, LK, QS, DL, WL, ZH and JT; Writing—original draft preparation: BX and JL; Writing—review and editing: BX and PD; Supervision: WJ and PD; Project administration: ZP and PD; Funding acquisition: ZP and PD.
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Xiao, B., Luo, J., Xie, E. et al. Comparisons of screening strategies for identifying Lynch syndrome among patients with MLH1-deficient colorectal cancer. Eur J Hum Genet 28, 1555–1562 (2020). https://doi.org/10.1038/s41431-020-0687-8
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DOI: https://doi.org/10.1038/s41431-020-0687-8
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