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

Abstract

BackgroundMucinous 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.MethodsWe 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.ResultsOur 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.ConclusionsMNA genome-wide mutational analysis reveals genetic alterations distinct from colorectal cancer, in support of its unique pathophysiology and suggests new targeted therapeutic opportunities.

“The Jelly Belly”: Diagnostic Dilemmas and Current Concepts

“…Molecular analysis of the neoplastic cells demonstrated identical K-ras mutations in both the ovarian and appendiceal neoplasms. Further, loss of heterozygosity occurred in both the appendiceal and ovarian neoplasms in all cases except for one where there was preservation of both alleles in the appendix [12,13]. This was attributed to a loss of heterozygosity as a part of tumor progression by the ovaries.…”

Genomics of peritoneal surface malignancies

“…Its mutation was originally found in pituitary tumors, intraductal papillary mucinous neoplasms of the pancreas (IPMN), gastric, and intestinal adenomas as well as CRC. 20 Prevalence of KRAS & GNAS mutations in LAMN and PMP tumor samples has been reported in various studies with high variability ranging from 53-100% & 40-63% respectively (Table 1). [21][22][23][24][25][26] Differences in cell enrichment methods, genomic sequencing techniques, regional variation and small number patients in most of these studies may have contributed to this variation.…”

“…Alakus et al reported KRAS and GNAS mutations in 10/10 and 9/10 tumor samples respectively, which is quite higher than previous studies. 20 It may be quite possible that due to hypocellular nature of this disease, prevalence of these mutations may have been underestimated in other studies. However, APC and p53 mutation are uncommon in PMP of appendiceal origin in contrast to colon cancer.…”

“…However, APC and p53 mutation are uncommon in PMP of appendiceal origin in contrast to colon cancer. 20 High-level microsatellite instability (MSI) is also rare (3%) in appendiceal cancers, whereas approximately 15% of colorectal carcinomas (CRCs) display highlevel MSI. 27,28 Sio et al identified MCL1 and JUN1 amplification in 30% of PMP cases using next-generation sequencing assay with Illumina HiSeq2000 platform.…”

Familial appendiceal tumours in Diffuse Peritoneal Adenomucinosis and peritoneal mucinous carcinomatosis: A rare familial predisposition?

“…[10] Overexpression of p53 is reported to be rare in appendiceal tumours and, although KRAS mutation and p53 overexpression can be seen in half of PMP cases of appendiceal origin. [11] Microsatellite instability has also been shown to be rare in appendiceal carcinoma, and hyper-methylation is not a mechanism for genetic instability in these tumours although some hyperplastic polyps and sessile serrated adenomas of the appendix show decreased expression of MLH1 and BRAF mutation is more common in serrated polyps. [7] The only consistent risk factor identified for appendiceal cancer is increasing age.…”