Somatic mutations of the coding microsatellites within the beta-2-microglobulin gene in mismatch repair-deficient colorectal cancers and adenomas

  • Mark Clendenning
  • Alvin Huang
  • Harindra Jayasekara
  • Marie Lorans
  • Susan Preston
  • Neil O’Callaghan
  • Bernard J. Pope
  • Finlay A. Macrae
  • Ingrid M. Winship
  • Roger L. Milne
  • Graham G. Giles
  • Dallas R. English
  • John L. Hopper
  • Aung K. Win
  • Mark A. Jenkins
  • Melissa C. Southey
  • Christophe Rosty
  • Daniel D. Buchanan
  • On behalf of investigators from the Melbourne Collaborative Cohort Study and the Australasian Colorectal Cancer Family Registry Cohort
Original Article
  • 93 Downloads

Abstract

In colorectal cancers (CRCs) with tumour mismatch repair (MMR) deficiency, genes involved in the host immune response that contain microsatellites in their coding regions, including beta-2-microglobulin (B2M), can acquire mutations that may alter the immune response, tumour progression and prognosis. We screened the coding microsatellites within B2M for somatic mutations in MMR-deficient CRCs and adenomas to determine associations with tumour subtypes, clinicopathological features and survival. Incident MMR-deficient CRCs from Australasian Colorectal Cancer Family Registry (ACCFR) and the Melbourne Collaborative Cohort Study participants (n = 144) and 63 adenomas from 41 MMR gene mutation carriers from the ACCFR were screened for somatic mutations within five coding microsatellites of B2M. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival by B2M mutation status were estimated using Cox regression, adjusting for age at CRC diagnosis, sex, AJCC stage and grade. B2M mutations occurred in 30 (20.8%) of the 144 MMR-deficient CRCs (29% of the MLH1-methylated, 17% of the Lynch syndrome and 9% of the suspected Lynch CRCs). No B2M mutations were identified in the 63 adenomas tested. B2M mutations differed by site, stage, grade and lymphocytic infiltration although none reached statistical significance (p > 0.05). The HR for overall survival for B2M mutated CRC was 0.65 (95% CI 0.29–1.48) compared with B2M wild-type. We observed differences in B2M mutation status in MMR-deficient CRC by tumour subtypes, site, stage, grade, immune infiltrate and for overall survival that warrant further investigation in larger studies before B2M mutation status can be considered to have clinical utility.

Keywords

B2M Colorectal cancer Mismatch repair deficiency Microsatellite instability Lynch syndrome MLH1 methylation 

Supplementary material

10689_2017_13_MOESM1_ESM.docx (29 kb)
Supplementary material 1 (DOCX 28 KB)
10689_2017_13_MOESM2_ESM.docx (15 kb)
Supplementary material 2 (DOCX 14 KB)

