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01-04-2015 | Original Article

Hierarchical clustering identifies a subgroup of colonic adenocarcinomas expressing crypt-like differentiation markers, associated with MSS status and better prognosis

Authors: Laure Droy-Dupré, Céline Bossard, Christelle Volteau, Stéphane Bezieau, Christian L. Laboisse, Jean-François Mosnier

Published in: Virchows Archiv | Issue 4/2015

Abstract

The aim of this study was to identify in the group of colonic adenocarcinomas, not otherwise specified (NOS), subgroups of oncogenetic and prognostic significance based on the expression of immunohistochemical markers of epithelial cell differentiation of the gastrointestinal tract. Hierarchical clustering analysis of 122 adenocarcinomas (NOS) identified four clusters based on how closely their profile of immunohistochemical expression of differentiation markers was related: (i) a major cluster of 83 adenocarcinomas (68 %) called crypt-like carcinoma (CLA) with a immunohistochemically expressing colonic crypt differentiation markers (cytokeratin 20+, CDX2+, MUC2+ or MUC2−) and (ii) three minor clusters, characterized by the loss of colonic crypt differentiation markers and/or the acquisition of expression of markers of metaplastic foveolar gastric differentiation (MUC5AC+) and/or aberrant cytokeratin 7 expression. CLAs were invariably MSS (χ ² test: p < 0.0001). The sole parameters associated with worse overall survival of the 122 patients with adenocarcinoma (NOS) were pT stage, pN+ stage, and advanced clinical stage. Interestingly, CLA lineage of differentiation was an independent prognostic parameter for better overall survival among the 40 patients with an adenocarcinoma (NOS) stage III. In conclusion, hierarchical clustering led to the identification of a main cluster of adenocarcinoma (NOS) with crypt-like differentiation, associated with MSS status and better prognosis. Its value as a biomarker of response to conventional chemotherapeutic agents deserves to be examined in randomized therapy trials.

Jass JR (2007) Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 50:113–130CrossRefPubMed

Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM, Bos JL (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319:525–532CrossRefPubMed

Tomlinson I, Bodmer W (1999) Selection, the mutation rate and cancer: ensuring that the tail does not wag the dog. Nat Med 5:11–12CrossRefPubMed

Fodde R, Kuipers J, Rosenberg C, Smits R, Kielman M, Gaspar C, van Es JH, Breukel C, Wiegant J, Giles RH, Clevers H (2001) Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat Cell Biol 3:433–438CrossRefPubMed

Aaltonen LA, Peltomäki P, Leach FS, Sistonen P, Pylkkänen L, Mecklin JP, Järvinen H, Powell SM, Jen J, Hamilton SR et al (1993) Clues to the pathogenesis of familial colorectal cancer. Science 260:812–816CrossRefPubMed

Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:558–561CrossRefPubMed

Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260:816–819CrossRefPubMed

Cunningham JM, Christensen ER, Tester DJ, Kim CY, Roche PC, Burgart LJ, Thibodeau SN (1998) Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res 58:3455–3460PubMed

Gafà R, Maestri I, Matteuzzi M, Santini A, Ferretti S, Cavazzini L, Lanza G (2000) Sporadic colorectal adenocarcinomas with high-frequency microsatellite instability. Cancer 89:2025–2037CrossRefPubMed

10.

Alexander J, Watanabe T, Wu TT, Rashid A, Li S, Hamilton SR (2001) Histopathological identification of colon cancer with microsatellite instability. Am J Pathol 158:527–535CrossRefPubMedCentralPubMed

11.

Greenson JK, Huang SC, Herron C, Moreno V, Bonner JD, Tomsho LP, Ben-Izhak O, Cohen HI, Trougouboff P, Bejhar J, Sova Y, Pinchev M, Rennert G, Gruber SB (2009) Pathologic predictors of microsatellite instability in colorectal cancer. Am J Surg Pathol 33:126–133CrossRefPubMedCentralPubMed

12.

