Article | Published:

SATB2 and CDX2 are prognostic biomarkers in DNA mismatch repair protein deficient colon cancer

Abstract

DNA mismatch repair protein deficient colon cancer frequently displays reduced CDX2 expression, and recent literature has suggested that negative CDX2 expression is a poor prognostic biomarker in colon cancer. We have recently demonstrated that SATB2 is an immunohistochemical marker that is complementary to CDX2. Using a tissue microarray approach, we evaluated SATB2 and CDX2 immunohistochemical expression in 514 patients with colonic adenocarcinoma including 146 with mismatch repair protein deficient tumors and correlated expression with histopathologic variables, molecular alterations, and survival. Overall, SATB2-negative and/or CDX2-negative expression was identified in 33% of mismatch repair protein deficient tumors compared with only 15% of mismatch repair protein proficient tumors (p < 0.001) and in 36% of BRAF V600E mutated compared with only 13% of BRAF wild-type tumors (p < 0.001). Both SATB2-negative and CDX2-negative colonic adenocarcinomas more often displayed lymphatic invasion, venous invasion, and perineural invasion (all with p < 0.05). SATB2-negative expression was also more frequently identified in tumors with mucinous or signet ring cell differentiation (p < 0.01 for both). In a multivariable analysis of survival in patients with mismatch repair protein deficient tumors (n = 131), only tumor stage (p= 0.01) and SATB2-negative and/or CDX2-negative expression (p = 0.009) independently predicted disease-specific survival. Of the 99 patients with stage II or III mismatch repair protein deficient tumors, death from disease only occurred in patients with either SATB2-negative or CDX2-negative tumors, and no patients with SATB2-positive/CDX2-positive tumors developed recurrence or died of disease. SATB2 and CDX2 expression had no effect on patient survival in mismatch repair protein proficient, BRAF-mutated, or KRAS-mutated tumors. In summary, our results suggest that SATB2 and CDX2 are prognostic biomarkers in patients with mismatch repair protein deficient colon cancer and that inclusion of SATB2 and CDX2 immunohistochemistry may be helpful as part of a comprehensive pathologic risk assessment in mismatch repair protein deficient colon cancer.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.

  2. 2.

    Bockelman C, Engelmann BE, Kaprio T, Hansen TF, Glimelius B. Risk of recurrence in patients with colon cancer stage II and III: a systematic review and meta-analysis of recent literature. Acta Oncol. 2015;54:5–16.

  3. 3.

    Kannarkatt J, Joseph J, Kurniali PC, Al-Janadi A, Hrinczenko B. Adjuvant chemotherapy for stage II colon cancer: a Clinical Dilemma. J Oncol Pract. 2017;13:233–41.

  4. 4.

    Phipps AI, Limburg PJ, Baron JA, Burnett-Hartman AN, Weisenberger DJ, Laird PW, et al. Association between molecular subtypes of colorectal cancer and patient survival. Gastroenterology. 2015;148:77–87.

  5. 5.

    Sinicrope FA, Shi Q, Smyrk TC, Thibodeau SN, Dienstmann R, Guinney J, et al. Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes. Gastroenterology. 2015;148:88–99.

  6. 6.

    Landau MA, Zhu B, Akwuole FN, Pai RK. Site-specific differences in colonic adenocarcinoma: KRAS mutations and high tumor budding are more frequent in cecal adenocarcinoma. Am J Surg Pathol. 2018;42:351–8.

  7. 7.

    Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005;23:609–18.

  8. 8.

    Klingbiel D, Saridaki Z, Roth AD, Bosman FT, Delorenzi M, Tejpar S. Prognosis of stage II and III colon cancer treated with adjuvant 5-fluorouracil or FOLFIRI in relation to microsatellite status: results of the PETACC-3 trial. Ann Oncol. 2015;26:126–32.

  9. 9.

    Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349:247–57.

  10. 10.

    Sinicrope FA, Foster NR, Thibodeau SN, Marsoni S, Monges G, Labianca R, et al. DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. J Natl Cancer Inst. 2011;103:863–75.

  11. 11.

    Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010;28:3219–226.

  12. 12.

    Mohan HM, Ryan E, Balasubramanian I, Kennelly R, Geraghty R, Sclafani F, et al. Microsatellite instability is associated with reduced disease specific survival in stage III colon cancer. Eur J Surg Oncol. 2016;42:1680–6.

  13. 13.

    Zhang BY, Jones JC, Briggler AM, Hubbard JM, Kipp BR, Sargent DJ, et al. Lack of caudal-type homeobox transcription factor 2 expression as a prognostic biomarker in metastatic colorectal cancer. Clin Colorectal Cancer. 2017;16:124–8.

  14. 14.

    Dalerba P, Sahoo D, Paik S, Guo X, Yothers G, Song N, et al. CDX2 as a prognostic biomarker in stage II and stage III colon cancer. N Engl J Med. 2016;374:211–22.

  15. 15.

    Bae JM, Lee TH, Cho NY, Kim TY, Kang GH. Loss of CDX2 expression is associated with poor prognosis in colorectal cancer patients. World J Gastroenterol. 2015;21:1457–67.

