Genetic Clustering of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Patients of Colorectal Origin: KRAS and Not TP53 Cluster Alterations are Associated with Poor Outcomes

Ann Surg Oncol. 2024 Sep;31(9):6252-6261. doi: 10.1245/s10434-024-15786-9. Epub 2024 Jul 13.

Abstract

Background: The prognostic impact of genetic mutations for patients who undergo cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) of colorectal origin (CRC) is not well defined.

Objective: We aimed to describe the genetic classifications in an unsupervised fashion, and the outcomes of this patient population.

Methods: A retrospective, bi-institutional study was performed on patients who underwent CRS-HIPEC with targeted mutation data with a median follow-up time of 61 months. Functional link analysis was performed using STRING v11.5. Genes with similar functional significance were clustered using unsupervised k-means clustering. Chi-square, Kaplan-Meier, and the log-rank test were used for comparative statistics.

Results: Sixty-four patients with peritoneal carcinomatosis from CRC origin underwent CRS-HIPEC between 2007 and 2022 and genetic mutation data were extracted. We identified 19 unique altered genes, with KRAS (56%), TP53 (33%), and APC (22%) being the most commonly altered; 12.5% had co-altered KRAS/TP53. After creating an interactome map, k-means clustering revealed three functional clusters. Reactome Pathway analysis on three clusters showed unique pathways (1): Ras/FGFR3 signaling; (2) p53 signaling; and (3): NOTCH signaling. Seventy-one percent of patients in cluster 1 had KRAS mutations and a median overall survival of 52.3 months (p < 0.05).

Conclusions: Patients with peritoneal carcinomatosis (PC) of CRC origin who underwent CRS-HIPEC and with tumors that harbored mutations in cluster 1 (Ras/FGFR3 signaling) had worse outcomes. Pathway disruption and a cluster-centric perspective may affect prognosis more than individual genetic alterations in patients with PC of CRC origin.

Keywords: APC; CRS-HIPEC; Genetic clustering; Genetic pathways; KRAS; TP53.

Publication types

  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers, Tumor / genetics
  • Colorectal Neoplasms* / genetics
  • Colorectal Neoplasms* / pathology
  • Colorectal Neoplasms* / therapy
  • Combined Modality Therapy
  • Cytoreduction Surgical Procedures*
  • Female
  • Follow-Up Studies
  • Humans
  • Hyperthermic Intraperitoneal Chemotherapy*
  • Male
  • Middle Aged
  • Mutation*
  • Peritoneal Neoplasms* / genetics
  • Peritoneal Neoplasms* / secondary
  • Peritoneal Neoplasms* / therapy
  • Prognosis
  • Proto-Oncogene Proteins p21(ras)* / genetics
  • Retrospective Studies
  • Survival Rate
  • Tumor Suppressor Protein p53* / genetics

Substances

  • KRAS protein, human
  • Proto-Oncogene Proteins p21(ras)
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Biomarkers, Tumor