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Genome Med. 2014 May 29;6(5):43. doi: 10.1186/gm559. eCollection 2014.

Genome-wide mutational landscape of mucinous carcinomatosis peritonei of appendiceal origin.

Author information

1
Division of Genome Information Sciences, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA, USA ; Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany.
2
Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA, USA.
3
Department of Medicine, University of California San Diego, La Jolla, CA, USA ; Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.
4
Bioinformatics Graduate Program, University of California San Diego, La Jolla, CA, USA.
5
Division of Genome Information Sciences, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA, USA.
6
RainDance Technologies, Lexington, MA, USA.
7
Department of Pathology, University of California San Diego, La Jolla, CA, USA.
8
Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA, USA ; Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.
9
Division of Genome Information Sciences, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA, USA ; Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA ; Clinical and Translational Science Institute, University of California San Diego, La Jolla, CA, USA ; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
10
Division of Genome Information Sciences, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA, USA ; Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA ; Clinical and Translational Science Institute, University of California San Diego, La Jolla, CA, USA.

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 TGFβ 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.

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