Universität zu Köln

Alakus, Hakan, Babicky, Michele L., Ghosh, Pradipta, Yost, Shawn ORCID: 0000-0001-6653-1056, Jepsen, Kristen, Dai, Yang, Arias, Angelo, Samuels, Michael L., Mose, Evangeline S., Schwab, Richard B., Peterson, Michael R., Lowy, Andrew M., Frazer, Kelly A. and Harismendy, Olivier (2014). Genome-wide mutational landscape of mucinous carcinomatosis peritonei of appendiceal origin. Genome Med., 6. LONDON: BMC. ISSN 1756-994X

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Abstract

Background Mucinous neoplasms of the appendix (MNA) are rare tumors which may progress from benign to malignant disease with an aggressive biological behavior. MNA is often diagnosed after metastasis to the peritoneal surfaces resulting in mucinous carcinomatosis peritonei (MCP). Genetic alterations in MNA are poorly characterized due to its low incidence, the hypo-cellularity of MCPs, and a lack of relevant pre-clinical models. As such, application of targeted therapies to this disease is limited to those developed for colorectal cancer and not based on molecular rationale. Methods We sequenced the whole exomes of 10 MCPs of appendiceal origin to identify genome-wide somatic mutations and copy number aberrations and validated significant findings in 19 additional cases. Results Our study demonstrates that MNA has a different molecular makeup than colorectal cancer. Most tumors have co-existing oncogenic mutations in KRAS (26/29) and GNAS (20/29) and are characterized by downstream PKA activation. High-grade tumors are GNAS wild-type (5/6), suggesting they do not progress from low-grade tumors. MNAs do share some genetic alterations with colorectal cancer including gain of 1q (5/10), Wnt, and TGF beta pathway alterations. In contrast, mutations in TP53 (1/10) and APC (0/10), common in colorectal cancer, are rare in MNA. Concurrent activation of the KRAS and GNAS mediated signaling pathways appears to be shared with pancreatic intraductal papillary mucinous neoplasm. Conclusions MNA genome-wide mutational analysis reveals genetic alterations distinct from colorectal cancer, in support of its unique pathophysiology and suggests new targeted therapeutic opportunities.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Alakus, Hakan UNSPECIFIED UNSPECIFIED UNSPECIFIED Babicky, Michele L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ghosh, Pradipta UNSPECIFIED UNSPECIFIED UNSPECIFIED Yost, Shawn UNSPECIFIED orcid.org/0000-0001-6653-1056 UNSPECIFIED Jepsen, Kristen UNSPECIFIED UNSPECIFIED UNSPECIFIED Dai, Yang UNSPECIFIED UNSPECIFIED UNSPECIFIED Arias, Angelo UNSPECIFIED UNSPECIFIED UNSPECIFIED Samuels, Michael L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mose, Evangeline S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwab, Richard B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Peterson, Michael R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lowy, Andrew M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Frazer, Kelly A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Harismendy, Olivier UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-425771
DOI:	10.1186/gm559
Journal or Publication Title:	Genome Med.
Volume:	6
Date:	2014
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1756-994X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PSEUDOMYXOMA-PERITONEI; KRAS MUTATIONS; CLINICOPATHOLOGICAL ANALYSIS; GENETIC-ANALYSIS; VILLOUS ADENOMA; GNAS MUTATIONS; FREQUENT GNAS; SECRETION; NEOPLASMS; PATHWAY Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/42577