Skip to main content
Erschienen in: Annals of Surgical Oncology 10/2020

23.04.2020 | Translational Research and Biomarkers

Clinical Significance of a Gene Signature Generated from Tumor Budding Grade in Colon Cancer

verfasst von: Eiji Shinto, MD, Yuichiro Yoshida, PhD, Yoshiki Kajiwara, MD, Koichi Okamoto, MD, Satsuki Mochizuki, PhD, Masato Yamadera, MD, Takehiro Shiraishi, MD, Ken Nagata, MD, Hitoshi Tsuda, MD, Kazuo Hase, MD, Yoji Kishi, MD, Hideki Ueno, MD

Erschienen in: Annals of Surgical Oncology | Ausgabe 10/2020

Einloggen, um Zugang zu erhalten

Abstract

Background

Tumor budding, a microscopic finding of dedifferentiation at the invasive margin, has been reported as a definite prognostic marker in colon cancer (CC). Herein, we aimed to generate a molecular budding signature (MBS) based on DNA microarray data and to examine its prognostic significance.

Methods

Frozen tissue samples from 85 patients with stage II/III CC were used for DNA microarray analyses. First, we selected candidate genes that were differentially expressed (twofold change) between the invasive frontal regions and corresponding tumor centers of three extremely high-grade budding tumors. Subsequently, using microarray data from whole-tissue sections of the 85 patients, we selected MBS-constituent genes from the candidates based on correlation to the pathological budding grade. The MBS score was calculated using the sum of the logarithm of the expression of each gene.

Results

We selected seven MBS-constituent genes: MSLN, SLC4A11, WNT11, SCEL, RUNX2, MGAT3, FOXC1. A comparison of relapse-free survival (RFS) rates revealed a significant impact of the MBS score [5-year RFS, 77.4% (score-high) vs. 95.1% (score-low); P = 0.044]. Analyses of public databases revealed that low MBS score patients exhibited better prognosis than those with high-score cancers (GSE14333: 5-year RFS, 83.1% vs. 66.6%, P = 0.028; GSE39582: 5-year disease-free survival, 72.2% vs. 58.1%, P = 0.0005). Multivariate analysis revealed that the MBS score is an independent prognostic indicator in GSE39582 (hazard ratio, 1.611; P = 0.013).

