HMG-CoA reductase expression in primary colorectal cancer correlates with favourable clinicopathological characteristics and an improved clinical outcome

Diagnostic Pathology

Karin Jirström²  Signe Borgquist²  Mathias Uhlén¹  Jakob Eberhard²  Björn Nodin²  Sakarias Wangefjord²  Pashtrik Nerjovaj²  Erik Bengtsson² 

[1] School of Biotechnology, AlbaNova University Center, Royal Institute of Technology, 106 91 Stockholm, Sweden;Department of Clinical Sciences, Oncology and Pathology, Lund University, 221 85 Lund, Sweden

关键词: Prognosis;    Colorectal cancer;    Immunohistochemistry;    HMG-CoA reductase;   

Others  :  801984
DOI  :  10.1186/1746-1596-9-78

 received in 2013-07-22, accepted in 2014-03-29,  发布年份 2014

【 摘 要 】

Background

An association between tumor-specific HMG-CoA reductase (HMGCR) expression and good prognosis has previously been demonstrated in breast and ovarian cancer. In this study, the expression, clinicopathological correlates and prognostic value of HMGCR expression in colorectal cancer was examined.

Findings

Immunohistochemical expression of HMGCR was assessed in tissue microarrays with primary tumours from 557 incident cases of colorectal cancer in the Malmö Diet and Cancer Study. Pearson’s Chi Square test was applied to explore the associations between HMGCR expression and clinicopathological factors and other investigative biomarkers. Kaplan Meier analysis and Cox proportional hazards modeling were used to assess the relationship between HMGCR expression and cancer-specific survival (CSS) according to negative vs positive HMGCR expression.

A total number of 535 (96.0%) tumours were suitable for analysis, of which 61 (11.4%) were HMGCR negative. Positive cytoplasmic HMGCR expression was associated with distant metastasis-free disease at diagnosis (p = 0.002), lack of vascular invasion (p = 0.043), microsatellite-instability (p = 0.033), expression of cyclin D1 (p = <0.001) and p21 (p = <0.001). Positive HMGCR expression was significantly associated with a prolonged CSS in unadjusted Cox regression analysis in the entire cohort (HR = 1.79; 95% CI 1.20-2.66) and in Stage III-IV disease (HR = 1.71; 95% CI 1.09-2.68), but not after adjustment for established clinicopathological parameters.

Conclusions

Findings from this prospective cohort study demonstrate that HMGCR is differentially expressed in colorectal cancer and that positive expression is associated with favourable tumour characteristics and a prolonged survival in unadjusted analysis. The utility of HMGCR as a predictor of response to neoadjuvant or adjuvant statin treatment in colorectal cancer merits further study.

Virtual slides

The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2115647072103464 webcite.

