EXTERNAL VALIDATION OF IMP3 EXPRESSION AS AN INDEPENDENT PROGNOSTIC MARKER FOR METASTATIC PROGRESSION AND DEATH FOR PATIENTS WITH CLEAR CELL RENAL CELL CARCINOMA

Abstract

Great emphasis has recently been placed on the elucidation of molecular expression profiles that define so-called ‘signatures’ associated with high-risk forms of cancer, either localized cancers that are predisposed to disease progression after attempted extirpation or advanced malignancies that may respond poorly to systemic therapy. This is the case for renal cell carcinoma (RCC), especially RCC of the clear cell subtype (ccRCC). The importance of identifying tumor-associated molecules that collectively define at-risk populations is that such molecules could potentially be utilized to identify patients most apt to fail therapy and therefore might benefit from early adjunctive intervention to preempt impending cancer progression. In addition, such tumor-associated molecules might reveal important mechanisms driving malignant inception and progression. Finally, some prognostic molecules may doubly serve as useful targets for antitumoral therapy. To our knowledge to date, several molecules have been reported as independent prognostic markers for RCC, including, but not limited to, nuclear antigen Ki-67, survivin, carbonic anhydrase IX, and IMP3.1–4 In addition, we have recently reported that the T-cell coregulatory ligands, B7-H1 and B7-H4, independently portend aggressive ccRCC tumor behavior and adverse patient outcome.5,6 However, to our knowledge, most of these prognostic markers, with the exception of Ki-67,7 have not undergone large-scale, external validation by outside investigators. Recent reviews of this process have suggested that single studies of a given biomarker within 1 cohort of patients are often inadequate to firmly establish its prognostic value. For example, Altmann and Royston8 have stated that prognostic models are not generalizable until validated in additional and, ideally, independent cohorts of patients. Bleeker et al.9 have also echoed this sentiment, demonstrating that prognostic models perform best when applied to datasets from which the prognostic model was originally constructed, but perform much less well when used to assess outcomes for external cohorts of patients not incorporated into the prognostic model during its derivation. This deterioration of prognostic model performance with broader application over time could be, in part, because of the finding that different studies often collect and control for different sets of variables not taken into account during the original derivation of the prognostic model.10 In addition, there can be difficult-to-quantify biases associated with study populations arising from a single institution. Such biases may stem from, but are certainly not limited to, genetic clustering of study populations, as well as aspects of treatment and follow-up that are highly unique to regional or institution-specific standards of care. As such, Justice et al.10 concluded that diverse assessment of any prognostic tool is imperative to confirm its ability to make predictions in an otherwise untested setting. Prompted by this, we initiated the current study to provide external validation of IMP3 expression as an independent prognostic marker of poor outcome among patients treated surgically for ccRCC. IMP3 is a member of the insulin-like growth factor-II (IGF-II) mRNA binding protein family. Although IMP3 is expressed within developing epithelia, myocytes, and placenta during human and mouse embryogenesis, its expression is low or undetectable in postnatal tissues and virtually absent in adult tissues. IMP3 is believed to participate in the protection and intracellular distribution of IGF-II mRNA and thus has been implicated in regulating the production of IGF-II. It is interesting to note that some reports suggest that RCC tumors, especially aggressive tumors exhibiting sarcomatoid differentiation, express increased IGF-II expression. Most recently, Jiang et al.1 systematically studied the expression of IMP3 in a cohort of 371 patients with localized tumors of the clear cell, papillary, chromophobe, or unclassified RCC subtypes. In that study, Jiang et al.1 reported that tumor cell IMP3 expression was significantly associated with progression to distant metastases and death, even after multivariate adjustment for patient age, sex, tumor size, stage, grade, and histologic subtype. In keeping with the aforementioned imperative for external validation of prognostic markers pertaining to human malignancy, we report an independent and large-scale analysis of IMP3 expression using 716 consecutive ccRCC specimens. We demonstrate that IMP3 expression correlates with advanced tumor stage and grade, as well as the presence of several other adverse pathologic features including coagulative tumor necrosis and sarcomatoid differentiation. We further show that even after multivariate adjustment for well-known ccRCC prognostic features, IMP3 expression is independently associated with death from RCC. For patients who present with TNM stage I disease, ccRCC IMP3 expression is associated with a 6-fold increased risk of progression to distant metastases. This risk of metastases is similarly increased for patients presenting with stage II and III ccRCC tumors that express IMP3. Hence, we confirm the findings of Jiang et al,1 thereby validating tumor cell IMP3 expression as an independent predictor of aggressive ccRCC tumor behavior.