Implementation of a Systematic Tumor Screening Program for Lynch Syndrome in an Integrated Health Care Setting
A subset of colorectal cancer (CRC) cases are attributable to Lynch syndrome (LS), a hereditary form of CRC. Effective evaluation for LS can be done on CRC tumors to guide diagnostic testing. Increased diagnosis of LS allows for surveillance and risk reduction, which can mitigate CRC-related burden and prevent cancer-related deaths. We evaluated participation in LS screening among newly diagnosed adult CRC patients. Some cases were referred for genetics evaluation prior to study recruitment (selective screening). Those not referred directly were randomized to the intervention or control (usual care) arms. Control cases were observed for one year, then given information about LS screening. Patients who declined participation were followed through the medical record. Of 601 cases of CRC, 194 (32%) enrolled in our study and were offered LS screening, 43 (7%) were followed as a control group, 148 (25%) declined participation and 216 (36%) were ineligible [63 (10%) of which received prior selective screening]. Six and nine cases of LS were identified through the intervention and selective screening groups, respectively. Overall, a higher proportion of PMS2 variants were identified in the intervention (3/6, 50%) versus selective screening groups (2/9, 22%) (not statistically significant). Eighty-eight percent and 23% of intervention and control patients, respectively, received LS screening. No control patients were found to have LS. Systems-based approaches are needed to ensure we fully identify LS cases. The proportion of LS cases from this program was 4% of newly diagnosed cases of CRC, similar to other programs.
KeywordsGenetics Colorectal cancer (CRC) DNA mismatch repair (MMR) genes
This work was supported through grants by the National Cancer Institute: R01CA140377 (Goddard) and R01CA132829 (Syngal). The funding body had no role in the design of the study, collection and analysis of data or decision to publish. Dr. Syngal reports being a consultant for Myriad Genetics, Inc.
Compliance with ethical standards
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 3.Kohlmann W, Gruber SB (1993) Lynch syndrome. In: Pagon RA, Adam MP, Ardinger HH et al (eds) Gene Reviews(R). University of Washington, Seattle. All Rights Reserved, Seattle (WA)Google Scholar
- 4.Chen S, Wang W, Lee S, Nafa K, Lee J, Romans K, Watson P, Gruber SB, Euhus D, Kinzler KW, Jass J, Gallinger S, Lindor NM, Casey G, Ellis N, Giardiello FM, Offit K, Parmigiani G (2006) Prediction of germline mutations and cancer risk in the Lynch syndrome. Jama 296(12):1479–1487. https://doi.org/10.1001/jama.296.12.1479 CrossRefGoogle Scholar
- 5.Lindor NM, Petersen GM, Hadley DW, Kinney AY, Miesfeldt S, Lu KH, Lynch P, Burke W, Press N (2006) Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA 296(12):1507–1517. https://doi.org/10.1001/jama.296.12.1507 CrossRefGoogle Scholar
- 6.Kastrinos F, Uno H, Ukaegbu C, Alvero C, McFarland A, Yurgelun MB, Kulke MH, Schrag D, Meyerhardt JA, Fuchs CS, Mayer RJ, Ng K, Steyerberg EW, Syngal S (2017) Development and validation of the PREMM5 Model for comprehensive risk assessment of Lynch syndrome. J Clin Oncol 35(19):2165–2172. https://doi.org/10.1200/jco.2016.69.6120 CrossRefGoogle Scholar
- 8.Giardiello FM, Allen JI, Axilbund JE, Boland CR, Burke CA, Burt RW, Church JM, Dominitz JA, Johnson DA, Kaltenbach T, Levin TR, Lieberman DA, Robertson DJ, Syngal S, Rex DK (2014) 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 109(8):1159–1179. https://doi.org/10.1038/ajg.2014.186 CrossRefGoogle Scholar