Hamilton SR, Bosman FT, Boffetta P, Ilyas M, Morreau H, Nakamura S-I, Quirke P, Riboli E, Sobin LH (2010) Carcinoma of the colon and rectum. In: Bosman FT, Carneiro F, Hruban RH, Theise ND (eds) WHO classification of tumours of the digestive system. IARC Press, Lyon, pp 134–146

13.

Sobin LH, Brierley J (2009) Colon and rectum. In: Sobin LH, Gospodarowicz MK, Wittekind C (eds) TNM classification of malignant tumours, 7th edn. Wiley-Blackwell, Oxford, pp 100–105

14.

Liu CL, Prapong W, Natkunam Y, Alizadeh A, Montgomery K, Gilks CB, van de Rijn M (2002) Software tools for high-throughput analysis and archiving of immunohistochemistry staining data obtained with tissue microarrays. Am J Pathol 161:1557–1565CrossRefPubMedCentralPubMed

15.

Eisen MB, Spellman PT, Brown PO, Botstein D (1998) Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A 95:14863–14868CrossRefPubMedCentralPubMed

16.

Suraweera N, Duval A, Reperant M, Vaury C, Furlan D, Leroy K, Seruca R, Iacopetta B, Hamelin R (2002) Evaluation of tumor microsatellite instability using five quasimonomorphic mononucleotide repeats and pentaplex PCR. Gastroenterology 123:1804–1811CrossRefPubMed

17.

Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403:503–511CrossRefPubMed

18.

Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Lønning PE, Børresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869–10874CrossRefPubMedCentralPubMed

19.

Makretsov NA, Huntsman DG, Nielsen TO, Yorida E, Peacock M, Cheang MC, Dunn SE, Hayes M, van de Rijn M, Bajdik C, Gilks CB (2004) Hierarchical clustering analysis of tissue microarray immunostaining data identifies prognostically significant groups of breast carcinoma. Clin Cancer Res 10:6143–6151CrossRefPubMed

20.

Jacquemier J, Ginestier C, Rougemont J, Bardou VJ, Charafe-Jauffret E, Geneix J, Adélaïde J, Koki A, Houvenaeghel G, Hassoun J, Maraninchi D, Viens P, Birnbaum D, Bertucci F (2005) Protein expression profiling identifies subclasses of breast cancer and predicts prognosis. Cancer Res 65:767–779PubMed

21.

Alkushi A, Clarke BA, Akbari M, Makretsov N, Lim P, Miller D, Magliocco A, Coldman A, van de Rijn M, Huntsman D, Parker R, Gilks CB (2007) Identification of prognostically relevant and reproducible subsets of endometrial adenocarcinoma based on clustering analysis of immunostaining data. Mod Pathol 20:1156–1165CrossRefPubMed

22.

Lorentz O, Duluc I, Arcangelis AD, Simon-Assmann P, Kedinger M, Freund JN (1997) Key role of the Cdx2 homeobox gene in extracellular matrix-mediated intestinal cell differentiation. J Cell Biol 139:1553–1565CrossRefPubMedCentralPubMed

23.

Silberg DG, Swain GP, Suh ER, Traber PG (2000) Cdx1 and cdx2 expression during intestinal development. Gastroenterology 119:961–971CrossRefPubMed

24.

Moll R, Löwe A, Laufer J, Franke WW (1992) Cytokeratin 20 in human carcinomas. A new histodiagnostic marker detected by monoclonal antibodies. Am J Pathol 140:427–447PubMedCentralPubMed

25.

Chang SK, Dohrman AF, Basbaum CB, Ho SB, Tsuda T, Toribara NW, Gum JR, Kim YS (1994) Localization of mucin (MUC2 and MUC3) messenger RNA and peptide expression in human normal intestine and colon cancer. Gastroenterology 107:28–36PubMed

26.

Uesaka T, Kageyama N, Watanabe H (2004) Identifying target genes regulated downstream of Cdx2 by microarray analysis. J Mol Biol 337:647–660CrossRefPubMed

27.

