Molecular Profiling of Appendiceal Epithelial Tumors Using Massively Parallel Sequencing to Identify Somatic Mutations

Li, Xiaoying; Mody, Kabir; Abreu, Francine B. de; Pipas, J. Marc; Peterson, Julie; Gallagher, Torrey L.; Suriawinata, Arief A.; Ripple, Gregory H.; Hourdequin, Kathryn Cunningham; Smith, Kerrington D.; Barth, Richard J.; Colacchio, Thomas A.; Tsapakos, Michael J.; Zaki, Bassem I.; Gardner, Timothy B.; Gordon, Stuart R.; Amos, Christopher I.; Wells, Wendy A.; Tsongalis, Gregory J.

doi:10.1373/clinchem.2014.225565

Cited by 83 publications

(99 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Molecular profiling has been used effectively in other cancers to identify novel treatment options. Only two studies to date have reviewed the molecular profile of appendiceal cancers; those studies had very few patients (n=38 and 149) (18,19), and the analysis was limited to gene mutations. Our analysis encompassed multiple profiling platforms from gene alterations to gene amplification and protein expression levels, and 588 patients were evaluated, almost four times more than the previous studies.…”

Section: Introductionmentioning

confidence: 99%

Potential actionable targets in appendiceal cancer detected by immunohistochemistry, fluorescent in situ hybridization, and mutational analysis

Borazanci¹,

Millis²,

Kimbrough³

et al. 2017

J. Gastrointest. Oncol.

View full text Add to dashboard Cite

Background: Appendiceal cancers are rare and consist of carcinoid, mucocele, pseudomyxoma peritonei (PMP), goblet cell carcinoma, lymphoma, and adenocarcinoma histologies. Current treatment involves surgical resection or debulking, but no standard exists for adjuvant chemotherapy or treatment for metastatic disease. Methods: Samples were identified from approximately 60,000 global tumors analyzed at a referral molecular profiling CLIA-certified laboratory. A total of 588 samples with appendix primary tumor sites were identified (male/female ratio of 2:3; mean age =55). Sixty-two percent of samples were adenocarcinomas (used for analysis); the rest consisted of 9% goblet cell, 15% mucinous; 6% pseudomyxoma, and less than 5% carcinoids and 2% Results: Profiling across all appendiceal cancer histological subtypes for IHC revealed: 97% BRCP, 81% MRP1, 81% COX-2, 71% MGMT, 56% TOPO1, 5% PTEN, 52% EGFR, 40% ERCC1, 38% SPARC, 35% PDGFR, 35% TOPO2A, 25% RRM1, 21% TS, 16% cKIT, and 12% for TLE3. NGS revealed mutations in the following genes: 50.4% KRAS, 21.9% P53, 17.6% GNAS, 16.5% SMAD4, 10% APC, 7.5% ATM, 5.5% PIK3CA, 5.0% FBXW7, and 1.8% BRAF.Conclusions: Appendiceal cancers show considerable heterogeneity with high levels of drug resistance proteins (BCRP and MRP1), which highlight the difficulty in treating these tumors and suggest an individualized approach to treatment. The incidence of low TS (79%) could be used as a backbone of therapy (using inhibitors such as 5FU/capecitabine or newer agents). Therapeutic options includeTOPO1 inhibitors (irinotecan/topotecan), EGFR inhibitors (erlotinib, cetuximab), PDGFR antagonists (regorafenib, axitinib), KRAS, p53, GNAS, SMAD4, APC, ATM, PIK3CA, FBXW7, and BRAF may be also considered. Overall, appendiceal cancers have similar patterns in their molecular profile to pancreatic cancers (can we say this, any statistical analysis done?) and have differential expression from colorectal cancers. These findings indicate the need to evaluate patient samples for patterns in marker expression and alteration, in order to better understand the molecular biology and formulate a personalized therapy approach in these difficult to treat cancers (supported by a grant from Caris Life Sciences). MGMT (temozolomide). Clinical trials targeting pathways involving IntroductionCancers arising from the appendix are rare. In reports of appendectomy specimens, the incidence of malignancy has been reported to be between 0.58% to 0.9% (1,2). The histological spectrum is quite varied, with recent reports through large database studies indicating adenocarcinoma being the most common subtype (3,4). Other histological variants include carcinoid or neuroendocrine and a mixed histology tumor of both carcinoid and adenocarcinoma subtype termed goblet cell carcinoma (5). Finally, another epithelial variant of appendiceal cancer is pseudomyxoma peritonei (PMP), a mucinous neoplasm that clinically presents as gelatinous ascites (6,7). Due to the rarity of these malignancies limited prospective trials exist gu...

