Prognostic and predictive value of TOPK stratified by KRAS and BRAF gene alterations in sporadic, hereditary and metastatic colorectal cancer patients

Abstract

BACKGROUND: Our aim was to investigate the prognostic and predictive value of the oncogenic MAPKK-like protein T-cell-originated protein kinase (TOPK) stratified by KRAS and BRAF mutations in patients with sporadic, hereditary and metastatic colorectal cancer (CRC) treated with anti-EGFR therapy. METHODS: Immunohistochemistry (IHC) for TOPK was performed on four study groups. Group 1 included two subgroups of 543 and 501 sporadic CRC patients used to test the reliability of TOPK expression by IHC. In Group 2, representing an additional 222 sporadic CRCs, the prognostic effect of TOPK stratified by KRAS and BRAF was assessed. The prognostic effect of TOPK was further analysed in Group 3, representing 71 hereditary Lynch syndrome-associated CRC patients. In Group 4, the predictive and prognostic value of TOPK was analysed on 45 metastatic patients treated with cetuximab or panitumumab stratified by KRAS and BRAF gene status. RESULTS: In both sporadic CRC subgroups (Group 1), associations of diffuse TOPK expression with clinicopathological features were reproducible. Molecular analysis of sporadic CRCs in Group 2 showed that diffuse TOPK expression was associated with KRAS and BRAF mutations (po0.001) and with poor outcome in patients with either mutation in univariate and multivariate analysis (P ¼ 0.017). In hereditary patients (Group 3), diffuse TOPK was linked to advanced pT stage. In metastatic patients treated with anti-EGFR therapy (Group 4), diffuse TOPK expression was linked to dismal outcome despite objective response to treatment (P ¼ 0.01). CONCLUSION: TOPK expression is an unfavourable prognostic indicator in sporadic patients with KRAS or BRAF mutations and also in patients with metastatic disease experiencing a response to anti-EGFR therapies. The inhibition of TOPK, which could benefit 30 -40% of CRC patients, may represent a new avenue of investigation for targeted therapy.

PBK/TOPK expression correlates with mutant p53 and affects patients' prognosis and cell proliferation and viability in lung adenocarcinoma

“…These observations are partly consistent with the primary findings that patients with TOPK overexpression had a significantly poorer prognosis in stage I lung adenocarcinoma [16]. Zlobec and colleagues [18] also found that TOPK was a valuable prognostic factor in colorectal cancer.…”

“…For example, TOPK is involved with highly proliferative cells and tissues and is highly expressed in many types of tumors such as lymphoma, leukemia, breast cancer, Ewing sarcoma, and colorectal cancer [6][7][8][9][10]. High TOPK expression can promote cell proliferation [11][12][13] and prevent apoptosis [14,15] and is associated with a poor prognosis [16][17][18][19]. Moreover, TOPK expression may play an important role in the progress of cytokinesis and inflammation [20][21][22].…”

TOPK/PBK promotes cell migration via modulation of the PI3K/PTEN/AKT pathway and is associated with poor prognosis in lung cancer

“…Recently, Zlobec et al (2010) showed that expression of TOPK, in combination with KRAS and/or BRAF mutations, is linked to an unfavorable prognosis in sporadic colorectal cancer. In this study, we also found that high expression of TOPK is significantly associated with advanced stage and lymph node involvement (Table 1).…”

KRAS Mutational Status in Japanese Patients with Colorectal Cancer: Results from a Nationwide, Multicenter, Cross-sectional Study

“…The KRAS gene mutation-positive rate reported outside Japan is 30 -40% (13). When comparing data from overseas, or when discussing the relationship between background primary factors and mutation-positive rate, it is necessary to keep the positive-rate measurement error to within a fixed range.…”