- 9.Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, Clendenning M, Sotamaa K, Prior T, Westman JA, Panescu J, Fix D, Lockman J, LaJeunesse J, Comeras I, de la Chapelle A (2008) Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol 26(35):5783–5788. https://doi.org/10.1200/JCO.2008.17.5950 CrossRefGoogle Scholar
- 10.P. D. Q. Cancer Genetics Editorial Board (2002) Genetics of colorectal cancer (PDQ(R)): health professional version. In: PDQ cancer information summaries. National Cancer Institute (US), BethesdaGoogle Scholar
- 11.Giardiello FM, Allen JI, Axilbund JE, Boland CR, Burke CA, Burt RW, Church JM, Dominitz JA, Johnson DA, Kaltenbach T, Levin TR, Lieberman DA, Robertson DJ, Syngal S, Rex DK (2014) Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer. Gastroenterology 147(2):502–526. https://doi.org/10.1053/j.gastro.2014.04.001 CrossRefGoogle Scholar
- 14.Stoffel E, Mukherjee B, Raymond VM, Tayob N, Kastrinos F, Sparr J, Wang F, Bandipalliam P, Syngal S, Gruber SB (2009) Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome. Gastroenterology 137(5):1621–1627. https://doi.org/10.1053/j.gastro.2009.07.039 CrossRefGoogle Scholar
- 15.Cross DS, Rahm AK, Kauffman TL, Webster J, Le AQ, Spencer Feigelson H, Alexander G, Meier P, Onitilo AA, Pawloski PA, Williams AE, Honda S, Daida Y, McCarty CA, Goddard KA (2013) Underutilization of Lynch syndrome screening in a multisite study of patients with colorectal cancer. Genet Med 15(12):933–940. https://doi.org/10.1038/gim.2013.43 CrossRefGoogle Scholar
- 16.Julie C, Tresallet C, Brouquet A, Vallot C, Zimmermann U, Mitry E, Radvanyi F, Rouleau E, Lidereau R, Coulet F, Olschwang S, Frebourg T, Rougier P, Nordlinger B, Laurent-Puig P, Penna C, Boileau C, Franc B, Muti C, Hofmann-Radvanyi H (2008) Identification in daily practice of patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer): revised Bethesda guidelines-based approach versus molecular screening. Am J Gastroenterol 103(11):2825–2835. https://doi.org/10.1111/j.1572-0241.2008.02084.x CrossRefGoogle Scholar
- 17.Perez-Carbonell L, Ruiz-Ponte C, Guarinos C, Alenda C, Paya A, Brea A, Egoavil CM, Castillejo A, Barbera VM, Bessa X, Xicola RM, Rodriguez-Soler M, Sanchez-Fortun C, Acame N, Castellvi-Bel S, Pinol V, Balaguer F, Bujanda L, De-Castro ML, Llor X, Andreu M, Carracedo A, Soto JL, Castells A, Jover R (2012) Comparison between universal molecular screening for Lynch syndrome and revised Bethesda guidelines in a large population-based cohort of patients with colorectal cancer. Gut 61(6):865–872. https://doi.org/10.1136/gutjnl-2011-300041 CrossRefGoogle Scholar
- 19.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 in relatives. Genet Med 11 (1):35–41. https://doi.org/10.1097/GIM.0b013e31818fa2ff CrossRefGoogle Scholar
- 20.Hunter JE, Zepp JM, Gilmore MJ, Davis JV, Esterberg EJ, Muessig KR, Peterson SK, Syngal S, Acheson LS, Wiesner GL, Reiss JA, Goddard KA (2015) Universal tumor screening for Lynch syndrome: assessment of the perspectives of patients with colorectal cancer regarding benefits and barriers. Cancer 121(18):3281–3289. https://doi.org/10.1002/cncr.29470 CrossRefGoogle Scholar
- 21.Hunter JE, Arnold KA, Cook JE, Zepp J, Gilmore MJ, Rope AF, Davis JV, Bergen KM, Esterberg E, Muessig KR, Peterson SK, Syngal S, Acheson L, Wiesner G, Reiss J, Goddard KAB (2017) Universal screening for Lynch syndrome among patients with colorectal cancer: patient perspectives on screening and sharing results with at-risk relatives. Fam Cancer 16(3):377–387. https://doi.org/10.1007/s10689-017-9972-2 CrossRefGoogle Scholar
