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Original article
Clinical characteristics of patients with colorectal cancer with double somatic mismatch repair mutations compared with Lynch syndrome
  1. Rachel Pearlman1,
  2. Sigurdis Haraldsdottir2,
  3. Albert de la Chapelle3,
  4. Jon G Jonasson4,5,
  5. Sandya Liyanarachchi3,
  6. Wendy L Frankel6,
  7. Thorunn Rafnar7,
  8. Kari Stefansson7,
  9. Colin C Pritchard8,
  10. Heather Hampel1
  1. 1 Internal Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio, USA
  2. 2 Internal Medicine, Stanford University, Stanford, California, USA
  3. 3 Cancer Biology and Genetics, Ohio State University Wexner Medical Center, Columbus, Ohio, USA
  4. 4 Pathology, Landspitali-National University Hospital, Reykjavik, Iceland
  5. 5 University of Iceland, Reykjavik, Iceland
  6. 6 Pathology, Ohio State University Wexner Medical Center, Columbus, Ohio, USA
  7. 7 deCODE Genetics, Reykjavik, Iceland
  8. 8 Laboratory Medicine, University of Washington, Seattle, Washington, USA
  1. Correspondence to Ms. Rachel Pearlman, MS, LGC Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, Division of Human Genetics, 2012 Kenny Rd, Room 255, Columbus, OH 43221; rachel.pearlman{at}osumc.edu

Abstract

Background Patients with colorectal cancer (CRC) with mismatch repair-deficient (dMMR) tumours without MLH1 methylation or germline MMR pathogenic variants (PV) were previously thought to have Lynch syndrome (LS). It is now appreciated that they can have double somatic (DS) MMR PVs. We explored the clinical characteristics between patients with DS tumours and LS in two population-based cohorts.

Methods We included patients with CRC from Ohio 2013–2016 and Iceland 2000–2009. All had microsatellite instability testing and/or immunohistochemistry (IHC) of MMR proteins, and MLH1 methylation testing when indicated. Germline next-generation sequencing was performed for all with dMMR tumours; tumour sequencing followed for patients with unexplained dMMR. Clinical characteristics of DS patients and patients with LS were compared.

Results Of the 232 and 51 patients with non-methylated dMMR tumours in the Ohio and Iceland cohorts, respectively, 57.8% (n=134) and 45.1% (n=23) had LS, 32.8% (n=76) and 31.4% (n=16) had DS PVs, 6% (n=14) and 9.8% (n=5) were unexplained and 4.3% (n=10) and 13.7% (n=7) had incorrect IHC. Age of diagnosis for DS patients was older than patients with LS (p=3.73×10−4) in the two cohorts. Patients with LS were more likely to meet Amsterdam II criteria (OR=15.81, p=8.47×10−6) and have multiple LS-associated tumours (OR=6.67, p=3.31×10−5). Absence of MLH1/PMS2 was predictive of DS PVs; isolated MSH6 and PMS2 absence was predictive of LS in both cohorts.

Conclusions Individuals with LS are 15× more likely to meet Amsterdam II criteria and >5× more likely to have multiple cancers as compared with those with DS tumours. Furthermore, isolated loss of MSH6 or PMS2 protein predicts LS.

  • DNA repair system
  • somatic mutation
  • tumour testing
  • Lynch-like syndrome
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Footnotes

  • RP and SH contributed equally.

  • Contributors RP: study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; study supervision. SH: study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; obtained funding; study supervision. SL: critical revision of the manuscript for important intellectual content; statistical analysis. WLF, TR, CCP: analysis and interpretation of data; critical revision of the manuscript for important intellectual content; administrative, technical or material support. KS, JGJ: critical revision of the manuscript for important intellectual content; administrative, technical or material support. AdlC: study concept and design; critical revision of the manuscript for important intellectual content; study supervision. HH: study concept and design; acquisition of data; analysis and interpretation of data; critical revision of the manuscript for important intellectual content; statistical analysis; obtained funding; study supervision.

  • Funding The data reported here were derived from the Ohio Colorectal Cancer Prevention Initiative, which is supported by a grant from Pelotonia, an annual cycling event in Columbus, Ohio, that supports cancer research at The Ohio State University Comprehensive Cancer Center–James Cancer Hospital and Solove Research Institute. This study was supported in part by grant P30 CA016058, National Cancer Institute, Bethesda, MD.

  • Competing interests HH is on the scientific advisory board for InVitae Genetics and Genome Medical, has conducted collaborative research with Myriad Genetics Laboratories, Ambry Genetics and InVitae Genetics, and has stock in Genome Medical. RP has done collaborative research with Myriad Genetics Laboratories and InVitae Genetics. TR and KS are employees of deCODE Genetics/Amgen. SH, AdlC, JGJ, WLF, CCP and SL have no conflicts to disclose.

  • Ethics approval Institutional Review Board (IRB) approval for the Ohio Colorectal Cancer Prevention Initiative was obtained by the individual participating hospitals, Community Oncology Programs or by ceding review to the Ohio State University (OSU) IRB (2012C0123; IRB of record). The Iceland study was approved by the Icelandic National Bioethics Committee (VSNb2013010033/03.15), the Icelandic Data Protection Authority (2013010109TS) and the OSU IRB (2013C0144).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Author note Rachel Pearlman and Sigurdis Haraldsdottir are co-first authors.

  • Patient consent for publication Not required.

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