  16. 16.

    FitzPatrick DR, Carr IM, McLaren L, Leek JP, Wightman P, Williamson K, et al. Identification of SATB2 as the cleft palate gene on 2q32-q33. Hum Mol Genet. 2003;12:2491–501.

  17. 17.

    Magnusson K, de Wit M, Brennan DJ, Johnson LB, McGee SF, Lundberg E, et al. SATB2 in combination with cytokeratin 20 identifies over 95% of all colorectal carcinomas. Am J Surg Pathol. 2011;35:937–48.

  18. 18.

    Ma C, Olevian DC, Lowenthal BM, Jayachandran P, Kozak MM, Chang DT, et al. Loss of SATB2 expression in colorectal carcinoma Is associated with DNA mismatch repair protein deficiency and BRAF mutation. Am J Surg Pathol. 2018;42:1409–17.

  19. 19.

    Lin F, Shi J, Zhu S, Chen Z, Li A, Chen T, et al. Cadherin-17 and SATB2 are sensitive and specific immunomarkers for medullary carcinoma of the large intestine. Arch Pathol Lab Med. 2014;138:1015–26.

  20. 20.

    Dragomir A, de Wit M, Johansson C, Uhlen M, Ponten F. The role of SATB2 as a diagnostic marker for tumors of colorectal origin: results of a pathology-based clinical prospective study. Am J Surg Pathol. 2014;141:630–8.

  21. 21.

    Moh M, Krings G, Ates D, Aysal A, Kim GE, Rabban JT. SATB2 expression distinguishes ovarian metastases of colorectal and appendiceal origin from primary ovarian tumors of mucinous or endometrioid type. Am J Surg Pathol. 2016;40:419–32.

  22. 22.

    Strickland S, Wasserman JK, Giassi A, Djordjevic B, Parra-Herran C. Immunohistochemistry in the diagnosis of mucinous neoplasms involving the ovary: the added value of SATB2 and biomarker discovery through protein expression database mining. Int J Gynecol Pathol. 2016;35:191–208.

  23. 23.

    Li Z, Roth R, Rock JB, Lehman A, Marsh WL, Suarez A, et al. Dual immunostain with SATB2 and CK20 differentiates appendiceal mucinous neoplasms from ovarian mucinous neoplasms. Am J Clin Pathol. 2017;147:484–91.

  24. 24.

    Mansour MA, Hyodo T, Ito S, Kurita K, Kokuryo T, Uehara K, et al. SATB2 suppresses the progression of colorectal cancer cells via inactivation of MEK5/ERK5 signaling. FEBS J. 2015;282:1394–405.

  25. 25.

    Wang S, Zhou J, Wang XY, Hao JM, Chen JZ, Zhang XM, et al. Down-regulated expression of SATB2 is associated with metastasis and poor prognosis in colorectal cancer. J Pathol. 2009;219:114–22.

  26. 26.

    Eberhard J, Gaber A, Wangefjord S, Nodin B, Uhlen M, Ericson Lindquist K, et al. A cohort study of the prognostic and treatment predictive value of SATB2 expression in colorectal cancer. Br J Cancer. 2012;106:931–8.

  27. 27.

    Kim JH, Rhee YY, Bae JM, Cho NY, Kang GH. Loss of CDX2/CK20 expression is associated with poorly differentiated carcinoma, the CpG island methylator phenotype, and adverse prognosis in microsatellite-unstable colorectal cancer. Am J Surg Pathol. 2013;37:1532–41.

  28. 28.

    Lugli A, Tzankov A, Zlobec I, Terracciano LM. Differential diagnostic and functional role of the multi-marker phenotype CDX2/CK20/CK7 in colorectal cancer stratified by mismatch repair status. Mod Pathol. 2008;21:1403–12.

  29. 29.

    McGregor DK, Wu TT, Rashid A, Luthra R, Hamilton SR. Reduced expression of cytokeratin 20 in colorectal carcinomas with high levels of microsatellite instability. Am J Surg Pathol. 2004;28:712–8.

  30. 30.

    Zlobec I, Bihl M, Foerster A, Rufle A, Lugli A. Comprehensive analysis of CpG island methylator phenotype (CIMP)-high, -low, and -negative colorectal cancers based on protein marker expression and molecular features. J Pathol. 2011;225:336–43.

  31. 31.

    Liu CL, Prapong W, Natkunam Y, Alizadeh A, Montgomery K, Gilks CB, et al. Software tools for high-throughput analysis and archiving of immunohistochemistry staining data obtained with tissue microarrays. Am J Pathol. 2002;161:1557–65.

  32. 32.

    Greenson JK, Bonner JD, Ben-Yzhak O, Cohen HI, Miselevich I, Resnick MB, et al. Phenotype of microsatellite unstable colorectal carcinomas: well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability. Am J Surg Pathol. 2003;27:563–70.

  33. 33.

    Lugli A, Kirsch R, Ajioka Y, Bosman F, Cathomas G, Dawson H, et al. Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Mod Pathol. 2017;30:1299–311.

  34. 34.

