The role of PDGFRA as a therapeutic target in young colorectal cancer patients

Tae Won Kim,Chung Lee,Woong-Yang Park,Jung Wook Huh,Yoon Ah Park,Je-Gun Joung,Woo Yong Lee,Sunmin Kim,Seong Hyeon Yun,Hee Cheol Kim,Hye Kyung Hong,Yong Beom Cho

doi:10.1186/s12967-021-03088-7

Abstract

BackgroundYoung patients with colorectal cancer (CRC) exhibit poor prognoses compared to older patients due to the difficulty in early diagnosis and treatment. However, the underlying molecular characteristics are still unclear.MethodsWe conducted a comprehensive analysis of 49 CRC patients without hereditary CRC using the whole-exome and RNA sequencing with tumor and matched normal samples. A total of 594 TCGA samples and 4 patient-derived cells were utilized for validation.ResultsConsensus molecular subtype 4 (CMS4) (53.85%) and CMS2 (38.46%) were enriched in the young (≤ 40 years) and old (> 60 years) age groups, respectively. A CMS4-associated gene, platelet-derived growth factor receptor α (PDGFRA), was significantly upregulated in young patients with CRC (FC = 3.21, p = 0.0001) and was negatively correlated with age (p = 0.0001, R = − 0.526). Moreover, PDGFRA showed a positive co-expression with metastasis-related genes in young CRC patients. In vitro validation confirmed that young patient-derived cells (PDCs) showed an enriched expression of PDGFRA compared to old PDCs and a reduced proliferation rate by knockdown of PDGFRA. Furthermore, young CRC patients were more sensitive to regorafenib, a PDGFRA-targeting drug, than old CRC patients.ConclusionsOur study suggests that CRC in young patients is associated with CMS4 and PDGFRA. In addition, PDGFRA may serve potential of novel therapeutic strategies and represent a predictive biomarker of response to regorafenib for young CRC patients.

Highlights

Young patients with colorectal cancer (CRC) exhibit poor prognoses compared to older patients due to the difficulty in early diagnosis and treatment
consensus molecular subtypes (CMS) classification according to age of CRC patients To clarify the difference in the molecular characteristics between young and old patients, we divided the samples into three groups according to the age of 49 CRC patients (Table 1)
Consensus molecular subtype 4 (CMS4) frequency gradually decreased with age, while CMS2 was more frequent in the old age group (Fig. 1 a-c)

Summary

Introduction

Young patients with colorectal cancer (CRC) exhibit poor prognoses compared to older patients due to the difficulty in early diagnosis and treatment. According to a study with a selected gene set showing several somatic mutations that tend to be frequent. Kim et al J Transl Med (2021) 19:446 in CRC patients, several early-onset CRCs are caused by inherited genetic mutations [10], except for hereditary cancer syndromes [11]. A gene expression study of young patients without a family history of the disease suggested that upregulated genes, compared with healthy controls, are involved in various biological processes [12].

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Discussion

Conclusion