방사선의학 웹진

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Abstract
Purpose: This work aimed to explore in depth the genomic and molecular underpinnings of hepatocellular carcinoma (HCC) with increased 2[18F]fluoro-2-deoxy-d-glucose (FDG) uptake in PET and to identify therapeutic targets based on this imaging-genomic surrogate.

Experimental design: We used RNA sequencing and whole-exome sequencing data obtained from 117 patients with HCC who underwent hepatic resection with preoperative FDG-PET/CT imaging as a discovery cohort. The primary radiogenomic results were validated with transcriptomes from a second cohort of 81 patients with more advanced tumors. All patients were allocated to an FDG-avid or FDG-non-avid group according to the PET findings. We also screened potential drug candidates targeting FDG-avid HCCs in vitro and in vivo.

Results: High FDG avidity conferred worse recurrence-free survival after HCC resection. Whole transcriptome analysis revealed upregulation of mTOR pathway signals in the FDG-avid tumors, together with higher abundance of associated mutations. These clinical and genomic findings were replicated in the validation set. A molecular signature of FDG-avid HCCs identified in the discovery set consistently predicted poor prognoses in the public-access datasets of two cohorts. Treatment with an mTOR inhibitor resulted in decreased FDG uptake followed by effective tumor control in both the hyperglycolytic HCC cell lines and xenograft mouse models.

Conclusions: Our PET-based radiogenomic analysis indicates that mTOR pathway genes are markedly activated and altered in HCCs with high FDG retention. This nuclear imaging biomarker may stimulate umbrella trials and tailored treatments in precision care of patients with HCC.

Affiliations

Jihyun An #  1 , Minyoung Oh #  2 , Seog-Young Kim #  3   4 , Yoo-Jin Oh  5 , Bora Oh  5 , Ji-Hye Oh  6 , Wonkyung Kim  6 , Jin Hwa Jung  3 , Ha Il Kim  7 , Jae-Seung Kim  2 , Chang Ohk Sung  8 , Ju Hyun Shim  9   10
1 Gastroenterology and Hepatology, Hanyang University College of Medicine, Guri, Gyeonggi, Republic of Korea.
2 Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
3 Convergence Medicine Research Center, Asan Medical Center, Seoul, Republic of Korea.
4 Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.
5 Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.
6 Center for Cancer Genome Discovery, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
7 Gastroenterology, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea.
8 Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
9 Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
10 Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
# Contributed equally.