Oncofetal protein IMP3: A novel molecular marker that predicts metastasis of papillary and chromophobe renal cell carcinomas

Renal cell carcinoma (RCC) is the most common type of kidney cancer and accounts for about 85% of malignant kidney tumors.1,2 The incidence of RCC has been rising steadily.3 It is expected that about 51,190 new cases of kidney cancer will be diagnosed in the US in 2007 with approximately 12,890 mortalities.4 There are several subtypes of RCC according to the Union International Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC) recommendations,5 originally proposed at the Heidelberg conference.6 Of these, the most common subtypes are clear cell or conventional (70%), papillary (10%–15%) and chromophobe (5%) RCC.5 These subtypes of RCC not only exhibit distinct cytogenetic abnormalities but also affect patient prognosis differently.7–13 Clear-cell RCCs are characterized by loss of genetic material in the chromosome 3p.5 Fifty percent of clear-cell RCCs show somatic mutations in the von Hippel-Lindau (VHL) gene and an additional 10% to 20% of these tumors show inactivation of the VHL gene.5 Papillary RCCs are characterized by trisomies (chromosomes 3q, 7, 12, 16, 17, and 20) and loss of the Y chromosome.5 Chromophobe RCCs are characterized by monosomy of multiple chromosomes (1, 2, 6, 10, 13, 17, and 21) and hypodiploidy.5 Localized papillary and chromophobe RCCs exhibit favorable prognosis with less frequent metastasis relative to clear-cell RCCs.7–14 Consequently, relatively little is known about molecular expression profiles associated with metastatic progression of papillary and chromophobe tumors compared with clear-cell RCC, which has been the dominant focus of studies reported in the literature. IMP3 is a member of the insulin-like growth factor II (IGF-II) mRNA binding protein (IMP) family that consists of IMP1, IMP2, and IMP3.15 IMP family members play an important role in RNA trafficking and stabilization, cell growth, and cell migration during the early stages of embryogenesis.16 The IMP3 gene is located on chromosome 7p11.217 and is identical to the KOC (KH domain containing protein overexpressed in cancer) protein that was originally cloned from a pancreatic tumor cDNA screen.18 IMP3 is expressed in developing epithelia, muscle, and placenta during early stages of human and mouse embryogenesis, but it is expressed at low or undetectable levels in adult tissues.15,16 The expression of IMP3/KOC is also found in malignant tumors including pancreas, lung, stomach, and colon cancers, and soft tissue sarcomas but it is not detected in adjacent benign tissues.15,18–20 Moreover, recent studies have demonstrated that IMP3 is an important protein for tumor cell proliferation and invasion.21,22 These findings indicate that IMP3 is an oncofetal protein that may play a critical role in malignant transformation and tumor progression. Recently, we have found that IMP3 oncofetal protein is a new biomarker for aggressive localized RCC.23 In addition, a validation study has confirmed that IMP3 is an independent prognostic marker for the clear cell (conventional) subtype of RCCs.24 In this validation study, 163 of 629 (25.9%) localized clear-cell RCC specimens expressed tumor cell IMP3. Patients with localized clear-cell RCC and positive IMP3 expression were nearly 5 times more likely to progress to distant metastasis compared with patients with IMP3-negative tumors (risk ratio [RR] 4.71; P <.001). As the predominance of RCCs are of the clear cell subtype, it is unclear whether IMP3 plays an important role to predict metastasis for other relatively rare subtypes, such as papillary and chromophobe RCCs. In the current study we investigated the association of IMP3 expression with clinicopathologic features and outcome using a multi-institutional cohort of patients with localized papillary and chromophobe RCC subtypes to evaluate whether IMP3 could serve as an independent biomarker to predict tumor progression and metastasis.