Reduced expression of a senescence-associated protein is associated with worse outcome in patients with renal cell carcinoma (RCC), study findings show.
Patients with tumors with decreased expression of the protein – p400 – combined with high proliferation were found to have a “very unfavorable” clinical course, say the study researchers, with a 5-year cancer-specific survival rate of just 44%. This compared with 76% for patients with decreased p400 expression and low proliferative RCCs and 92% for those with increased p400 expression and low proliferation.
The team, led by Stephan Macher-Goeppinger (University of Heidelberg, Germany), investigated p400 following reports that it may be a mediating factor in the induction of senescence by the von Hippel–Lindau tumor suppressor gene.
Complete loss of p400 was detected in 64% of 787 RCC tumors studied, and the proportion increased with advancing tumor stage, from 59% in T1 tumors to 72% of T3/4 tumors. Decreased p400 expression was also associated with higher grade of malignancy and regional lymph node metastasis.
Raw data indicated that patients with increased, compared with decreased, p400 expression (5+ versus 0) had improved overall survival, cancer-specific survival, and progression-free survival by 49%, 63%, and 71%, respectively, but these associations were no longer significant in multivariate analysis that accounted for established prognostic factors such as tumor extent and lymph node metastasis.
As cellular senescence denotes a stable loss of proliferative capacity, the researchers used Ki-67 labelling to estimate the proliferation of the tumors.
Approximately 12% (n=91/753) of the patients were diagnosed with highly proliferative (Ki-67 index ≥10) tumors that showed decreased p400 expression. And these patients had a poor prognosis, with a 1.43-fold increased risk for cancer-specific death, compared with patients with low proliferative tumors with decreased p400 expression.
Despite Ki-67 being an “established and well-known prognostic factor in RCCs,” the researchers note that in multivariate analysis, highly proliferative carcinomas were only associated with significantly worse outcome if they also had decreased p400 protein levels. The hazard ratio for cancer-specific death was a nonsignificant 1.53 for those with highly proliferative carcinomas with increased p400 expression.
Another key finding was that, in low-grade tumors, high proliferation was more common in those with high p400 expression than in those with decreased p400 expression. Indeed, the two factors were significantly and positively correlated in well-differentiated tumors, whereas there was almost no association in G3 tumors.
“This may indicate that retained p400 expression is required for proliferation in low grade carcinomas whereas in dedifferentiated tumors other mechanisms might contribute to the escape of senescence,” the researchers comment in Oncology Reports.
They add: “Therefore, patients with highly proliferative and p400-positive RCCs may in particular benefit from new pro-senescence therapy strategies.”
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