Download PDF
Clin Colon Rectal Surg 2017; 30(05): 415-422
DOI: 10.1055/s-0037-1606373
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Molecular Biology: Are We Getting Any Closer to Providing Clinically Useful Information?

Georgios Karagkounis
1   Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
,
Matthew F. Kalady
1   Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
› Author Affiliations
Further Information

Publication History

Publication Date:
27 November 2017 (online)

    Permissions and Reprints

Abstract

Advances in molecular biology and biomarker research have significantly impacted our understanding and treatment of multiple solid malignancies. In rectal cancer, where neoadjuvant chemoradiation is widely used for locally advanced disease, most efforts have focused on the identification of predictors of response in an attempt to appropriately select patients for multimodality therapy. A variety of biomarkers have been studied, including genetic mutations, chromosomal copy number alterations, and single as well as multigene expression patterns. Also, as transanal resection of rectal tumors requires accurate preoperative detection of lymph node metastasis, the identification of biomarkers of regional nodal involvement has been another important field of active research. While preliminary results have been promising, lack of external validation means has a limited translation to clinical use. This review summarizes recent developments in rectal cancer biomarker research, highlighting the challenges associated with their adoption, and evaluating their potential for clinical use.

Keywords

rectal cancer - biomarkers - neoadjuvant chemoradiation - prognosis - molecular markers - gene signatures
 

