MICROSATELLITE-UNSTABLE COLORECTAL CANCER IN ELDERLY PATIENTS: CLINICAL FEATURES AND THE ROLE OF IMMUNODEFICIENCY

Background. Tumors demonstrating the phenomenon of microsatellite instability (MSI) represent a special category of colorectal cancer (CRC). Such neoplasms account for up to 20 % of CRC and are characterized by specific molecular and clinical manifestations, including high immunogenicity and sensitivity to immunotherapy. MSI phenotype occurs in two different groups of patients: young individuals with Lynch syndrome and patients older than 70 years with non-hereditary CRC. We assume that the development of sporadic MSI-positive tumors in elderly patients may be associated with age-dependent decrease in immune defense.

The aim of the study was to investigate clinical and morphological characteristics in elderly patients with MSI-positive colorectal cancer.

Material and methods. MSI status and mutations in the BRAF gene were tested in a group of 384 CRC patients older than 65 years by PCR-based techniques. A comparative analysis of clinico-pathological features was further conducted in the groups of 23 MSI-positive and 34 MSI-negative CRC cases.

Results. MSI-positive phenotype was associated with the proximal tumor location, low degree of differentiation and the presence of the mucinous component in the tumor (p<0.0001, p=0.005, and p=0.0001, respectively). Patients with MSI-positive CRC containing BRAF mutations showed a significant prevalence of RhD-negative erythrocyte phenotype (53.3 % vs 11.8 %, p=0.004). In patients with MSI-positive carcinomas, the increased frequency of preoperative leukocytosis (p=0.009) and lymphopenia (p=0.014) was observed.

Conclusion. The increased occurrence of Rh-negative erythrocyte phenotype and white blood formula changes in elderly patients with MSI-positive CRC may indicate the role of immune system disorders in the development of microsatellite-unstable carcinomas.

1. Hatch S.B., Lightfoot H.M.Jr., Garwacki C.P., Moore D.T., Calvo B.F., Woosley J.T., Sciarrotta J., Funkhouser W.K., Farber R.A. Microsatellite instability testing in colorectal carcinoma: choice of markers affects sensitivity of detection of mismatch repair‑deficient tumors. Clin Cancer Res. 2005 Mar 15; 11(6): 2180–7.

2. Morandi L., de Biase D., Visani M., Monzoni A., Tosi A., Brulatti M., Turchetti D., Baccarini P., Tallini G., Pession A. T([20]) repeat in the 3’‑untranslated region of the MT1X gene: a marker with high sensitivity and specificity to detect microsatellite instability in colorectal cancer. Int J Colorectal Dis. 2012 May; 27(5): 647–56. doi: 10.1007/s00384‑011‑1365‑7.

3. Piñol V., Castells A., Andreu M., Castellví-Bel S., Alenda C., Llor X., Xicola R.M., Rodríguez-Moranta F., Payá A., Jover R., Bessa X.; Gastrointestinal Oncology Group of the Spanish Gastroenterological Association. Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. JAMA. 2005 Apr 27; 293(16): 1986–94. doi: 10.1001/jama.293.16.1986.

4. Vilar E., Gruber S.B. Microsatellite instability in colorectal cancer‑ the stable evidence. Nat Rev Clin Oncol. 2010 Mar; 7(3): 153–62. doi: 10.1038/nrclinonc.2009.237.

5. Boland C.R., Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010; 138(6): 2073–2087. doi: 10.1053/j.gastro.2009.12.064.

6. Buecher B., Cacheux W., Rouleau E., Dieumegard B., Mitry E., Lièvre A. Role of microsatellite instability in the management of colorectal cancers. Dig Liver Dis. 2013 Jun; 45(6): 441–9. doi: 10.1016/j.dld.2012.10.006.

7. Geiersbach K.B., Samowitz W.S. Microsatellite instability and colorectal cancer. Pathol Lab Med. 2011 Oct; 135(10): 1269–77. doi: 10.5858/arpa.2011‑0035‑RA.

8. Heinimann K. Toward a molecular classification of colorectal cancer: the role of microsatellite instability status. Front Oncol. 2013 Oct 31; 3: 272. doi: 10.3389/fonc.2013.00272.

9. Kane M.F., Loda M., Gaida G.M., Lipman J., Mishra R., Goldman H., Jessup J.M., Kolodner R. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair‑defective human tumor cell lines. Cancer Res. 1997 Mar 1; 57(5): 808–11.

10. Parsons M.T., Buchanan D.D., Thompson B., Young J.P., Spurdle A.B. Correlation of tumor BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) gene mutation status: a literature review assessing utility of tumor features for MMR variant classification. J Med Genet. 2012 Mar; 49(3): 151–7. doi: 10.1136/jmedgenet‑2011‑100714.

11. Vilar E., Tabernero J. Molecular dissection of microsatellite instable colorectal cancer. Cancer Discov. 2013; 3(5): 502–11. doi: 10.1158/2159‑8290.CD‑12‑0471.

12. Banerjea A., Bustin S.A., Dorudi S. The immunogenicity of colorectal cancers with high‑degree microsatellite instability. World J Surg Oncol. 2005 May 12; 3:26.

13. Bauer K., Nelius N., Reuschenbach M., Koch M., Weitz J., Steinert G., Kopitz J., Beckhove P., Tariverdian M., von Knebel Doeberitz M., Kloor M. T cell responses against microsatellite instability‑induced frameshift peptides and influence of regulatory T cells in colorectal cancer. Cancer Immunol Immunother. 2013 Jan; 62(1): 27–37. doi: 10.1007/s00262‑012‑1303‑8.

