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. 2018 Aug 8:2:PO.17.00302.
doi: 10.1200/PO.17.00302. eCollection 2018.

Genomic Landscape of Appendiceal Neoplasms

Celina S-P Ang  1 , John Paul Shen  1 , Camille J Hardy-Abeloos  1 , Justin K Huang  1 , Jeffrey S Ross  1 , Vincent A Miller  1 , Miriam T Jacobs  1 , Ingrid L Chen  1 , David Xu  1 , Siraj M Ali  1 , Joel Baumgartner  1 , Andrew Lowy  1 , Paul Fanta  1 , Trey Ideker  1 , Sherri Z Millis  1 , Olivier Harismendy  1
Affiliations

Genomic Landscape of Appendiceal Neoplasms

Celina S-P Ang et al. JCO Precis Oncol. .

Abstract

Purpose: Appendiceal neoplasms are heterogeneous and are often treated with chemotherapy similarly to colorectal cancer (CRC). Genomic profiling was performed on 703 appendiceal cancer specimens to compare the mutation profiles of appendiceal subtypes to CRC and other cancers, with the ultimate aim to identify potential biomarkers and novel therapeutic targets.

Methods: Tumor specimens were submitted to a Clinical Laboratory Improvement Amendments-certified laboratory (Foundation Medicine, Cambridge, MA) for hybrid-capture-based sequencing of 3,769 exons from 315 cancer-related genes and 47 introns of 28 genes commonly rearranged in cancer. Interactions between genotype, histologic subtype, treatment, and overall survival (OS) were analyzed in a clinically annotated subset of 76 cases.

Results: There were five major histopathologic subtypes: mucinous adenocarcinomas (46%), adenocarcinomas (30%), goblet cell carcinoids (12%), pseudomyxoma peritonei (7.7%), and signet ring cell carcinomas (5.2%). KRAS (35% to 81%) and GNAS (8% to 72%) were the most frequent alterations in epithelial cancers; APC and TP53 mutations were significantly less frequent in appendiceal cancers relative to CRC. Low-grade and high-grade tumors were enriched for GNAS and TP53 mutations, respectively (both χ2 P < .001). GNAS and TP53 were mutually exclusive (Bonferroni corrected P < .001). Tumor grade and TP53 mutation status independently predicted OS. The mutation status of GNAS and TP53 strongly predicted OS (median, 37.1 months for TP53 mutant v 75.8 GNAS-TP53 wild type v 115.5 GNAS mutant; log-rank P = .0031) and performed as well as grade in risk stratifying patients.

Conclusion: Epithelial appendiceal cancers and goblet cell carcinoids show differences in KRAS and GNAS mutation frequencies and have mutation profiles distinct from CRC. This study highlights the benefit of performing molecular profiling on rare tumors to identify prognostic and predictive biomarkers and new therapeutic targets.

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Conflict of interest statement

Conception and design: Celina S.-P. Ang, John Paul Shen, Paul Fanta, Trey Ideker, Sherri Z. Millis, Olivier Harismendy Financial support: John Paul Shen, Paul Fanta, Trey Ideker Administrative support: John Paul Shen, Paul Fanta Provision of study material or patients: John Paul Shen, Jeffrey S. Ross, Joel Baumgartner, Andrew Lowy, Paul Fanta, Sherri Z. Millis Collection and assembly of data: John Paul Shen, Jeffrey S. Ross, Miriam T. Jacobs, Ingrid L. Chen, David Xu, Siraj M. Ali, Andrew Lowy, Paul Fanta, Sherri Z. Millis Data analysis and interpretation: Celina S.-P. Ang, John Paul Shen, Camille J. Hardy-Abeloos, Justin K. Huang, Jeffrey S. Ross, Vincent A. Miller, Miriam T. Jacobs, Ingrid L. Chen, Siraj M. Ali, Joel Baumgartner, Paul Fanta, Trey Ideker, Sherri Z. Millis, Olivier Harismendy Manuscript writing: All authors Final approval of manuscript: All authors

Figures

Fig 1.
Fig 1.
Genomic profiles of appendiceal tumors. (A) Distribution of tissue site submitted for sequencing. (B) Frequency of mutation for selected genes, separated by histologic subtype. (C) Comutation plot from targeted sequencing of 703 appendix cancer tumors. A selection of genes relevant to the disease is represented. (D) Frequency of alteration for specific pathways. Ad, adenocarcinoma; GCC, goblet cell carcinoid; MAd, mucinous adenocarcinoma; PMP, pseudomyxoma peritonei; SRCC, signet ring cell carcinoma.
Fig 2.
Fig 2.
Clinical and molecular features predictive of survival. (A) Overall survival (OS) stratified by histologic subtype. Goblet cell carcinoid (four tumors) was removed from survival analysis. (B) OS stratified by histologic grade. (C) OS stratified by GNAS mutation status. (D) OS TP53 mutation status. (E) OS stratified by KRAS mutation status. (F) OS of patients with KRAS wild-type disease, stratified by irinotecan use. Ad, adenocarcinoma; MAd, mucinous adenocarcinoma; mut, mutant; PMP, pseudomyxoma peritonei; wt, wild type.
Fig 3.
Fig 3.
Association of tumor grade with GNAS and TP53 mutation status. (A) Overall survival (OS) of patients with GNAS mutation, stratified by grade. (B) OS of patients with TP53 mutation, stratified by grade. (C) OS stratified by combined TP53-GNAS mutation status. There was only one tumor with both TP53 and GNAS mutations; this group was not included in the survival analysis. (D) Median OS of selected subpopulations.
Fig A1.
Fig A1.
Mutation burden and spectrum in appendiceal tumors. (A) Tumor mutation frequency (mutations per megabase) for each subtype. Incidence and location of mutations in (B) KRAS, (C) GNAS, and (D) TP53. (E) Tumor mutation burden (mutations per megabase) for each histologic subtype. Ad, adenocarcinoma; GCC, goblet cell carcinoid; MAd, mucinous adenocarcinoma; PMP, pseudomyxoma peritonei; TMB, tumor mutational burden.
Fig A2.
Fig A2.
Clinical and molecular features predictive of survival. (A) Overall survival of adenocarcinoma (Ad) versus mucinous adenocarcinoma (MAd). (B) Overall survival of patients with KRAS mutations, stratified by irinotecan use.
Fig A3.
Fig A3.
Correlation of grade with GNAS, TP53 mutation status. (A) GNAS mutation frequency, by grade. (B) TP53, by grade. (C) Adenocarcinoma versus mucinous adenocarcinoma frequency, by grade.
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