  • References

  • 1 Maas M, Nelemans PJ, Valentini V. , et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 2010; 11 (09) 835-844
    CrossrefPubMedGoogle Scholar
  • 2 Mace AG, Pai RK, Stocchi L, Kalady MF. American Joint Committee on Cancer and College of American Pathologists regression grade: a new prognostic factor in rectal cancer. Dis Colon Rectum 2015; 58 (01) 32-44
    CrossrefPubMedGoogle Scholar
  • 3 Habr-Gama A, Perez RO, Nadalin W. , et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg 2004; 240 (04) 711-717 , discussion 717–718
    CrossrefPubMedGoogle Scholar
  • 4 Habr-Gama A, Sabbaga J, Gama-Rodrigues J. , et al. Watch and wait approach following extended neoadjuvant chemoradiation for distal rectal cancer: are we getting closer to anal cancer management?. Dis Colon Rectum 2013; 56 (10) 1109-1117
    CrossrefPubMedGoogle Scholar
  • 5 Ghadimi BM, Grade M, Difilippantonio MJ. , et al. Effectiveness of gene expression profiling for response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. J Clin Oncol 2005; 23 (09) 1826-1838
    CrossrefPubMedGoogle Scholar
  • 6 Heidelberger C, Chaudhuri NK, Danneberg P. , et al. Fluorinated pyrimidines, a new class of tumour-inhibitory compounds. Nature 1957; 179 (4561): 663-666
    CrossrefPubMedGoogle Scholar
  • 7 Conradi LC, Bleckmann A, Schirmer M. , et al. Thymidylate synthase as a prognostic biomarker for locally advanced rectal cancer after multimodal treatment. Ann Surg Oncol 2011; 18 (09) 2442-2452
    CrossrefPubMedGoogle Scholar
  • 8 Negri FV, Campanini N, Camisa R. , et al. Biological predictive factors in rectal cancer treated with preoperative radiotherapy or radiochemotherapy. Br J Cancer 2008; 98 (01) 143-147
    CrossrefPubMedGoogle Scholar
  • 9 Jakob C, Aust DE, Meyer W. , et al. Thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase expression, and histological tumour regression after 5-FU-based neo-adjuvant chemoradiotherapy in rectal cancer. J Pathol 2004; 204 (05) 562-568
    CrossrefPubMedGoogle Scholar
  • 10 Kaneda S, Takeishi K, Ayusawa D, Shimizu K, Seno T, Altman S. Role in translation of a triple tandemly repeated sequence in the 5′-untranslated region of human thymidylate synthase mRNA. Nucleic Acids Res 1987; 15 (03) 1259-1270
    CrossrefPubMedGoogle Scholar
  • 11 Kawakami K, Salonga D, Park JM. , et al. Different lengths of a polymorphic repeat sequence in the thymidylate synthase gene affect translational efficiency but not its gene expression. Clin Cancer Res 2001; 7 (12) 4096-4101
    PubMedGoogle Scholar
  • 12 Villafranca E, Okruzhnov Y, Dominguez MA. , et al. Polymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer. J Clin Oncol 2001; 19 (06) 1779-1786
    CrossrefPubMedGoogle Scholar
  • 13 Spindler KL, Nielsen JN, Lindebjerg J, Jakobsen A. Germline polymorphisms may act as predictors of response to preoperative chemoradiation in locally advanced T3 rectal tumors. Dis Colon Rectum 2007; 50 (09) 1363-1369
    CrossrefPubMedGoogle Scholar
  • 14 Tan BR, Thomas F, Myerson RJ. , et al. Thymidylate synthase genotype-directed neoadjuvant chemoradiation for patients with rectal adenocarcinoma. J Clin Oncol 2011; 29 (07) 875-883
    CrossrefPubMedGoogle Scholar
  • 15 Lowe SW, Ruley HE, Jacks T, Housman DE. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 1993; 74 (06) 957-967
    CrossrefPubMedGoogle Scholar
  • 16 McIlwrath AJ, Vasey PA, Ross GM, Brown R. Cell cycle arrests and radiosensitivity of human tumor cell lines: dependence on wild-type p53 for radiosensitivity. Cancer Res 1994; 54 (14) 3718-3722
    PubMedGoogle Scholar
  • 17 Spitz FR, Giacco GG, Hess K. , et al. p53 immunohistochemical staining predicts residual disease after chemoradiation in patients with high-risk rectal cancer. Clin Cancer Res 1997; 3 (10) 1685-1690
    PubMedGoogle Scholar
  • 18 Luna-Perez P, Arriola EL, Cuadra Y, Alvarado I, Quintero A. p53 protein overexpression and response to induction chemoradiation therapy in patients with locally advanced rectal adenocarcinoma. Ann Surg Oncol 1998; 5 (03) 203-208
    CrossrefPubMedGoogle Scholar
  • 19 Lin LC, Lee HH, Hwang WS. , et al. p53 and p27 as predictors of clinical outcome for rectal-cancer patients receiving neoadjuvant therapy. Surg Oncol 2006; 15 (04) 211-216
    CrossrefPubMedGoogle Scholar
  • 20 Esposito G, Pucciarelli S, Alaggio R. , et al. P27kip1 expression is associated with tumor response to preoperative chemoradiotherapy in rectal cancer. Ann Surg Oncol 2001; 8 (04) 311-318
    CrossrefPubMedGoogle Scholar
  • 21 Tannapfel A, Nüsslein S, Fietkau R, Katalinic A, Köckerling F, Wittekind C. Apoptosis, proliferation, bax, bcl-2 and p53 status prior to and after preoperative radiochemotherapy for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 1998; 41 (03) 585-591
    CrossrefPubMedGoogle Scholar