References

  1. 1.
    Haggar FA, Boushey RP (2009) Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg 22(4):191–197. doi:10.1055/s-0029-1242458 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Ferlay J, Soerjomataram I, Dikshit R et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386. doi:10.1002/ijc.29210 CrossRefPubMedGoogle Scholar
  3. 3.
    Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260(5109):816–819CrossRefPubMedGoogle Scholar
  4. 4.
    Guastadisegni C, Colafranceschi M, Ottini L, Dogliotti E (2010) Microsatellite instability as a marker of prognosis and response to therapy: a meta-analysis of colorectal cancer survival data. Eur J Cancer 46(15):2788–2798. doi:10.1016/j.ejca.2010.05.009 CrossRefPubMedGoogle Scholar
  5. 5.
    Ligtenberg MJ, Kuiper RP, Chan TL et al (2009) Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1. Nat Genet 41(1):112–117. doi:10.1038/ng.283 CrossRefPubMedGoogle Scholar
  6. 6.
    Herman JG, Umar A, Polyak K et al (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 95(12):6870–6875CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Haraldsdottir S, Hampel H, Tomsic J et al (2014) Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. Gastroenterology 147(6):1308-16 e1. doi:10.1053/j.gastro.2014.08.041 CrossRefGoogle Scholar
  8. 8.
    Mensenkamp AR, Vogelaar IP, van Zelst-Stams WA et al (2014) Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors. Gastroenterology 146(3):643-6 e8. doi:10.1053/j.gastro.2013.12.002 CrossRefGoogle Scholar
  9. 9.
    Sourrouille I, Coulet F, Lefevre JH et al (2013) Somatic mosaicism and double somatic hits can lead to MSI colorectal tumors. Fam Cancer 12(1):27–33. doi:10.1007/s10689-012-9568-9 CrossRefPubMedGoogle Scholar
  10. 10.
    Buchanan DD, Rosty C, Clendenning M, Spurdle AB, Win AK (2014) Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome). Appl Clin Genet 7:183–193. doi:10.2147/TACG.S48625 PubMedPubMedCentralGoogle Scholar
  11. 11.
    Hampel H, Frankel WL, Martin E et al (2008) Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol 26(35):5783–5788. doi:10.1200/JCO.2008.17.5950 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Boland CR, Goel A (2010) Microsatellite instability in colorectal cancer. Gastroenterology 138(6):2073-87 e3. doi:10.1053/j.gastro.2009.12.064 CrossRefGoogle Scholar
  13. 13.
    Buchanan DD, Clendenning M, Rosty C et al (2017) Tumor testing to identify lynch syndrome in two Australian colorectal cancer cohorts. J Gastroenterol Hepatol 32(2):427–438. doi:10.1111/jgh.13468 CrossRefPubMedGoogle Scholar
  14. 14.
    Kloor M, von Knebel Doeberitz M (2016) The immune biology of microsatellite-unstable cancer. Trends Cancer 2(3):121–133. doi:10.1016/j.trecan.2016.02.004 CrossRefGoogle Scholar
  15. 15.
    Yamamoto H, Yamashita K, Perucho M (2001) Somatic mutation of the beta2-microglobulin gene associates with unfavorable prognosis in gastrointestinal cancer of the microsatellite mutator phenotype. Gastroenterology 120(6):1565–1567CrossRefPubMedGoogle Scholar
  16. 16.
    Kloor M, Michel S, Buckowitz B et al (2007) Beta2-microglobulin mutations in microsatellite unstable colorectal tumors. Int J Cancer 121(2):454–458. doi:10.1002/ijc.22691 CrossRefPubMedGoogle Scholar
  17. 17.
    Tikidzhieva A, Benner A, Michel S et al (2012) Microsatellite instability and Beta2-Microglobulin mutations as prognostic markers in colon cancer: results of the FOGT-4 trial. Br J Cancer 106(6):1239–1245. doi:10.1038/bjc.2012.53 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Bicknell DC, Kaklamanis L, Hampson R, Bodmer WF, Karran P (1996) Selection for beta 2-microglobulin mutation in mismatch repair-defective colorectal carcinomas. Curr Biol 6(12):1695–1697CrossRefPubMedGoogle Scholar
  19. 19.
    Koelzer VH, Baker K, Kassahn D, Baumhoer D, Zlobec I (2012) Prognostic impact of beta-2-microglobulin expression in colorectal cancers stratified by mismatch repair status. J Clin Pathol 65(11):996–1002. doi:10.1136/jclinpath-2012-200742 CrossRefPubMedGoogle Scholar
  20. 20.
    Giles GG, English DR (2002) The Melbourne collaborative cohort study. IARC Sci Publ 156:69–70PubMedGoogle Scholar
  21. 21.
    Newcomb PA, Baron J, Cotterchio M et al (2007) Colon Cancer Family Registry: an international resource for studies of the genetic epidemiology of colon cancer. Cancer Epidemiol Biomark Prev 16(11):2331–2343CrossRefGoogle Scholar
  22. 22.
    Cicek MS, Lindor NM, Gallinger S et al (2011) Quality assessment and correlation of microsatellite instability and immunohistochemical markers among population- and clinic-based colorectal tumors results from the Colon Cancer Family Registry. J Mol Diagn 13(3):271–281. doi:10.1016/j.jmoldx.2010.12.004 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Walsh MD, Buchanan DD, Pearson SA et al (2012) Immunohistochemical testing of conventional adenomas for loss of expression of mismatch repair proteins in Lynch syndrome mutation carriers: a case series from the Australasian site of the colon cancer family registry. Mod Pathol 25(5):722–730. doi:10.1038/modpathol.2011.209 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Rosty C, Young JP, Walsh MD et al (2013) Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features. Mod Pathol 26(6):825–834. doi:10.1038/modpathol.2012.240 CrossRefPubMedGoogle Scholar
  25. 25.
    Korn EL, Graubard BI, Midthune D (1997) Time-to-event analysis of longitudinal follow-up of a survey: choice of the time-scale. Am J Epidemiol 145(1):72–80CrossRefPubMedGoogle Scholar
  26. 26.
    Rozek LS, Schmit SL, Greenson JK et al. (2016) Tumor-infiltrating lymphocytes, Crohn’s-like lymphoid reaction, and survival from colorectal cancer. J Natl Cancer Inst. doi:10.1093/jnci/djw027 PubMedGoogle Scholar
  27. 27.
    Linnebacher M, Gebert J, Rudy W et al (2001) Frameshift peptide-derived T-cell epitopes: a source of novel tumor-specific antigens. Int J Cancer 93(1):6–11CrossRefPubMedGoogle Scholar
  28. 28.
    Saeterdal I, Bjorheim J, Lislerud K et al (2001) Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer. Proc Natl Acad Sci USA 98(23):13255–13260. doi:10.1073/pnas.231326898 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Ripberger E, Linnebacher M, Schwitalle Y, Gebert J, von Knebel Doeberitz M (2003) Identification of an HLA-A0201-restricted CTL epitope generated by a tumor-specific frameshift mutation in a coding microsatellite of the OGT gene. J Clin Immunol 23(5):415–423CrossRefPubMedGoogle Scholar
  30. 30.
    Schwitalle Y, Linnebacher M, Ripberger E, Gebert J, von Knebel Doeberitz M (2004) Immunogenic peptides generated by frameshift mutations in DNA mismatch repair-deficient cancer cells. Cancer Immun 4:14PubMedGoogle Scholar
  31. 31.
    Schwitalle Y, Kloor M, Eiermann S et al (2008) Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology 134(4):988–997. doi:10.1053/j.gastro.2008.01.015 CrossRefPubMedGoogle Scholar
  32. 32.
    von Knebel Doeberitz M, Kloor M (2013) Towards a vaccine to prevent cancer in Lynch syndrome patients. Fam Cancer 12(2):307–312. doi:10.1007/s10689-013-9662-7 CrossRefGoogle Scholar
  33. 33.
    Le DT, Uram JN, Wang H et al (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372(26):2509–2520. doi:10.1056/NEJMoa1500596 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Xiao Y, Freeman GJ (2015) The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy. Cancer Discov 5(1):16–18. doi:10.1158/2159-8290.CD-14-1397 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Zaretsky JM, Garcia-Diaz A, Shin DS et al (2016) Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med 375(9):819–829. doi:10.1056/NEJMoa1604958 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Malesci A, Laghi L, Bianchi P et al (2007) Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer. Clin Cancer Res 13(13):3831–3839. doi:10.1158/1078-0432.CCR-07-0366 CrossRefPubMedGoogle Scholar
  37. 37.
    Mlecnik B, Bindea G, Angell HK et al (2016) Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability. Immunity 44(3):698–711. doi:10.1016/j.immuni.2016.02.025 CrossRefPubMedGoogle Scholar
  38. 38.
    Masugi Y, Nishihara R, Yang J et al (2016) Tumour CD274 (PD-L1) expression and T cells in colorectal cancer. Gut. doi:10.1136/gutjnl-2016-311421 Google Scholar
  39. 39.
    Echterdiek F, Janikovits J, Staffa L et al (2016) Low density of FOXP3-positive T cells in normal colonic mucosa is related to the presence of beta2-microglobulin mutations in Lynch syndrome-associated colorectal cancer. Oncoimmunology 5(2):e1075692 doi:10.1080/2162402X.2015.1075692 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2017