Stosiek P, Bräutigam E, Kasper M (1991) Expression of cytokeratin 7 in human glandular epithelium of fetal stomach. Acta Histochem 91:21–23CrossRefPubMed

28.

Tatsumi N, Kushima R, Vieth M, Mukaisho K, Kakinoki R, Okabe H, Borchard F, Stolte M, Okanoue T, Hattori T (2006) Cytokeratin 7/20 and mucin core protein expression in ulcerative colitis-associated colorectal neoplasms. Virchows Arch 448:756–762CrossRefPubMed

29.

Forgue-Lafitte ME, Fabiani B, Levy PP, Maurin N, Fléjou JF, Bara J (2007) Abnormal expression of M1/MUC5AC mucin in distal colon of patients with diverticulitis, ulcerative colitis and cancer. Int J Cancer 121:1543–1549CrossRefPubMed

30.

Hinoi T, Tani M, Lucas PC, Caca K, Dunn RL, Macri E, Loda M, Appelman HD, Cho KR, Fearon ER (2001) Loss of CDX2 expression and microsatellite instability are prominent features of large cell minimally differentiated carcinomas of the colon. Am J Pathol 159:2239–2248CrossRefPubMedCentralPubMed

31.

McGregor DK, Wu TT, Rashid A, Luthra R, Hamilton SR (2004) Reduced expression of cytokeratin 20 in colorectal carcinomas with high levels of microsatellite instability. Am J Surg Pathol 28:712–718CrossRefPubMed

32.

Biemer-Hüttmann AE, Walsh MD, McGuckin MA, Simms LA, Young J, Leggett BA, Jass JR (2000) Mucin core protein expression in colorectal cancers with high levels of microsatellite instability indicates a novel pathway of morphogenesis. Clin Cancer Res 6:1909–1916PubMed

33.

Yao T, Nishiyama KI, Oya M, Kouzuki T, Kajiwara M, Tsuneyoshi M (2000) Multiple ‘serrated adenocarcinomas’ of the colon with a cell lineage common to metaplastic polyp and serrated adenoma. Case report of a new subtype of colonic adenocarcinoma with gastric differentiation. J Pathol 190:444–449CrossRefPubMed

34.

Buisine MP, Janin A, Maunoury V, Audié JP, Delescaut MP, Copin MC, Colombel JF, Degand P, Aubert JP, Porchet N (1996) Aberrant expression of a human mucin gene (MUC5AC) in rectosigmoid villous adenoma. Gastroenterology 110:84–91CrossRefPubMed

35.

Iacopetta B, Kawakami K, Watanabe T (2008) Predicting clinical outcome of 5-fluorouracil-based chemotherapy for colon cancer patients: is the CpG island methylator phenotype the 5-fluorouracil-responsive subgroup? Int J Clin Oncol 13:498–503CrossRefPubMed

36.

Boland CR, Goel A (2010) Microsatellite instability in colorectal cancer. Gastroenterology 138:2073–2087CrossRefPubMedCentralPubMed

37.

Varadhachary GR, Raber MN, Matamoros A, Abbruzzese JL (2008) Carcinoma of unknown primary with a colon-cancer profile-changing paradigm and emerging definitions. Lancet Oncol 9:596–599CrossRefPubMed

Title: Hierarchical clustering identifies a subgroup of colonic adenocarcinomas expressing crypt-like differentiation markers, associated with MSS status and better prognosis
Authors: Laure Droy-Dupré
Céline Bossard
Christelle Volteau
Stéphane Bezieau
Christian L. Laboisse
Jean-François Mosnier
Publication date: 01-04-2015
Publisher: Springer Berlin Heidelberg
Published in: Virchows Archiv / Issue 4/2015
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-015-1724-9

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Hierarchical clustering identifies a subgroup of colonic adenocarcinomas expressing crypt-like differentiation markers, associated with MSS status and better prognosis

Abstract

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Abstract

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