Pancreatic endocrine tumours: mutational and immunohistochemical survey of protein kinases reveals alterations in targetable kinases in cancer cell lines and rare primaries - PubMed (original) (raw)

Pancreatic endocrine tumours: mutational and immunohistochemical survey of protein kinases reveals alterations in targetable kinases in cancer cell lines and rare primaries

V Corbo et al. Ann Oncol. 2012 Jan.

Abstract

Background: Kinases represent potential therapeutic targets in pancreatic endocrine tumours (PETs).

Patients and methods: Thirty-five kinase genes were sequenced in 36 primary PETs and three PET cell lines: (i) 4 receptor tyrosine kinases (RTK), epithelial growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), tyrosine-protein kinase KIT (KIT), platelet-derived growth factor receptor alpha (PDGFRalpha); (ii) 6 belonging to the Akt/mTOR pathway; and (iii) 25 frequently mutated in cancers. The immunohistochemical expression of the four RTKs and the copy number of EGFR and HER2 were assessed in 140 PETs.

Results: Somatic mutations were found in KIT in one and ATM in two primary neoplasms. Among 140 PETs, EGFR was immunopositive in 18 (13%), HER2 in 3 (2%), KIT in 16 (11%), and PDGFRalpha in 135 (96%). HER2 amplification was found in 2/130 (1.5%) PETs. KIT membrane immunostaining was significantly associated with tumour aggressiveness and shorter patient survival. PET cell lines QGP1, CM and BON harboured mutations in FGFR3, FLT1/VEGFR1 and PIK3CA, respectively.

Conclusions: Only rare PET cases, harbouring either HER2 amplification or KIT mutation, might benefit from targeted drugs. KIT membrane expression deserves further attention as a prognostic marker. ATM mutation is involved in a proportion of PET. The finding of specific mutations in PET cell lines renders these models useful for preclinical studies involving pathway-specific therapies.

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Figures

Figure 1.

Figure 1.

Immunohistochemical staining for receptor tyrosine kinases in pancreatic endocrine tumours. Shown are positive staining for KIT (A), EGFR (B) and HER2 (C) in tumour cells; positive staining in tumour cells and in the stroma is shown for PDGFRalpha (D). Original magnification, x20.

Figure 2.

Figure 2.

Fluorescent in situ hybridisation (FISH) analysis for EGFR and HER2 in pancreatic endocrine tumours. FISH analysis showing monosomy for EGFR (A), and gene amplification for HER2 (B). Original magnification, ×100. EGFR and HER2 signal red, centromeric probes signal green.

Figure 3.

Figure 3.

Correlation between KIT membrane immunostaining and patients’ survival. Kaplan–Meier estimates of survival with regard to KIT membrane immunostaining (P < 0.001). Follow-up, months; KIT+, membrane-positive immunostaining; KIT−, membrane-negative immunostaining.

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References

    1. Antonello D, Gobbo S, Corbo V, et al. Update on the molecular pathogenesis of pancreatic tumors other than common ductal adenocarcinoma. Pancreatology. 2009;9:25–33. - PubMed
    1. Capelli P, Martignoni G, Pedica F, et al. Endocrine neoplasms of the pancreas: pathologic and genetic features. Arch Pathol Lab Med. 2009;133:350–364. - PubMed
    1. Corbo V, Dalai I, Scardoni M, et al. MEN1 in pancreatic endocrine tumors: analysis of gene and protein status in 169 sporadic neoplasms reveals alterations in the vast majority of cases. Endocr Relat Cancer. 2010;17:771–783. - PubMed
    1. Kloppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann N Y Acad Sci. 2004;1014:13–27. - PubMed
    1. Bettini R, Mantovani W, Boninsegna L, et al. Primary tumour resection in metastatic nonfunctioning pancreatic endocrine carcinomas. Dig Liver Dis. 2009;41:49–55. - PubMed

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