Evaluation of yield and experiences of age-related molecular investigation for heritable and nonheritable causes of mismatch repair deficient colorectal cancer to identify Lynch syndrome

J.R. Vos, I.E. Fakkert, L. Spruijt, R.W. Willems, S. Langenveld, A.R. Mensenkamp, E.M. Leter, I.D. Nagtegaal, M.J.L. Ligtenberg, N. Hoogerbrugge*, FINAL Group

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Universal mismatch repair deficiency (dMMR) testing of colorectal cancer (CRC) is promoted as routine diagnostics to prescreen for Lynch syndrome. We evaluated the yield and experience of age-related molecular investigation for heritable and nonheritable causes of dMMR in CRC below age 70 to identify Lynch Syndrome. In a prospective cohort of 3602 newly diagnosed CRCs below age 70 from 19 hospitals, dMMR, MLH1 promoter hypermethylation, germline MMR gene and somatic MMR gene testing was assessed in daily practice. Yield was evaluated using data from the Dutch Pathology Registry (PALGA) and two regional genetic centers. Experiences of clinicians were evaluated through questionnaires. Participating clinicians were overwhelmingly positive about the clinical workflow. Pathologists routinely applied dMMR-testing in 84% CRCs and determined 10% was dMMR, largely due to somatic MLH1 hypermethylation (66%). Of those, 69% with dMMR CRC below age 70 without hypermethylation were referred for genetic testing, of which 55% was due to Lynch syndrome (hereditary) and 43% to somatic biallelic pathogenic MMR (nonhereditary). The prevalence of Lynch syndrome was 18% in CRC < 40, 1.7% in CRC age 40-64 and 0.7% in CRC age 65-69. Age 65-69 represents most cases with dMMR, in which dMMR due to somatic causes (13%) is 20 times more prevalent than Lynch syndrome. In conclusion, up to age 65 routine diagnostics of (non-)heritable causes of dMMR CRCs effectively identifies Lynch syndrome and reduces Lynch-like diagnoses. Above age 64, the effort to detect one Lynch syndrome patient in dMMR CRC is high and germline testing rarely needed.

Original languageEnglish
Pages (from-to)2150-2158
Number of pages9
JournalInternational Journal of Cancer
Issue number8
Publication statusPublished - 15 Oct 2020


  • colorectal cancer
  • diagnosis
  • germline
  • germline mutation
  • guidelines
  • lynch syndrome
  • mechanisms
  • mismatch repair deficiency
  • mlh1
  • recognition
  • risk
  • somatic mutation

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