show abstract

Section: Introductionmentioning

confidence: 99%

Potential actionable targets in appendiceal cancer detected by immunohistochemistry, fluorescent in situ hybridization, and mutational analysis

Borazanci¹,

Millis²,

Kimbrough³

et al. 2017

J. Gastrointest. Oncol.

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Pseudomyxoma Peritonei Genomicsmentioning

confidence: 99%

“…These tumors typically have different molecular pathways to carcinogenesis and do not have KRAS or GNAS mutations. 25 Given that KRAS mutations are associated with lack of response to anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies (Cetuximab, Panitumumab), its absence in appendiceal adenocarcinomas with goblet cell features may allow for targeted anti-EGFR therapy. 32 …”

Section: Pseudomyxoma Peritonei Genomicsmentioning

confidence: 99%

Genomics of peritoneal surface malignancies

2017

View full text Add to dashboard Cite

Peritoneal malignancies and metastasis are traditionally approached as a terminal disease, however with multiple lines of clinical therapy; long-term survival can be achieved in selected patients using aggressive cytoreduction and hyperthermic intraperitoneal chemotherapy. This is especially true for Pseudomyxoma peritonei from appendiceal neoplasms, peritoneal mesothelioma and peritoneal metastasis from colorectal cancer. In this article, we discuss the nature of genomic alterations in these three peritoneal malignancies and their potential as prognostic and therapeutic markers in clinical decisions. Genomic characterization of malignancies using technological advances including what is now widely used and accepted next-generation genomic sequencing methods has identified genomic anomalies (i.e. mutations, epigenetic modifications, transcription and expression changes in RNA) which is used for targeted therapy, prognostication, surveillance and prediction of response to therapy. BackgroundOngoing efforts to further characterize the genomics of peritoneal malignancies and metastasis remain essential. Although the appendix is considered as a part of the colon, its cancer genomic landscape is very different from colorectal cancer, suggesting that much like the variation in right and left-sided CRC, regional variation in gastrointestinal tract (GIT) tissues contributes to the unique disease phenotype. Equally, in Pseudomyxoma peritonei (PMP) of appendiceal origin, the most common gene mutations are in KRAS and GNAS. In addition, unlike CRC, DNA microsatellite instability and mutations in housekeeping DNA repair genes are typically rare (approximately 3%) and is therefore not a common phenotype of PMP. Research and discovery are still needed on genomic alterations driving peritoneal metastasis from CRC, although there is some evidence that BRAF mutations are associated with higher incidence of peritoneal metastasis. A better understanding of disease pathways linked with genomic alteration would contribute to our clinical goals of personalized medicine.

show abstract

“…Le gène GNAS code pour la sous-unité ␣ de la stimulatory guanine nucleotide-binding protein, qui régule l'adénylate cyclase des récepteurs couplés aux protéines-G. Des mutations somatiques activatrices de GNAS sont présentes dans diverses néoplasies et ont été récemment rapportées dans des LAMN et des PP [15,16]. En utilisant une technique moléculaire à haut débit (Next Generation Sequencing), Sio a montré que 24 % des PP présentent des mutations de GNAS [17].…”

Section: Marqueurs Moléculaires Des Ppunclassified

Pathologie tumorale du péritoine : cas no 2 : une tumeur péritonéale récidivante

Sabourin

2015

Annales de Pathologie

View full text Add to dashboard Cite

Molecular Profiling of Appendiceal Epithelial Tumors Using Massively Parallel Sequencing to Identify Somatic Mutations

Cited by 83 publications

References 18 publications

Potential actionable targets in appendiceal cancer detected by immunohistochemistry, fluorescent in situ hybridization, and mutational analysis

Potential actionable targets in appendiceal cancer detected by immunohistochemistry, fluorescent in situ hybridization, and mutational analysis

Genomics of peritoneal surface malignancies

Pathologie tumorale du péritoine : cas no 2 : une tumeur péritonéale récidivante

Contact Info

Product

Resources

About