Loss of heterozygosity at the mannose 6-phosphate/insulin-like growth factor 2 receptor locus: a frequent but late event in adrenocortical tumorigenesis

Abstract

Objective: Recent studies have pointed to the role of the IGF system in adrenocortical tumorigenesis. The IGF-II gene is overexpressed in malignant adrenocortical tumors and its proliferative effects are mediated by the type-1 IGF receptor (IGF1R). The mannose 6-phosphate/IGF2 receptor (M6P/IGF2R) plays a key role in regulating cell growth, by ensuring the clearance and inactivation of IGF-II and facilitating activation of the growth inhibitor, transforming growth factor b (TGFb1). The M6P/ IGF2R has been implicated as a tumor suppressor gene in various human tumors. Methods: The purpose of this study was to determine if the M6P/IGF2R is involved in adrenal tumorigenesis. Two polymorphisms in the 3 H untranslated region of M6P/IGF2R were used to screen a large series of 76 sporadic adrenocortical tumors for loss of heterozygosity (LOH) by PCR amplification of DNA. Tumors were classified into three groups based on pathological features: benign tumors n 25Y suspect tumors n 22 and malignant tumors n 29X Results: LOH at the M6P/IGF2R locus was detected in 15 of 57 (26%) informative tumors and was more frequent in malignant tumors (58%) than in benign and suspect tumors (9 and 13% respectively). Conclusion: These findings provide evidence that LOH at the M6P/IGF2R locus is a frequent event in adrenocortical tumors and support the hypothesis that it may function as a tumor suppressor gene in adrenocortical tumorigenesis.

Insulin-like growth factor 2 and its receptors (IGF 1R and IGF 2R/mannose 6-phosphate) in endometrial adenocarcinoma

“…As these changes were associated with the concomitant overexpression of IGF 2/IGF 1R, it is very likely that the IGF 2R gene acts as a tumor suppressor in endometrial adenocarcinoma, similar to what has been shown for some other human tumors. Namely, biallelic mutations, usually point mutation or small deletion in one allele and loss of heterozygosity in the other, have been reported in a variety of human malignancies, including hepatocarcinoma and adrenocortical tumors [34,35], aggressive early breast cancer [36], and lung cancers [12,13]. Furthermore, the IGF2/M6P locus at 6q has been reported to be a hot spot for mutation in tumors, including malignant melanoma [37], ovarian cancer [38] non-Hodgkin lymphoma [39], and renal cell carcinoma [40].…”

Insulin-Like Growth Factor System and Sporadic Malignant Melanoma

“…24 In particular, IGF-1R is a cell surface heterotetrameric tyrosine kinase receptor coupled to numerous intracellular second messenger pathways, including Raf/Ras-mitogen-activated protein kinase and phosphatidylinositol-3 kinase signaling cascades; for these reasons, IGF-1R is crucial for cell survival, whereas IGF-2 appears to have a tumor suppressor role because mutated or deleted forms have been reported in several cancers. 25 In contrast, some reports did not confirm a role for IGF-2 in intracellular signaling, its bioactivity being mediated via a particular isoform of the IGF-1R (ie, IGF-1R-A) derived from an alternative splicing of the IR gene. 26 …”

Demonstration of tumor suppression by mannose 6-phosphate/insulin-like growth factor 2 receptor

“…In a substantial portion of these tumors, functional mutations were identified in the remaining allele. LOH and function mutations in tumors have since been reported for breast cancer (Hankins et al, 1996;Seitz et al, 2003), head and neck cancer (Jamieson et al, 2003), oral squamous cell carcinoma (Zavras et al, 2003), lung cancer (Gemma et al, 2000;Kong et al, 2000;Oka et al, 2002), adrenocortical cancer (Leboulleux et al, 2001), and sporadic cancers of the gastrointestinal tract (Caligo et al, 2000;Calin et al, 2000).…”