The classification of human cancers represents one of the cornerstones of modern pathology. Over the last century, surgical pathologists established the current taxonomy of neoplasia using traditional histopathological parameters, which include tumor architecture, cytological features and cellular proliferation. This morphological classification is efficient and robust with high reproducibility and has served patients and health care providers well. The most recent decade has witnessed an explosion of genome-wide molecular genetic and epigenetic data for most cancers, including tumors of endocrine organs. The availability of this expansive multi-dimensional genomic data, collectively termed the cancer genome, has catalyzed a re-examination of the classification of endocrine tumors. Here, recent cancer genome studies of various endocrine tumors, including those of the thyroid, pituitary and adrenal glands, pancreas, small bowel, lung and skin, are presented with special emphasis on how genomic insights are impacting endocrine tumor classification.
Raffaele Ciampi, Thomas J Giordano, Kathryn Wikenheiser-Brokamp, Ronald J Koenig and Yuri E Nikiforov
Chromosomal rearrangements of the RET proto-oncogene (RET/PTC) are the common feature of papillary thyroid carcinoma (PTC). In this study, we report the identification, cloning, and functional characterization of a novel type of RET/PTC rearrangement that results from the fusion of the 3′-portion of RET coding for the tyrosine kinase (TK) domain of the receptor to the 5′-portion of the Homo sapiens hook homolog 3 (HOOK3) gene. The novel fusion was identified in a case of PTC that revealed a gene expression signature characteristic of RET/PTC on DNA microarray analysis, but was negative for the most common types of RET rearrangement. A fusion product between exon 11 of HOOK3 and exon 12 of RET gene was identified by 5′RACE, and the presence of chimeric HOOK3-RET protein of 88 kDa was detected by western blot analysis with an anti-RET antibody. The protein is predicted to contain a portion of the coiled-coil domains of HOOK3 and the intact TK domain of RET. Expression of the HOOK3-RET cDNA in NIH3T3 cells resulted in the formation of transformed foci and in tumor formation after injection into nude mice, confirming the oncogenic nature of HOOK3-RET.
Antonio M Lerario, Kazutaka Nanba, Amy R Blinder, Sachiko Suematsu, Masao Omura, Tetsuo Nishikawa, Thomas J Giordano, William E Rainey and Tobias Else
Somatic variants in genes that regulate intracellular ion homeostasis have been identified in aldosterone-producing adenomas (APAs). Although the mechanisms leading to increased aldosterone production in APA cells have been well studied, the molecular events that cause cell proliferation and tumor formation are poorly understood. In the present study, we have performed whole-exome sequencing (WES) to characterize the landscape of somatic alterations in a homogeneous series of APA with pathogenic KCNJ5 variants. In the WES analysis on 11 APAs, 84 exonic somatic events were called by 3 different somatic callers. Besides the KCNJ5 gene, only two genes (MED13 and ZNF669) harbored somatic variants in more than one APA. Unlike adrenocortical carcinomas, no chromosomal instability was observed by the somatic copy-number alteration and loss of heterozygosity analyses. The estimated tumor purity ranged from 0.35 to 0.67, suggesting a significant proportion of normal cell infiltration. Based on the results of PureCN analysis, the KCNJ5 variants appear to be clonal. In conclusion, in addition to KCNJ5 somatic pathogenic variants, no significant somatic event that would obviously explain proliferation or tumor growth was observed in our homogeneous cohort of KCNJ5-mutated APA. The molecular mechanisms causing APA growth and tumorigenesis remain to be elucidated.
Isobel C Mouat, Kei Omata, Andrew S McDaniel, Namita G Hattangady, Debnita Talapatra, Andi K Cani, Daniel H Hovelson, Scott A Tomlins, William E Rainey, Gary D Hammer, Thomas J Giordano and Tobias Else
Several somatic mutations specific to aldosterone-producing adenomas (APAs) have been described. A small proportion of adrenocortical carcinomas (ACCs) are associated with hyperaldosteronism, either primary aldosteronism or hyperreninemic hyperaldosteronism. However, it is unknown whether they harbor mutations of the same spectrum as APAs. The objective of this study is to describe the clinical phenotype and molecular genotype of ACCs with hyperaldosteronism, particularly the analysis for common APA-associated genetic changes. Patients were identified by retrospective chart review at a specialized referral center and by positive staining for CYP11B2 of tissue microarrays. Twenty-five patients with ACC and hyperaldosteronism were initially identified by retrospective chart review, and tissue for further analysis was available on 13 tumors. Seven patients were identified by positive staining for CYP11B2 in a tissue microarray, of which two were already identified in the initial chart review. Therefore, a total number of 18 patients with a diagnosis of ACC and features of either primary aldosteronism or hyperreninemic hyperaldosteronism were therefore included in the final study. Mutational status for a select list of oncogenes, tumor suppressor genes and genes known to carry mutations in APAs were analyzed by next-generation sequencing. Review of clinical data suggested autonomous aldosterone production in the majority of cases, while for some cases, hyperreninemic hyperaldosteronism was the more likely mechanism. The mutational landscape of ACCs associated with hyperaldosteronism was not different from ACCs with a different hormonal phenotype. None of the ACCs harbored mutations of known APA-associated genes, suggesting an alternative mechanism conferring aldosterone production.
Steven E Justiniano, Joseph P McElroy, Lianbo Yu, Ayse Selen Yilmaz, Kevin R Coombes, Leigha Senter, Rebecca Nagy, Paul Wakely Jr, Stefano Volinia, Michelle Vinco, Thomas J Giordano, Carlo M Croce, Motoyasu Saji and Matthew D Ringel
Graeme Eisenhofer, Stefan R Bornstein, Frederieke M Brouwers, Nai-Kong V Cheung, Patricia L Dahia, Ronald R de Krijger, Thomas J Giordano, Lloyd A Greene, David S Goldstein, Hendrik Lehnert, William M Manger, John M Maris, Hartmut P H Neumann, Karel Pacak, Barry L Shulkin, David I Smith, Arthur S Tischler and William F Young Jr
Pheochromocytomas are rare catecholamine-producing neuroendocrine tumors that are usually benign, but which may also present as or develop into a malignancy. Predicting such behavior is notoriously difficult and there are currently no curative treatments for malignant tumors. This report follows from a workshop at the Banbury Conference Center, Cold Spring Harbor, New York, on the 16th–18th November 2003, held to review the state of science and to facilitate future progress in the diagnosis and treatment of malignant pheochromocytoma. The rarity of the tumor and the resulting fragmented nature of studies, typically involving small numbers of patients, represent limiting factors to the development of effective treatments and diagnostic or prognostic markers for malignant disease. Such development is being facilitated by the availability of new genomics-based tools, but for such approaches to succeed ultimately requires comprehensive clinical studies involving large numbers of patients, stringently collected clinical data and tumor samples, and interdisciplinary collaborations among multiple specialist centers. Nevertheless, the well-characterized hereditary basis and the unique functional nature of these neuroendocrine tumors provide a useful framework that offers advantages for establishing the pathways of tumorigenesis and malignancy. Such findings may have relevance for understanding the basis of other more common malignancies where similar frameworks are not available. As the relevant pathways leading to pheochromocytoma are established it should be possible to take advantage of the new generation of drugs being developed to target specific pathways in other malignancies. Again the success of this will require well-designed and coordinated multicenter studies.