14. Bustin S.A., Li S.R., Phillips S., Dorudi S. Expression of HLA class II in colorectal cancer: evidence for enhanced immunogenicity of microsatellite‑instability‑positive tumours. Tumour Biol. 2001 Sep‑Oct; 22(5): 294. doi: 10.1159/000050630.

15. Deschoolmeester V., Baay M., Lardon F., Pauwels P., Peeters M. Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI. Cancer Microenviron. 2011 Dec; 4(3): 377–92. doi: 10.1007/s12307‑011‑0068‑5.

16. Drescher K.M., Sharma P., Watson P., Gatalica Z., Thibodeau S.N., Lynch H.T. Lymphocyte recruitment into the tumor site is altered in patients with MSI‑H colon cancer. Fam Cancer. 2009; 8(3): 231–9. doi: 10.1007/s10689‑009‑9233‑0.

17. Jass J.R. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology. 2007 Jan; 50(1): 113–30. doi: 10.1111/j.1365‑2559.2006.02549.x.

18. Kloor M., Michel S., von Knebel Doeberitz M. Immune evasion of microsatellite unstable colorectal cancers. Int J Cancer. 2010 Sep 1; 127(5): 1001–10. doi: 10.1002/ijc.25283.

19. Malesci A., Laghi L., Bianchi P., Delconte G., Randolph A., Torri V., Carnaghi C., Doci R., Rosati R., Montorsi M., Roncalli M., Gennari L., Santoro A. Reduced likelihood of metastases in patients with microsatellite‑unstable colorectal cancer. Clin Cancer Res. 2007; 13(13): 3831–9. doi: 10.1158/1078‑0432.CCR‑07‑0366.

20. Michel S., Benner A., Tariverdian M., Wentzensen N., Hoefler P., Pommerencke T., Grabe N., von Knebel Doeberitz M., Kloor M. High density of FOXP3‑positive T cells infiltrating colorectal cancers with microsatellite instability. Br J Cancer. 2008 Dec 2; 99(11): 1867–73. doi: 10.1038/sj.bjc.6604756.

21. Ogino S., Nosho K., Irahara N., Meyerhardt J.A., Baba Y., Shima K., Glickman J.N., Ferrone C.R., Mino-Kenudson M., Tanaka N., Dranoff G., Giovannucci E.L., Fuchs C.S. Lymphocytic reaction to colorectal cancer is associated with longer survival, independent of lymph node count, microsatellite instability, and CpG island methylator phenotype. Clin Cancer Res. 2009 Oct 15; 15(20): 6412–20. doi: 10.1158/1078‑0432.CCR‑09‑1438.

22. von Knebel Doeberitz M., Kloor M. Towards a vaccine to prevent cancer in Lynch syndrome patients. Fam Cancer. 2013 Jun; 12(2): 307–12. doi: 10.1007/s10689‑013‑9662‑7.

23. Mandal R., Samstein R.M., Lee K.W., Havel J.J., Wang H., Krishna C., Sabio E.Y., Makarov V., Kuo F., Blecua P., Ramaswamy A.T., Durham J.N., Bartlett B., Ma X., Srivastava R., Middha S., Zehir A., Hechtman J.F., Morris L.G., Weinhold N., Riaz N., Le D.T., Diaz L.A.Jr., Chan T.A. Genetic diversity of tumors with mismatch repair deficiency influences anti‑PD‑1 immunotherapy response. Science. 2019 May 3; 364(6439): 485–491. doi: 10.1126/science.aau0447.

24. Yuza K., Nagahashi M., Watanabe S., Takabe K., Wakai T. Hypermutation and microsatellite instability in gastrointestinal cancers. Oncotarget. 2017 Dec 1; 8(67): 112103–112115. doi: 10.18632/oncotar‑get.22783.

25. López-Otín C., Blasco M.A., Partridge L., Serrano M., Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6; 153(6): 1194–217. doi: 10.1016/j.cell.2013.05.039.

26. Yanus G.A., Belyaeva A.V., Ivantsov A.O., Kuligina E.Sh., Suspitsin E.N., Mitiushkina N.V., Aleksakhina S.N., Iyevleva A.G., Zaitseva O.A., Yatsuk O.S., Gorodnova T.V., Strelkova T.N., Efremova S.A., Lepenchuk A.Y., Ochir-Garyaev A.N., Paneyah M.B., Matsko D.E., Togo A.V., Imyanitov E.N. Pattern of clinically relevant mutations in consecutive series of Russian colorectal cancer patients. Med Oncol. 2013; 30(3): 686. doi: 10.1007/s12032‑013‑0686‑5.

27. Flegel W.A. Molecular genetics and clinical applications for RH. Transfus Apher Sci. 2011 Feb; 44(1): 81–91. doi: 10.1016/j.transci.2010.12.013.

28. Kustu S., Inwood W. Biological gas channels for NH3 and CO2: evidence that Rh (Rhesus) proteins are CO2 channels. Transfus Clin Biol. 2006 Mar‑Apr; 13(1–2): 103–10. doi: 10.1016/j.tracli.2006.03.001.

29. Van Kim C.L., Colin Y., Cartron J.P. Rh proteins: key structural and functional components of the red cell membrane. Blood Rev. 2006 Mar; 20(2): 93–110. doi: 10.1016/j.blre.2005.04.002.

30. Flegr J., Hoffmann R., Dammann M. Worse Health Status and Higher Incidence of Health Disorders in Rhesus Negative Subjects. PLoS One. 2015 Oct 23; 10(10): e0141362. doi: 10.1371/journal.pone.0141362.