Histological and mutational profile of diffuse gastric cancer: current knowledge and future challenges. Issue 11 (2nd May 2021)

• Record Type: Journal Article
• Authors: Garcia‐Pelaez, José; Barbosa‐Matos, Rita; Gullo, Irene; Carneiro, Fátima; Oliveira, Carla
• Is Part Of: Molecular oncology. Volume 15:Issue 11(2021)
• Page Start: 2841
• Page End: 2867
• Publication Date: 2021-05-02
• Subjects: diffuse gastric cancer -- driver genes -- intestinal gastric cancer -- molecular classification -- poorly cohesive carcinomas -- signet‐ring cell carcinoma; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12948
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : Gastric cancer (GC) pathogenesis is complex and heterogeneous, reflecting morphological, molecular and genetic diversity. Diffuse gastric cancer (DGC) and intestinal gastric cancer (IGC) are the major histological types. GC may be sporadic or hereditary; sporadic GC is related to environmental and genetic low‐risk factors and hereditary GC is caused by inherited high‐risk mutations, so far identified only for the diffuse histotype. DGC phenotypic heterogeneity challenges the current understanding of molecular mechanisms underlying carcinogenesis. The definition of a DGC‐specific mutational profile remains controversial, possibly reflecting the heterogeneity of DGC‐related histological subtypes [signet‐ring cell carcinoma (SRCC) and poorly cohesive carcinoma not otherwise specified (PCC‐NOS)]. Indeed, DGC and DGC‐related subtypes may present specific mutational profiles underlying the particularly aggressive behaviour and dismal prognosis of DGC vs IGC and PCC‐NOS vs SRCC. In this systematic review, we revised the histological presentations, molecular classifications and approved therapies for gastric cancer, with a focus on DGC. We then analysed results from the most relevant studies, reporting mutational analysis data specifying mutational frequencies, and their relationship with DGC and IGC histological types, and with specific DGC subtypes (SRCC and PCC‐NOS). We aimed at identifying histology‐associated mutational profiles with an emphasis in DGC and its subtypes (DGC vs IGC; sporadic vs hereditary DGC; and SRCC vs PCC‐NOS). We further used these mutational profiles to identify the most commonly affected molecular pathways and biological functions, and explored the clinical trials directed specifically to patients with DGC. This systematic analysis is expected to expose a DGC‐specific molecular profile and shed light into potential targets for therapeutic intervention, which are currently missing. Abstract : The main diffuse gastric cancer (DGC) histological subtypes are signet‐ring cell carcinoma (SRCC) and poorly cohesive carcinoma not otherwise specified (PCC‐NOS). Clinical trials, targeted therapies and predictive markers of therapy response directed to any of these entities are residual. This systematic review exposes the lack of integrated knowledge in these clinical entities and uses their mutational profiles to rethink therapeutic intervention.