In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1700-1700
Abstract:
Background: The genomic mutation features of primary liver cancer (PLC) varied from various pathology and etiology. Alterations in DNA damage repair (DDR) genes could induce genomic instability and accumulate tumor mutation burden (TMB), which was related to the efficacy of immune-checkpoint blockade treatment. However, the characteristics of DDR gene alterations and its association with TMB in PLC remain largely undefined. Method: We enrolled 357 Chinese PLC patients as training cohort and used the TCGA-LIHC data of 373 hepatocellular cancer patients as validation cohort. FFPE tumor tissues and matched blood samples were collected from these Chinese patients for next-generation-sequencing (NGS)-based 450 genes panel assay, which contains 35 DDR genes. All histological diagnoses were confirmed by independent pathologists. Correlation of the DDR pathway genes alterations with TMB was assessed by multiple linear regression model using R package “nlme”. The receiver operating characteristic (ROC) curve was applied to determine the diagnostic efficiency of DDR pathway genes for TMB high (which was defined as the top quantile) using R package “pROC”. Results: The training cohort of Chinese PLC patients included 282 males and 75 females with the mean age of 56.3 years old. The pathologic subtypes include 214 hepatocellular carcinoma (HCC), 122 intrahepatic cholangiocarcinoma (ICC) and 21 mixed hepato-cholangiocellular carcinoma (H-ChC). There are 25.8% (92/357) patients had at least one DDR gene alteration. The DDR mutation rate showed no significant differences among three subtypes of PLC (HCC vs ICC vs H-Chc: 22.9% (49/214) vs 30.3% (37/122) vs 28.6% (6/21), P=0.311). In addition, 16.3% (15/92) of the patients with DDR gene mutations have germline variations. The TMB in HCC patients was significantly higher than that in ICC patients but not in H-ChC patients (median TMB for HCC, ICC and H-ChC was 5.4, 3.1, and 3.9 Muts/Mb, Kruskal-Wallis test, P & lt;0.001). Importantly, PLC patients with DDR gene mutations had significantly higher TMB compared to patients without DDR gene mutation (6.2 vs 3.9 Muts/Mb, P & lt;0.001), which was further validated in TCGA-LIHC data (95 vs 64 mutations, P & lt;0.001). The patients with germline DDR gene mutations had significant lower TMB compared with patients with somatic DDR gene mutations (3.1 vs 6.3 Muts/Mb, Wilcox test, P=0.041). We further defined 3 subtypes of DDR pathways (BER, FA and MMR) that significantly correlated with TMB in the training cohort, which exhibited diagnostic efficiency in distinguishing TMB-high or TMB-low PLC in TCGA-LIHC dataset (AUC: 0.67). Conclusion: DDR gene alterations were significantly positively associated with TMB in PLC. Mutations occurred in BER, FA or MMR pathways indicated higher TMB in PLC, which have the potential to serve as markers to predict the TMB level to guide the immune-checkpoint inhibitor therapy. Citation Format: Jianzhen Lin, Honglin Guo, Junping Shi, Xu Yang, Yan Jiang, Yi Bai, Junyu Long, Dongxu Wang, Jin Bian, Ming Yao, Kai Wang, Haitao Zhao. Alterations of DNA damage repair genes in Chinese primary liver cancer patients and its association with tumor mutation burden [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1700.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2019-1700
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2019
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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