  • 22 Elsaleh H, Robbins P, Joseph D. , et al. Can p53 alterations be used to predict tumour response to pre-operative chemo-radiotherapy in locally advanced rectal cancer?. Radiother Oncol 2000; 56 (02) 239-244
    CrossrefPubMedGoogle Scholar
  • 23 Saw RP, Morgan M, Koorey D. , et al. p53, deleted in colorectal cancer gene, and thymidylate synthase as predictors of histopathologic response and survival in low, locally advanced rectal cancer treated with preoperative adjuvant therapy. Dis Colon Rectum 2003; 46 (02) 192-202
    CrossrefPubMedGoogle Scholar
  • 24 Bertolini F, Bengala C, Losi L. , et al. Prognostic and predictive value of baseline and posttreatment molecular marker expression in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. Int J Radiat Oncol Biol Phys 2007; 68 (05) 1455-1461
    CrossrefPubMedGoogle Scholar
  • 25 Chen MB, Wu XY, Yu R. , et al. P53 status as a predictive biomarker for patients receiving neoadjuvant radiation-based treatment: a meta-analysis in rectal cancer. PLoS One 2012; 7 (09) e45388
    CrossrefPubMedGoogle Scholar
  • 26 Vogelstein B, Fearon ER, Hamilton SR. , et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988; 319 (09) 525-532
    CrossrefPubMedGoogle Scholar
  • 27 Normanno N, Tejpar S, Morgillo F, De Luca A, Van Cutsem E, Ciardiello F. Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nat Rev Clin Oncol 2009; 6 (09) 519-527
    CrossrefPubMedGoogle Scholar
  • 28 Garcia-Aguilar J, Chen Z, Smith DD. , et al. Identification of a biomarker profile associated with resistance to neoadjuvant chemoradiation therapy in rectal cancer. Ann Surg 2011; 254 (03) 486-492 , discussion 492–493
    CrossrefPubMedGoogle Scholar
  • 29 Duldulao MP, Lee W, Nelson RA. , et al. Mutations in specific codons of the KRAS oncogene are associated with variable resistance to neoadjuvant chemoradiation therapy in patients with rectal adenocarcinoma. Ann Surg Oncol 2013; 20 (07) 2166-2171
    CrossrefPubMedGoogle Scholar
  • 30 Erben P, Ströbel P, Horisberger K. , et al. KRAS and BRAF mutations and PTEN expression do not predict efficacy of cetuximab-based chemoradiotherapy in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2011; 81 (04) 1032-1038
    CrossrefPubMedGoogle Scholar
  • 31 Gaedcke J, Grade M, Jung K. , et al. KRAS and BRAF mutations in patients with rectal cancer treated with preoperative chemoradiotherapy. Radiother Oncol 2010; 94 (01) 76-81
    CrossrefPubMedGoogle Scholar
  • 32 Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995; 19 (03) 183-232
    CrossrefPubMedGoogle Scholar
  • 33 Liang K, Ang KK, Milas L, Hunter N, Fan Z. The epidermal growth factor receptor mediates radioresistance. Int J Radiat Oncol Biol Phys 2003; 57 (01) 246-254
    CrossrefPubMedGoogle Scholar
  • 34 Giralt J, Eraso A, Armengol M. , et al. Epidermal growth factor receptor is a predictor of tumor response in locally advanced rectal cancer patients treated with preoperative radiotherapy. Int J Radiat Oncol Biol Phys 2002; 54 (05) 1460-1465
    CrossrefPubMedGoogle Scholar
  • 35 Kim JS, Kim JM, Li S. , et al. Epidermal growth factor receptor as a predictor of tumor downstaging in locally advanced rectal cancer patients treated with preoperative chemoradiotherapy. Int J Radiat Oncol Biol Phys 2006; 66 (01) 195-200
    CrossrefPubMedGoogle Scholar
  • 36 Zlobec I, Vuong T, Compton CC. , et al. Combined analysis of VEGF and EGFR predicts complete tumour response in rectal cancer treated with preoperative radiotherapy. Br J Cancer 2008; 98 (02) 450-456
    CrossrefPubMedGoogle Scholar
  • 37 Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol 2000; 182 (03) 311-322
    CrossrefPubMedGoogle Scholar
  • 38 Kim NK, Park JK, Lee KY. , et al. p53, BCL-2, and Ki-67 expression according to tumor response after concurrent chemoradiotherapy for advanced rectal cancer. Ann Surg Oncol 2001; 8 (05) 418-424
    CrossrefPubMedGoogle Scholar
  • 39 Jakob C, Liersch T, Meyer W, Becker H, Baretton GB, Aust DE. Predictive value of Ki67 and p53 in locally advanced rectal cancer: correlation with thymidylate synthase and histopathological tumor regression after neoadjuvant 5-FU-based chemoradiotherapy. World J Gastroenterol 2008; 14 (07) 1060-1066
    CrossrefPubMedGoogle Scholar
  • 40 Karagkounis G, Thai L, DeVecchio J. , et al. NPTX2 is associated with neoadjuvant therapy response in rectal cancer. J Surg Res 2016; 202 (01) 112-117
    CrossrefPubMedGoogle Scholar
  • 41 Gantt GA, Chen Y, Dejulius K, Mace AG, Barnholtz-Sloan J, Kalady MF. Gene expression profile is associated with chemoradiation resistance in rectal cancer. Colorectal Dis 2014; 16 (01) 57-66
    CrossrefPubMedGoogle Scholar
  • 42 O'Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007; 445 (7123): 106-110
    CrossrefPubMedGoogle Scholar
  • 43 Lotti F, Jarrar AM, Pai RK. , et al. Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J Exp Med 2013; 210 (13) 2851-2872