【 授权许可】

   
2014 Bengtsson et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer J Int Du Cancer 2010, 127(12):2893-2917.
• [2]Borgquist S, Djerbi S, Ponten F, Anagnostaki L, Goldman M, Gaber A, Manjer J, Landberg G, Jirstrom K: HMG-CoA reductase expression in breast cancer is associated with a less aggressive phenotype and influenced by anthropometric factors. Int J Cancer 2008, 123(5):1146-1153.
• [3]Brennan DJ, Brandstedt J, Rexhepaj E, Foley M, Ponten F, Uhlen M, Gallagher WM, O’Connor DP, O’Herlihy C, Jirstrom K: Tumour-specific HMG-CoAR is an independent predictor of recurrence free survival in epithelial ovarian cancer. BMC Cancer 2010, 10:125.
• [4]Brennan DJ, Laursen H, O’Connor DP, Borgquist S, Uhlen M, Gallagher WM, Ponten F, Millikan RC, Ryden L, Jirstrom K: Tumor-specific HMG-CoA reductase expression in primary premenopausal breast cancer predicts response to tamoxifen. Breast Cancer Res 2011, 13(1):R12. BioMed Central Full Text
• [5]Bjarnadottir O, Romero Q, Bendahl PO, Jirstrom K, Ryden L, Loman N, Uhlen M, Johannesson H, Rose C, Grabau D, Borgquist S: Targeting HMG-CoA reductase with statins in a window-of-opportunity breast cancer trial. Breast Cancer Res Treat 2013, 138(2):499-508.
• [6]Broughton T, Sington J, Beales IL: Statin use is associated with a reduced incidence of colorectal cancer: a colonoscopy-controlled case–control study. BMC Gastroenterol 2012, 12:36. BioMed Central Full Text
• [7]Poynter JN, Gruber SB, Higgins PD, Almog R, Bonner JD, Rennert HS, Low M, Greenson JK, Rennert G: Statins and the risk of colorectal cancer. New Engl J Med 2005, 352(21):2184-2192.
• [8]Lipkin SM, Chao EC, Moreno V, Rozek LS, Rennert H, Pinchev M, Dizon D, Rennert G, Kopelovich L, Gruber SB: Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase modifies the chemopreventive activity of statins for colorectal cancer. Cancer Prev Res (Phila) 2010, 3(5):597-603.
• [9]Feleszko W, Jakobisiak M: Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells. Clin Cancer Res 2000, 6(3):1198-1199.
• [10]Xiao H, Zhang Q, Lin Y, Reddy BS, Yang CS: Combination of atorvastatin and celecoxib synergistically induces cell cycle arrest and apoptosis in colon cancer cells. Int J Cancer 2008, 122(9):2115-2124.
• [11]Berglund G, Elmstahl S, Janzon L, Larsson SA: The malmo diet and cancer study: design and feasibility. J Intern Med 1993, 233(1):45-51.
• [12]Brandstedt J, Wangefjord S, Nodin B, Gaber A, Manjer J, Jirstrom K: Gender, anthropometric factors and risk of colorectal cancer with particular reference to tumour location and TNM stage: a cohort study. Biol Sex Differ 2012, 3(1):23. BioMed Central Full Text
• [13]Brandstedt J, Wangefjord S, Borgquist S, Nodin B, Eberhard J, Manjer J, Jirstrom K: Influence of anthropometric factors on tumour biological characteristics of colorectal cancer in men and women: a cohort study. J Transl Med 2013, 11:293. BioMed Central Full Text
• [14]Edge SB, Compton CC: The American joint committee on cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010, 17(6):1471-1474.
• [15]Wangefjord S, Brandstedt J, Lindquist KE, Nodin B, Jirstrom K, Eberhard J: Associations of beta-catenin alterations and MSI screening status with expression of key cell cycle regulating proteins and survival from colorectal cancer. Diagn Pathol 2013, 8:10. BioMed Central Full Text
• [16]Larsson A, Johansson ME, Wangefjord S, Gaber A, Nodin B, Kucharzewska P, Welinder C, Belting M, Eberhard J, Johnsson A, Uhlen M, Jirstrom K: Overexpression of podocalyxin-like protein is an independent factor of poor prognosis in colorectal cancer. Br J Cancer 2011, 105(5):666-672.
• [17]Wangefjord S, Manjer J, Gaber A, Nodin B, Eberhard J, Jirstrom K: Cyclin D1 expression in colorectal cancer is a favourable prognostic factor in men but not women in a prospective, population-based cohort study. Biol Sex Differ 2011, 2(1):10. BioMed Central Full Text
• [18]Eberhard J, Gaber A, Wangefjord S, Nodin B, Uhlen M, Ericson Lindquist K, Jirstrom K: A cohort study of the prognostic and treatment predictive value of SATB2 expression in colorectal cancer. Br J Cancer 2012, 106(5):931-938.
• [19]Nodin B, Johannesson H, Wangefjord S, O’Connor DP, Ericson-Lindquist K, Uhlen M, Jirstrom K, Eberhard J: Molecular correlates and prognostic significance of SATB1 expression in colorectal cancer. Diagn Pathol 2012, 7(1):115. BioMed Central Full Text
• [20]Borgquist S, Jogi A, Ponten F, Ryden L, Brennan DJ, Jirstrom K: Prognostic impact of tumour-specific HMG-CoA reductase expression in primary breast cancer. Breast Cancer Res 2008, 10(5):R79. BioMed Central Full Text
• [21]Wangefjord S, Sundstrom M, Zendehrokh N, Lindquist KE, Nodin B, Jirstrom K, Eberhard J: Sex differences in the prognostic significance of KRAS codons 12 and 13, and BRAF mutations in colorectal cancer: a cohort study. Biol Sex Differ 2013, 4(1):17. BioMed Central Full Text
• [22]Nodin B, Zendehrokh N, Sundstrom M, Jirstrom K: Clinicopathological correlates and prognostic significance of KRAS mutation status in a pooled prospective cohort of epithelial ovarian cancer. Diagn Pathol 2013, 8:106. BioMed Central Full Text
• [23]Cheng H, Liang H, Qin Y, Liu Y: Nuclear beta-catenin overexpression in metastatic sentinel lymph node is associated with synchronous liver metastasis in colorectal cancer. Diagn Pathol 2011, 6:109. BioMed Central Full Text
• [24]Larsson AH, Nodin B, Syk I, Palmquist I, Uhlen M, Eberhard J, Jirstrom K: Podocalyxin-like protein expression in primary colorectal cancer and synchronous lymph node metastases. Diagn Pathol 2013, 8(1):109. BioMed Central Full Text
• [25]Barratt PL, Seymour MT, Stenning SP, Georgiades I, Walker C, Birbeck K, Quirke P: DNA markers predicting benefit from adjuvant fluorouracil in patients with colon cancer: a molecular study. Lancet 2002, 360(9343):1381-1391.
• [26]Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, Hamilton SR, Laurent-Puig P, Gryfe R, Shepherd LE, Tu D, Redston M, Gallinger S: Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003, 349(3):247-257.
• [27]Kim GP, Colangelo LH, Wieand HS, Paik S, Kirsch IR, Wolmark N, Allegra CJ: 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(7):767-772.
• [28]Gaber A, Stene C, Hotakainen K, Nodin B, Palmquist I, Bjartell A, Stenman UH, Jeppsson B, Johnson LB, Jirstrom K: Effects of radiation therapy on tissue and serum concentrations of tumour associated trypsin inhibitor and their prognostic significance in rectal cancer patients. Radiat Oncol 2011, 6:100. BioMed Central Full Text
• [29]Goldstein JL, Brown MS: Regulation of the mevalonate pathway. Nature 1990, 343(6257):425-430.