Conclusions

We developed a new gene classification method, i.e., MBS, and demonstrated its clinical relevance as an indicator of high recurrence risk of CC.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat O’Connell MJ, Lavery I, Yothers G, et al. Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J Clin Oncol. 2010;28:3937–44.CrossRef O’Connell MJ, Lavery I, Yothers G, et al. Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J Clin Oncol. 2010;28:3937–44.CrossRef
2.
Zurück zum Zitat Gray RG, Quirke P, Handley K, et al. Validation study of a quantitative multigene reverse transcriptase-polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer. J Clin Oncol. 2011;29:4611–9.CrossRef Gray RG, Quirke P, Handley K, et al. Validation study of a quantitative multigene reverse transcriptase-polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer. J Clin Oncol. 2011;29:4611–9.CrossRef
3.
Zurück zum Zitat Venook AP, Niedzwiecki D, Lopatin M, et al. Biologic determinants of tumor recurrence in stage II colon cancer: validation study of the 12-gene recurrence score in cancer and leukemia group B (CALGB) 9581. J Clin Oncol. 2013;31:1775–81.CrossRef Venook AP, Niedzwiecki D, Lopatin M, et al. Biologic determinants of tumor recurrence in stage II colon cancer: validation study of the 12-gene recurrence score in cancer and leukemia group B (CALGB) 9581. J Clin Oncol. 2013;31:1775–81.CrossRef
4.
Zurück zum Zitat Yamanaka T, Oki E, Yamazaki K, et al. 12-Gene recurrence score assay stratifies the recurrence risk in stage II/III colon cancer with surgery alone: the SUNRISE Study. J Clin Oncol. 2016;34:2906–13.CrossRef Yamanaka T, Oki E, Yamazaki K, et al. 12-Gene recurrence score assay stratifies the recurrence risk in stage II/III colon cancer with surgery alone: the SUNRISE Study. J Clin Oncol. 2016;34:2906–13.CrossRef
5.
Zurück zum Zitat Yothers G, O’Connell MJ, Lee M, et al. Validation of the 12-gene colon cancer recurrence score in NSABP C-07 as a predictor of recurrence in patients with stage II and III colon cancer treated with fluorouracil and leucovorin (FU/LV) and FU/LV plus oxaliplatin. J Clin Oncol. 2013;31:4512–9.CrossRef Yothers G, O’Connell MJ, Lee M, et al. Validation of the 12-gene colon cancer recurrence score in NSABP C-07 as a predictor of recurrence in patients with stage II and III colon cancer treated with fluorouracil and leucovorin (FU/LV) and FU/LV plus oxaliplatin. J Clin Oncol. 2013;31:4512–9.CrossRef
6.
Zurück zum Zitat Kumar A, Kennecke HF, Renouf DJ, et al. Adjuvant chemotherapy use and outcomes of patients with high-risk versus low-risk stage II colon cancer. Cancer. 2015;121:527–34.CrossRef Kumar A, Kennecke HF, Renouf DJ, et al. Adjuvant chemotherapy use and outcomes of patients with high-risk versus low-risk stage II colon cancer. Cancer. 2015;121:527–34.CrossRef
7.
Zurück zum Zitat Maak M, Simon I, Nitsche U, et al. Independent validation of a prognostic genomic signature (ColoPrint) for patients with stage II colon cancer. Ann Surg. 2013;257:1053–8.CrossRef Maak M, Simon I, Nitsche U, et al. Independent validation of a prognostic genomic signature (ColoPrint) for patients with stage II colon cancer. Ann Surg. 2013;257:1053–8.CrossRef
8.
Zurück zum Zitat Salazar R, Roepman P, Capella G, et al. Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. J Clin Oncol. 2011;29:17–24.CrossRef Salazar R, Roepman P, Capella G, et al. Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. J Clin Oncol. 2011;29:17–24.CrossRef
9.
Zurück zum Zitat Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21:1350–6.CrossRef Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21:1350–6.CrossRef
10.
Zurück zum Zitat Ueno H, Murphy J, Jass JR, Mochizuki H, Talbot IC. Tumour ‘budding’ as an index to estimate the potential of aggressiveness in rectal cancer. Histopathology. 2002;40:127–32.CrossRef Ueno H, Murphy J, Jass JR, Mochizuki H, Talbot IC. Tumour ‘budding’ as an index to estimate the potential of aggressiveness in rectal cancer. Histopathology. 2002;40:127–32.CrossRef
11.
Zurück zum Zitat Ueno H, Ishiguro M, Nakatani E, et al. Prospective multicenter study on the prognostic and predictive impact of tumor budding in stage II colon cancer: results from the SACURA Trial. J Clin Oncol. 2019;37:1886–94.CrossRef Ueno H, Ishiguro M, Nakatani E, et al. Prospective multicenter study on the prognostic and predictive impact of tumor budding in stage II colon cancer: results from the SACURA Trial. J Clin Oncol. 2019;37:1886–94.CrossRef
12.
Zurück zum Zitat Rogers AC, Winter DC, Heeney A, et al. Systematic review and meta-analysis of the impact of tumour budding in colorectal cancer. Br J Cancer. 2016;115:831–40.CrossRef Rogers AC, Winter DC, Heeney A, et al. Systematic review and meta-analysis of the impact of tumour budding in colorectal cancer. Br J Cancer. 2016;115:831–40.CrossRef
13.
Zurück zum Zitat Kevans D, Wang LM, Sheahan K, et al. Epithelial-mesenchymal transition (EMT) protein expression in a cohort of stage II colorectal cancer patients with characterized tumor budding and mismatch repair protein status. Int J Surg Pathol. 2011;19:751–60.CrossRef Kevans D, Wang LM, Sheahan K, et al. Epithelial-mesenchymal transition (EMT) protein expression in a cohort of stage II colorectal cancer patients with characterized tumor budding and mismatch repair protein status. Int J Surg Pathol. 2011;19:751–60.CrossRef
14.
Zurück zum Zitat Bronsert P, Enderle-Ammour K, Bader M, et al. Cancer cell invasion and EMT marker expression: a three-dimensional study of the human cancer-host interface. J Pathol. 2014;234:410–422.CrossRef Bronsert P, Enderle-Ammour K, Bader M, et al. Cancer cell invasion and EMT marker expression: a three-dimensional study of the human cancer-host interface. J Pathol. 2014;234:410–422.CrossRef
