Jing Su1, Guangxu Jin2, Konstantinos I Votanopoulos3, Lou Craddock2, Perry Shen3, Jeff W Chou1, Shadi Qasem4, Stacey S O'Neill4, Kathleen Cummins Perry3, Lance D Miller5,6, Edward A Levine7. 1. Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC, USA. 2. Wake Forest Baptist Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, USA. 3. Surgical Oncology Service, Department of General Surgery, Wake Forest School of Medicine, Winston-Salem, NC, USA. 4. Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA. 5. Wake Forest Baptist Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, USA. ldmiller@wakehealth.edu. 6. Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA. ldmiller@wakehealth.edu. 7. Surgical Oncology Service, Department of General Surgery, Wake Forest School of Medicine, Winston-Salem, NC, USA. elevine@wakehealth.edu.
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.
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.
Authors: Konstantinos I Votanopoulos; Greg Russell; Reese W Randle; Perry Shen; John H Stewart; Edward A Levine Journal: Ann Surg Oncol Date: 2014-10-16 Impact factor: 5.344
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Authors: Jing Su; Qianqian Song; Shadi Qasem; Stacey O'Neill; Jingyun Lee; Cristina M Furdui; Boris Pasche; Linda Metheny-Barlow; Adrianna H Masters; Hui-Wen Lo; Fei Xing; Kounosuke Watabe; Lance D Miller; Stephen B Tatter; Adrian W Laxton; Christopher T Whitlow; Michael D Chan; Michael H Soike; Jimmy Ruiz Journal: Front Oncol Date: 2021-04-06 Impact factor: 6.244
Authors: Jing Su; Lynn S Huang; Ryan Barnard; Graham Parks; James Cappellari; Christina Bellinger; Travis Dotson; Lou Craddock; Bharat Prakash; Jonathan Hovda; Hollins Clark; William Jeffrey Petty; Boris Pasche; Michael D Chan; Lance D Miller; Jimmy Ruiz Journal: Front Oncol Date: 2021-04-16 Impact factor: 6.244