- 25.Kastrinos F, Steyerberg EW, Mercado R, Balmana J, Holter S, Gallinger S, Siegmund KD, Church JM, Jenkins MA, Lindor NM, Thibodeau SN, Burbidge LA, Wenstrup RJ, Syngal S (2011) The PREMM(1,2,6) model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history. Gastroenterology 140(1):73–81. https://doi.org/10.1053/j.gastro.2010.08.021 CrossRefGoogle Scholar
- 28.Aaltonen LA, Salovaara R, Kristo P, Canzian F, Hemminki A, Peltomaki P, Chadwick RB, Kaariainen H, Eskelinen M, Jarvinen H, Mecklin JP de la CA (1998) Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med 338(21):1481–1487CrossRefGoogle Scholar
- 29.Salovaara R, Loukola A, Kristo P, Kaariainen H, Ahtola H, Eskelinen M, Harkonen N, Julkunen R, Kangas E, Ojala S, Tulikoura J, Valkamo E, Jarvinen H, Mecklin JP, Aaltonen LA, de la Chapelle A (2000) Population-based molecular detection of hereditary nonpolyposis colorectal cancer. J Clin Oncol 18(11):2193–2200CrossRefGoogle Scholar
- 31.Goverde A, Spaander MCW, Nieboer D, van den Ouweland AMW, Dinjens WNM, Dubbink HJ, Tops CJ, Ten Broeke SW, Bruno MJ, Hofstra RMW, Steyerberg EW, Wagner A (2017) Evaluation of current prediction models for Lynch syndrome: updating the PREMM5 model to identify PMS2 mutation carriers. Fam Cancer. https://doi.org/10.1007/s10689-017-0039-1 Google Scholar
- 32.Senter L, Clendenning M, Sotamaa K, Hampel H, Green J, Potter JD, Lindblom A, Lagerstedt K, Thibodeau SN, Lindor NM, Young J, Winship I, Dowty JG, White DM, Hopper JL, Baglietto L, Jenkins MA, de la Chapelle A (2008) The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology 135(2):419–428. https://doi.org/10.1053/j.gastro.2008.04.026 CrossRefGoogle Scholar
- 33.Moller P, Seppala T, Bernstein I, Holinski-Feder E, Sala P, Evans DG, Lindblom A, Macrae F, Blanco I, Sijmons R, Jeffries J, Vasen H, Burn J, Nakken S, Hovig E, Rodland EA, Tharmaratnam K, de Vos Tot Nederveen Cappel WH, Hill J, Wijnen J, Green K, Lalloo F, Sunde L, Mints M, Bertario L, Pineda M, Navarro M, Morak M, Renkonen-Sinisalo L, Frayling IM, Plazzer JP, Pylvanainen K, Sampson JR, Capella G, Mecklin JP, Moslein G (2017) Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut 66(3):464–472. https://doi.org/10.1136/gutjnl-2015-309675 CrossRefGoogle Scholar
- 35.Shia J (2008) Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part I. The utility of immunohistochemistry. J Mol Diagn 10(4):293–300. https://doi.org/10.2353/jmoldx.2008.080031 CrossRefGoogle Scholar
- 36.Hampel H, Pearlman R, Beightol M, Zhao W, Jones D, Frankel WL, Goodfellow PJ, Yilmaz A, Miller K, Bacher J, Jacobson A, Paskett E, Shields PG, Goldberg RM, de la Chapelle A, Shirts BH, Pritchard CC, Ohio Colorectal Cancer Prevention Initiative Study G (2018) Assessment of tumor sequencing as a replacement for Lynch syndrome screening and current molecular tests for patients with colorectal cancer. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2018.0104 Google Scholar
- 38.Batte BA, Bruegl AS, Daniels MS, Ring KL, Dempsey KM, Djordjevic B, Luthra R, Fellman BM, Lu KH, Broaddus RR (2014) Consequences of universal MSI/IHC in screening ENDOMETRIAL cancer patients for Lynch syndrome. Gynecol Oncol 134(2):319–325. https://doi.org/10.1016/j.ygyno.2014.06.009 CrossRefGoogle Scholar
- 39.Mills AM, Sloan EA, Thomas M, Modesitt SC, Stoler MH, Atkins KA, Moskaluk CA (2016) Clinicopathologic comparison of Lynch Syndrome-associated and “Lynch-like” endometrial carcinomas identified on universal screening Using mismatch repair protein immunohistochemistry. Am J Surg Pathol 40(2):155–165. https://doi.org/10.1097/pas.0000000000000544 Google Scholar