15.
Zurück zum Zitat Yamadera M, Shinto E, Kajiwara Y, et al. Differential survival benefits of 5-fluorouracil-based adjuvant chemotherapy for patients with microsatellite-stable stage III colorectal cancer according to the tumor budding status: a retrospective analysis. Dis Colon Rectum. 2019;62:1316–25.CrossRef Yamadera M, Shinto E, Kajiwara Y, et al. Differential survival benefits of 5-fluorouracil-based adjuvant chemotherapy for patients with microsatellite-stable stage III colorectal cancer according to the tumor budding status: a retrospective analysis. Dis Colon Rectum. 2019;62:1316–25.CrossRef
16.
Zurück zum Zitat Yamadera M, Shinto E, Kajiwara Y, et al. Differential clinical impacts of tumour budding evaluated by the use of immunohistochemical and haematoxylin and eosin staining in stage II colorectal cancer. Histopathology. 2019;74:1005–13.CrossRef Yamadera M, Shinto E, Kajiwara Y, et al. Differential clinical impacts of tumour budding evaluated by the use of immunohistochemical and haematoxylin and eosin staining in stage II colorectal cancer. Histopathology. 2019;74:1005–13.CrossRef
17.
Zurück zum Zitat Okamura T, Shimada Y, Nogami H, et al. Tumor budding detection by immunohistochemical staining is not superior to hematoxylin and eosin staining for predicting lymph node metastasis in pT1 colorectal cancer. Dis Colon Rectum. 2016;59:396–402.CrossRef Okamura T, Shimada Y, Nogami H, et al. Tumor budding detection by immunohistochemical staining is not superior to hematoxylin and eosin staining for predicting lymph node metastasis in pT1 colorectal cancer. Dis Colon Rectum. 2016;59:396–402.CrossRef
18.
Zurück zum Zitat De Smedt L, Palmans S, Andel D, et al. Expression profiling of budding cells in colorectal cancer reveals an EMT-like phenotype and molecular subtype switching. Br J Cancer. 2017;116:58–65.CrossRef De Smedt L, Palmans S, Andel D, et al. Expression profiling of budding cells in colorectal cancer reveals an EMT-like phenotype and molecular subtype switching. Br J Cancer. 2017;116:58–65.CrossRef
19.
Zurück zum Zitat Vasko V, Ferrand M, Di Cristofaro J, Carayon P, Henry JF, de Micco C. Specific pattern of RAS oncogene mutations in follicular thyroid tumors. J Clin Endocrinol Metab. 2003;88:2745–52.CrossRef Vasko V, Ferrand M, Di Cristofaro J, Carayon P, Henry JF, de Micco C. Specific pattern of RAS oncogene mutations in follicular thyroid tumors. J Clin Endocrinol Metab. 2003;88:2745–52.CrossRef
20.
Zurück zum Zitat Schmid K, Oehl N, Wrba F, Pirker R, Pirker C, Filipits M. EGFR/KRAS/BRAF mutations in primary lung adenocarcinomas and corresponding locoregional lymph node metastases. Clin Cancer Res. 2009;15:4554–60.CrossRef Schmid K, Oehl N, Wrba F, Pirker R, Pirker C, Filipits M. EGFR/KRAS/BRAF mutations in primary lung adenocarcinomas and corresponding locoregional lymph node metastases. Clin Cancer Res. 2009;15:4554–60.CrossRef
21.
Zurück zum Zitat Lehman TA, Bennett WP, Metcalf RA, et al. p53 mutations, ras mutations, and p53-heat shock 70 protein complexes in human lung carcinoma cell lines. Cancer Res. 1991;51:4090–6.PubMed Lehman TA, Bennett WP, Metcalf RA, et al. p53 mutations, ras mutations, and p53-heat shock 70 protein complexes in human lung carcinoma cell lines. Cancer Res. 1991;51:4090–6.PubMed
22.
Zurück zum Zitat Odenthal M, Barta N, Lohfink D, et al. Analysis of microsatellite instability in colorectal carcinoma by microfluidic-based chip electrophoresis. J Clin Pathol. 2009;62:850–2.CrossRef Odenthal M, Barta N, Lohfink D, et al. Analysis of microsatellite instability in colorectal carcinoma by microfluidic-based chip electrophoresis. J Clin Pathol. 2009;62:850–2.CrossRef
23.
Zurück zum Zitat Jorissen RN, Gibbs P, Christie M, et al. Metastasis-associated gene expression changes predict poor outcomes in patients with dukes stage B and C colorectal cancer. Clin Cancer Res. 2009;15:7642–51.CrossRef Jorissen RN, Gibbs P, Christie M, et al. Metastasis-associated gene expression changes predict poor outcomes in patients with dukes stage B and C colorectal cancer. Clin Cancer Res. 2009;15:7642–51.CrossRef
24.
Zurück zum Zitat Marisa L, de Reyniès A, Duval A, et al. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLOS Med. 2013;10:e1001453.CrossRef Marisa L, de Reyniès A, Duval A, et al. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLOS Med. 2013;10:e1001453.CrossRef
25.
Zurück zum Zitat Sandberg TP, Stuart M, Oosting J, Tollenaar R, Sier CFM, Mesker WE. Increased expression of cancer-associated fibroblast markers at the invasive front and its association with tumor-stroma ratio in colorectal cancer. BMC Cancer. 2019;19:284.CrossRef Sandberg TP, Stuart M, Oosting J, Tollenaar R, Sier CFM, Mesker WE. Increased expression of cancer-associated fibroblast markers at the invasive front and its association with tumor-stroma ratio in colorectal cancer. BMC Cancer. 2019;19:284.CrossRef
26.
Zurück zum Zitat Vermeulen L, Felipe De Sousa EM, Van Der Heijden M, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol. 2010;12:468–76.CrossRef Vermeulen L, Felipe De Sousa EM, Van Der Heijden M, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol. 2010;12:468–76.CrossRef
Metadaten
Titel
Clinical Significance of a Gene Signature Generated from Tumor Budding Grade in Colon Cancer
verfasst von
Eiji Shinto, MD
Yuichiro Yoshida, PhD
Yoshiki Kajiwara, MD
Koichi Okamoto, MD
Satsuki Mochizuki, PhD
Masato Yamadera, MD
Takehiro Shiraishi, MD
Ken Nagata, MD
Hitoshi Tsuda, MD
Kazuo Hase, MD
Yoji Kishi, MD
Hideki Ueno, MD
Publikationsdatum
23.04.2020
Verlag
Springer International Publishing
Erschienen in
Annals of Surgical Oncology / Ausgabe 10/2020
Print ISSN: 1068-9265
Elektronische ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-020-08498-3

