Published in:
01-05-2020 | Cytostatic Therapy | Peritoneal Surface Malignancy
Prognostic Molecular Classification of Appendiceal Mucinous Neoplasms Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy
Authors:
Jing Su, PhD, Guangxu Jin, PhD, Konstantinos I. Votanopoulos, MD, PhD, Lou Craddock, Perry Shen, MD, Jeff W. Chou, PhD, Shadi Qasem, MD, Stacey S. O’Neill, MD, PhD, Kathleen Cummins Perry, MS, Lance D. Miller, PhD, Edward A. Levine, MD
Published in:
Annals of Surgical Oncology
|
Issue 5/2020
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Abstract
Background
Appendiceal mucinous neoplasm (AMN) with peritoneal metastasis is a rare but deadly disease with few prognostic or therapy-predictive biomarkers to guide treatment decisions. Here, we investigated the prognostic and biological attributes of gene expression-based AMN molecular subtypes.
Methods
AMN specimens (n = 138) derived from a population-based subseries of patients treated at our institution with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) between 05/2000 and 05/2013 were analyzed for gene expression using a custom-designed NanoString 148-gene panel. Signed non-negative matrix factorization (sNMF) was used to define a gene signature capable of delineating robustly-classified AMN molecular subtypes. The sNMF class assignments were evaluated by topology learning, reverse-graph embedding and cross-cohort performance analysis.
Results
Three molecular subtypes of AMN were discerned by the expression patterns of 17 genes with roles in cancer progression or anti-tumor immunity. Tumor subtype assignments were confirmed by topology learning. AMN subtypes were termed immune-enriched (IE), oncogene-enriched (OE) and mixed (M) as evidenced by their gene expression patterns, and exhibited significantly different post-treatment survival outcomes. Genes with specialized immune functions, including markers of T-cells, natural killer cells, B-cells, and cytolytic activity showed increased expression in the low-risk IE subtype, while genes implicated in the promotion of cancer growth and progression were more highly expressed in the high-risk OE subtype. In multivariate analysis, the subtypes demonstrated independent prediction power for post-treatment survival.
Conclusions
Our findings suggest a greater role for the immune system in AMN than previously recognized. AMN subtypes may have clinical utility for predicting CRS/HIPEC treatment outcomes.