    CrossrefPubMedGoogle Scholar
  • 44 Huh JW, Lee JH, Kim HR. Pretreatment expression of 13 molecular markers as a predictor of tumor responses after neoadjuvant chemoradiation in rectal cancer. Ann Surg 2014; 259 (03) 508-515
    CrossrefPubMedGoogle Scholar
  • 45 Hiroishi K, Inomata M, Kashima K. , et al. Cancer stem cell-related factors are associated with the efficacy of pre-operative chemoradiotherapy for locally advanced rectal cancer. Exp Ther Med 2011; 2 (03) 465-470
    CrossrefPubMedGoogle Scholar
  • 46 Sprenger T, Conradi LC, Beissbarth T. , et al. Enrichment of CD133-expressing cells in rectal cancers treated with preoperative radiochemotherapy is an independent marker for metastasis and survival. Cancer 2013; 119 (01) 26-35
    CrossrefPubMedGoogle Scholar
  • 47 Teixeira MR, Heim S. Multiple numerical chromosome aberrations in cancer: what are their causes and what are their consequences?. Semin Cancer Biol 2005; 15 (01) 3-12
    CrossrefPubMedGoogle Scholar
  • 48 Grade M, Gaedcke J, Wangsa D. , et al. Chromosomal copy number changes of locally advanced rectal cancers treated with preoperative chemoradiotherapy. Cancer Genet Cytogenet 2009; 193 (01) 19-28
    CrossrefPubMedGoogle Scholar
  • 49 Chen Z, Liu Z, Li W. , et al. Chromosomal copy number alterations are associated with tumor response to chemoradiation in locally advanced rectal cancer. Genes Chromosomes Cancer 2011; 50 (09) 689-699
    CrossrefPubMedGoogle Scholar
  • 50 Ghadimi BM, Grade M, Difilippantonio MJ. , et al. Effectiveness of gene expression profiling for response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. J Clin Oncol 2005; 23 (09) 1826-1838
    CrossrefPubMedGoogle Scholar
  • 51 Watanabe T, Komuro Y, Kiyomatsu T. , et al. Prediction of sensitivity of rectal cancer cells in response to preoperative radiotherapy by DNA microarray analysis of gene expression profiles. Cancer Res 2006; 66 (07) 3370-3374
    CrossrefPubMedGoogle Scholar
  • 52 Kim IJ, Lim SB, Kang HC. , et al. Microarray gene expression profiling for predicting complete response to preoperative chemoradiotherapy in patients with advanced rectal cancer. Dis Colon Rectum 2007; 50 (09) 1342-1353
    CrossrefPubMedGoogle Scholar
  • 53 Brettingham-Moore KH, Duong CP, Greenawalt DM. , et al. Pretreatment transcriptional profiling for predicting response to neoadjuvant chemoradiotherapy in rectal adenocarcinoma. Clin Cancer Res 2011; 17 (09) 3039-3047
    CrossrefPubMedGoogle Scholar
  • 54 Casado E, García VM, Sánchez JJ. , et al. A combined strategy of SAGE and quantitative PCR Provides a 13-gene signature that predicts preoperative chemoradiotherapy response and outcome in rectal cancer. Clin Cancer Res 2011; 17 (12) 4145-4154
    CrossrefPubMedGoogle Scholar
  • 55 Rimkus C, Friederichs J, Boulesteix AL. , et al. Microarray-based prediction of tumor response to neoadjuvant radiochemotherapy of patients with locally advanced rectal cancer. Clin Gastroenterol Hepatol 2008; 6 (01) 53-61
    CrossrefPubMedGoogle Scholar
  • 56 Akiyoshi T, Kobunai T, Watanabe T. Predicting the response to preoperative radiation or chemoradiation by a microarray analysis of the gene expression profiles in rectal cancer. Surg Today 2012; 42 (08) 713-719
    CrossrefPubMedGoogle Scholar
  • 57 Al-Sukhni E, Milot L, Fruitman M. , et al. Diagnostic accuracy of MRI for assessment of T category, lymph node metastases, and circumferential resection margin involvement in patients with rectal cancer: a systematic review and meta-analysis. Ann Surg Oncol 2012; 19 (07) 2212-2223
    CrossrefPubMedGoogle Scholar
  • 58 Kalady MF, Coffey JC, Dejulius K, Jarrar A, Church JM. High-throughput arrays identify distinct genetic profiles associated with lymph node involvement in rectal cancer. Dis Colon Rectum 2012; 55 (06) 628-639
    CrossrefPubMedGoogle Scholar
  • 59 Fan XJ, Wan XB, Huang Y. , et al. Epithelial-mesenchymal transition biomarkers and support vector machine guided model in preoperatively predicting regional lymph node metastasis for rectal cancer. Br J Cancer 2012; 106 (11) 1735-1741
    CrossrefPubMedGoogle Scholar
  • 60 Chen Z, Liu Z, Deng X, Warden C, Li W, Garcia-Aguilar J. Chromosomal copy number alterations are associated with persistent lymph node metastasis after chemoradiation in locally advanced rectal cancer. Dis Colon Rectum 2012; 55 (06) 677-685
    CrossrefPubMedGoogle Scholar
  • 61 Gerlinger M, Rowan AJ, Horswell S. , et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366 (10) 883-892
    CrossrefPubMedGoogle Scholar
  • 62 Kalady MF, Sanchez JA, Manilich E, Hammel J, Casey G, Church JM. Divergent oncogenic changes influence survival differences between colon and rectal adenocarcinomas. Dis Colon Rectum 2009; 52 (06) 1039-1045
    CrossrefPubMedGoogle Scholar