Weitere Artikel der Ausgabe 10/2020

Annals of Surgical Oncology 10/2020 Zur Ausgabe

Update Chirurgie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

S3-Leitlinie „Diagnostik und Therapie des Karpaltunnelsyndroms“

CME: 2 Punkte

Prof. Dr. med. Gregor Antoniadis Das Karpaltunnelsyndrom ist die häufigste Kompressionsneuropathie peripherer Nerven. Obwohl die Anamnese mit dem nächtlichen Einschlafen der Hand (Brachialgia parästhetica nocturna) sehr typisch ist, ist eine klinisch-neurologische Untersuchung und Elektroneurografie in manchen Fällen auch eine Neurosonografie erforderlich. Im Anfangsstadium sind konservative Maßnahmen (Handgelenksschiene, Ergotherapie) empfehlenswert. Bei nicht Ansprechen der konservativen Therapie oder Auftreten von neurologischen Ausfällen ist eine Dekompression des N. medianus am Karpaltunnel indiziert.

Prof. Dr. med. Gregor Antoniadis
Berufsverband der Deutschen Chirurgie e.V.

S2e-Leitlinie „Distale Radiusfraktur“

CME: 2 Punkte

Dr. med. Benjamin Meyknecht, PD Dr. med. Oliver Pieske Das Webinar S2e-Leitlinie „Distale Radiusfraktur“ beschäftigt sich mit Fragen und Antworten zu Diagnostik und Klassifikation sowie Möglichkeiten des Ausschlusses von Zusatzverletzungen. Die Referenten erläutern, welche Frakturen konservativ behandelt werden können und wie. Das Webinar beantwortet die Frage nach aktuellen operativen Therapiekonzepten: Welcher Zugang, welches Osteosynthesematerial? Auf was muss bei der Nachbehandlung der distalen Radiusfraktur geachtet werden?

PD Dr. med. Oliver Pieske
Dr. med. Benjamin Meyknecht
Berufsverband der Deutschen Chirurgie e.V.

S1-Leitlinie „Empfehlungen zur Therapie der akuten Appendizitis bei Erwachsenen“

CME: 2 Punkte

Dr. med. Mihailo Andric
Inhalte des Webinars zur S1-Leitlinie „Empfehlungen zur Therapie der akuten Appendizitis bei Erwachsenen“ sind die Darstellung des Projektes und des Erstellungswegs zur S1-Leitlinie, die Erläuterung der klinischen Relevanz der Klassifikation EAES 2015, die wissenschaftliche Begründung der wichtigsten Empfehlungen und die Darstellung stadiengerechter Therapieoptionen.

Dr. med. Mihailo Andric
Berufsverband der Deutschen Chirurgie e.V.