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Published on: August 24, 2019
Establishing Novel Molecular Subtypes of Appendiceal Cancer
Mary Garland-Kledzik1, Anthony Scholer2, Miquel Ensenyat-Mendez3
1Division of Surgical Oncology, West Virginia University, Morgantown, WV, USA. mgkledzikmd@gmail.com.
Purpose:
Appendiceal cancer is a rare disease process with complex treatment strategies. The objective of this study was to identify mutation-based genetic subtypes that may differ from the current histological classification, compare the genetic make-up of primaries and metastases, and find novel targetable alterations.
Methods:
The analyses involved the curation and normalization of gene mutation panels from appendiceal adenocarcinoma and mucinous adenocarcinoma (n = 196) stored in the AACR GENIE Database v6.0. Genes mutated in less than one patient and tumors profiled with incomplete mutation panels were excluded from the study. The optimal number of AC subtypes was established using the Nonnegative Matrix Factorization algorithm. Statistical comparisons of mutation frequencies were performed using Pearson's χ2 test.
Results:
AC patients were stratified into five mutation subtypes, based on a final set of 41 cancer-related genes. AC0 had no mutations. The most frequently mutated genes varied between the subtypes were: AC1: KRAS (91.9%) and GNAS (77.4%); AC2: KRAS (52.5%), APC (32.5%), and GNAS (30%); AC3: KMT2D (38.7%), TP53 (38.7%), KRAS (35.5%), EP300 (22.6%); and AC4: TP53 (97.2%), KRAS (77.8%), and SMAD4 (36.1%). Additionally, AC3 was less likely to be mucinous (22.6% vs. 50.0-74.2%, p < 0.001) and had a higher mutation frequency (3.6 vs. 0-3.1, p < 0.001). There were no significant differences between primary tumors and metastases in the 41 assessed genes (p = 0.35).
Conclusions:
The characterization of these subtypes suggests a need for molecular approaches to complement anatomical and histopathological staging for AC. A prospective comparison of subtype prognosis and response to surgery and adjuvant treatment is needed to identify the clinical applications of the novel molecular subtypes.
Insights
Appendiceal cancer (AC) subtypes were identified based on gene mutations, revealing distinct genetic profiles. These molecular subtypes may offer new ways to classify and potentially treat this rare cancer.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Appendiceal cancer (AC) is a rare malignancy with complex treatment.
- Current classification relies on histology, but molecular subtypes may offer deeper insights.
Purpose of the Study:
- Identify mutation-based genetic subtypes of appendiceal cancer.
- Compare genetic profiles of primary tumors and metastases.
- Discover novel, targetable genetic alterations in AC.
Main Methods:
- Analyzed gene mutation panels from 196 appendiceal adenocarcinoma and mucinous adenocarcinoma cases.
- Utilized Nonnegative Matrix Factorization to define subtypes based on 41 cancer-related genes.
- Employed Pearson's χ² test for statistical comparisons of mutation frequencies.
Main Results:
- Stratified appendiceal cancer into five distinct mutation subtypes (AC0-AC4).
- Identified specific frequently mutated genes within each subtype (e.g., KRAS, GNAS, TP53, SMAD4).
- Found AC3 subtype less mucinous and with higher mutation frequency; no significant genetic differences between primary and metastatic tumors.
Conclusions:
- Appendiceal cancer subtypes based on molecular profiles complement current staging.
- Further research is needed to correlate these subtypes with prognosis and treatment response.
- Molecular classification holds potential for personalized treatment strategies in appendiceal cancer.
