Improved Outcome Prediction for Appendiceal Pseudomyxoma Peritonei by Integration of Cancer Cell and Stromal Transcriptional Profiles

Abstract

In recent years, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have substantially improved the clinical outcome of pseudomyxoma peritonei (PMP) originating from mucinous appendiceal cancer. However, current histopathological grading of appendiceal PMP frequently fails in predicting disease outcome. We recently observed that the integration of cancer cell transcriptional traits with those of cancer-associated fibroblasts (CAFs) improves prognostic prediction for tumors of the large intestine. We therefore generated global expression profiles on a consecutive series of 24 PMP patients treated with CRS plus HIPEC. Multiple lesions were profiled for nine patients. We then used expression data to stratify the samples by a previously published "high-risk appendiceal cancer" (HRAC) signature and by a CAF signature that we previously developed for colorectal cancer, or by a combination of both. The prognostic value of the HRAC signature was confirmed in our cohort and further improved by integration of the CAF signature. Classification of cases profiled for multiple lesions revealed the existence of outlier samples and highlighted the need of profiling multiple PMP lesions to select representative samples for optimal performances. The integrated predictor was subsequently validated in an independent PMP cohort. These results provide new insights into PMP biology, revealing a previously unrecognized prognostic role of the stromal component and supporting integration of standard pathological grade with the HRAC and CAF transcriptional signatures to better predict disease outcome.

Keywords: appendiceal cancer; cancer-associated fibroblasts.; gene expression profiling; peritoneal carcinosis; prognostic signatures; pseudomyxoma peritonei; tumor stroma.

Figure 1

Prognostic performance of the transcriptional HRAC score. (a) Bar plot representing the cohort of 24 pseudomyxoma peritonei (PMP) patients in terms of number of samples per patient and pathological classification, with diffuse peritoneal adenomucinosis (DPAM) in blue and peritoneal mucinous carcinomatosis (PMCA) in orange; (b) high-risk appendiceal cancer (HRAC) score calculated in each sample subdivided by patient of origin. Red dots represent the central sample for patients with multiple profiles; (c) receiver operating characteristic (ROC) curves on disease-free survival (DFS) for HRAC in the full dataset (DPAM + PMCA), DPAM, and PMCA (DFS event = relapse within 24 months). For patients with multiple profiles, curves in the top row include all samples as if they were from different patients, while curves in the bottom row only include central samples.

Figure 2

Prognostic performance of the transcriptional CAF score (a) Dot plot of cancer-associated fibroblast (CAF) score in DPAM, PMCA, and colorectal cancer (CRC) samples. (b) CAF score calculated in each sample subdivided by patient of origin. Red dots represent the central sample for patients with multiple profiles. (c) ROC curves for the CAF score vs DFS in the full dataset (DPAM + PMCA), DPAM, and PMCA (DFS event = relapse within 24 months). For patients with multiple profiles, curves in the top row include all samples as if they were from different patients, while curves in the bottom row only include central samples. AUC = area under the curve; CI = confidence interval.

Figure 3

Combined prognostic performance of the HRAC and CAF scores. (a) Classification of the 13 DPAM cases according to CAF and HRAC scores on central samples with DFS annotation (y axis); samples are subdivided on the basis of HRAC and CAF calls (upper panel), and subdivided in 2 groups: CAF AND HRAC good (green background) and CAF OR HRAC poor (red background). (b) Kaplan–Meier plot of DFS of HRAC and CAF score integration in the 13 DPAM cases. (c) Kaplan–Meier plot of DFS of HRAC and CAF score integration in the GSE75535 dataset.