Authors and Affiliations

  • Mark Clendenning
    • 1
  • Alvin Huang
    • 1
  • Harindra Jayasekara
    • 2
    • 3
    • 4
  • Marie Lorans
    • 1
  • Susan Preston
    • 1
  • Neil O’Callaghan
    • 1
  • Bernard J. Pope
    • 5
  • Finlay A. Macrae
    • 6
    • 7
    • 8
  • Ingrid M. Winship
    • 7
    • 8
  • Roger L. Milne
    • 2
    • 3
  • Graham G. Giles
    • 2
    • 3
  • Dallas R. English
    • 2
    • 3
  • John L. Hopper
    • 3
    • 9
  • Aung K. Win
    • 3
    • 8
  • Mark A. Jenkins
    • 3
  • Melissa C. Southey
    • 10
  • Christophe Rosty
    • 1
    • 11
    • 12
  • Daniel D. Buchanan
    • 1
    • 3
    • 8
  • On behalf of investigators from the Melbourne Collaborative Cohort Study and the Australasian Colorectal Cancer Family Registry Cohort
  1. 1.Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of PathologyThe University of MelbourneParkvilleAustralia
  2. 2.Cancer Epidemiology Centre, Cancer Council VictoriaSt KildaAustralia
  3. 3.Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneParkvilleAustralia
  4. 4.Centre for Alcohol Policy ResearchLa Trobe UniversityMelbourneAustralia
  5. 5.Melbourne BioinformaticsThe University of MelbourneParkvilleAustralia
  6. 6.Colorectal Medicine and GeneticsThe Royal Melbourne HospitalParkvilleAustralia
  7. 7.Department of MedicineThe University of MelbourneParkvilleAustralia
  8. 8.Genetic Medicine and Family Cancer ClinicRoyal Melbourne HospitalParkvilleAustralia
  9. 9.Department of Epidemiology and Institute of Health and Environment, School of Public HealthSeoul National UniversitySeoulSouth Korea
  10. 10.Genetic Epidemiology Laboratory, Department of PathologyThe University of MelbourneParkvilleAustralia
  11. 11.Envoi Specialist PathologistsHerstonAustralia
  12. 12.School of MedicineUniversity of QueenslandHerstonAustralia

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