    Kakar S, Shi C, Berho M, Driman DK, Fitzgibbons P, Frankel WL, et al. Protocol for the examination of specimens from patients with primary carcinoma of the colon and rectum. In: CAP (College of American Pathologists) Cancer Protocols, 2018 [cited 1 November 2018]. https://cap.objects.frb.io/protocols/cp-gilower-colonrectum-17protocol-4010.pdf

  35. 35.

    Pai RK, Jayachandran P, Koong AC, Chang DT, Kwok S, Ma L, et al. BRAF-mutated, microsatellite-stable adenocarcinoma of the proximal colon: an aggressive adenocarcinoma with poor survival, mucinous differentiation, and adverse morphologic features. Am J Surg Pathol. 2012;36:744–52.

  36. 36.

    Yousem SA, Nikiforova M, Nikiforov Y. The histopathology of BRAF-V600E-mutated lung adenocarcinoma. Am J Surg Pathol. 2008;32:1317–21.

  37. 37.

    Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

  38. 38.

    Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.

  39. 39.

    Grossman RL, Heath AP, Ferretti V, Varmus HE, Lowy DR, Kibbe WA, et al. Toward a shared vision for cancer genomic data. N Engl J Med. 2016;375:1109–12.

  40. 40.

    Benson AB, 3rd, Venook AP, Cederquist L, Chan E, Chen YJ, Cooper HS, et al. Colon cancer, version 1.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2017;15:370–98.

  41. 41.

    Koopman M, Kortman GA, Mekenkamp L, Ligtenberg MJ, Hoogerbrugge N, Antonini NF, et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer. 2009;100:266–73.

  42. 42.

    Roth AD, Tejpar S, Delorenzi M, Yan P, Fiocca R, Klingbiel D, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol. 2010;28:466–74.

  43. 43.

    Gkekas I, Novotny J, Pecen L, Strigard K, Palmqvist R, Gunnarsson U. Microsatellite instability as a prognostic factor in stage II colon cancer patients, a meta-analysis of published literature. Anticancer Res. 2017;37:6563–74.

  44. 44.

    Kim GP, Colangelo LH, Wieand HS, Paik S, Kirsch IR, Wolmark N, et al. Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project Collaborative Study. J Clin Oncol. 2007;25:767–72.

  45. 45.

    Pilati C, Taieb J, Balogoun R, Marisa L, de Reynies A, Laurent-Puig P. CDX2 prognostic value in stage II/III resected colon cancer is related to CMS classification. Ann Oncol. 2017;28:1032–5.

  46. 46.

    Bruun J, Sveen A, Barros R, Eide PW, Eilertsen I, Kolberg M, et al. Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer. Mol Oncol. 2018;12:1639–55.

  47. 47.

    Graule J, Uth K, Fischer E, Centeno I, Galvan JA, Eichmann M, et al. CDX2 in colorectal cancer is an independent prognostic factor and regulated by promoter methylation and histone deacetylation in tumors of the serrated pathway. Clin Epigenetics. 2018;10:120.

  48. 48.

    Baba Y, Nosho K, Shima K, Freed E, Irahara N, Philips J, et al. Relationship of CDX2 loss with molecular features and prognosis in colorectal cancer. Clin Cancer Res. 2009;15:4665–73.

  49. 49.

    Olsen J, Eiholm S, Kirkeby LT, Espersen ML, Jess P, Gogenur I, et al. CDX2 downregulation is associated with poor differentiation and MMR deficiency in colon cancer. Exp Mol Pathol. 2016;100:59–66.

  50. 50.

    Coebergh van den Braak RR, Martens JW, Ijzermans JN. CDX2 as a prognostic biomarker in colon cancer. N Engl J Med. 2016;374:2182.

  51. 51.

    Schirripa M, Loupakis F, Lenz HJ. CDX2 as a prognostic biomarker in colon cancer. N Engl J Med. 2016;374:2183.

  52. 52.

    Shen J, Ju Z, Zhao W, Wang L, Peng Y, Ge Z, et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat Med. 2018;24:556–62.

  53. 53.

    Salari K, Spulak ME, Cuff J, Forster AD, Giacomini CP, Huang S, et al. CDX2 is an amplified lineage-survival oncogene in colorectal cancer. Proc Natl Acad Sci USA. 2012;109:E3196–3205.

  54. 54.

    Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, et al. Patterns of somatic mutation in human cancer genomes. Nature. 2007;446:153–8.

  55. 55.

    Walsh MD, Clendenning M, Williamson E, Pearson SA, Walters RJ, Nagler B, et al. Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype. Mod Pathol. 2013;26:1642–56.

  56. 56.

    Olsen J, Espersen ML, Jess P, Kirkeby LT, Troelsen JT. The clinical perspectives of CDX2 expression in colorectal cancer: a qualitative systematic review. Surg Oncol. 2014;23:167–76.

  57. 57.

    Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch repair deficiency. N Engl J Med. 2015;372:2509–20.

  58. 58.

    Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–13.

Download references

Author information

Conflict of interest

The authors declare that they have no conflict of interest.

Correspondence to Reetesh K. Pai.

Supplementary information

  1. Supplemental Table 1

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1
Fig. 2
Fig. 3
Fig. 4