Characterization of the genomic landscape in large-scale Chinese patients with pancreatic cancer

Zhang, Xiaofei; Mao, Tiebo; Zhang, Bei; Xu, Haiyan; Cui, Jiujie; Jiao, Feng; Chen, Dongqin; Wang, Yu; Hu, Jiong; Xia, Qing; Ge, Weiting; Li, Shumin; Ming, Yue; Ma, Jingyu; Yao, Jiyong; Wang, Yongchao; Wang, Yanling; Shentu, Daiyuan; Zhang, Xiao; Chen, Shi-Qing; Bai, Yuezong; Wang, Yuexiang; Zhang, Xuebin; Liu, Qiang; Sun, Yongwei; Fu, Deliang; Liu, Yingbin; Xiong, Lei; Wang, Liwei

doi:10.1016/j.ebiom.2022.103897

Cited by 35 publications

(40 citation statements)

References 49 publications

(65 reference statements)

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“…All those results suggested that these gene mutations might not provide sufficient prognostic discrimination in PAC on their own. But after combing multiple genes, several groups ( 42 , 43 ) revealed that it is remarkably related to worse survival. Our trial did not show any significant association between four primary driver genes in tumor tissue with prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…Due to the complex genomic landscape with frequent copy number changes and point mutations, and the randomness and uncertainty of gene changes during the disease progression, ctDNA is still a controversial prognostic biomarker in pancreatic cancer ( 42 , 43 ). In addition, incongruent testing methods in research may result in different conclusions.…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of circulating tumor DNA as a prognostic biomarker for metastatic pancreatic adenocarcinoma

et al. 2022

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PurposePancreatic cancer is an aggressive solid tumor with a severe prognosis. Although tumor biomarkers are often used to identify advanced pancreatic cancer, this is not accurate, and the currently used biomarkers are not indicative of prognosis. The present study evaluated circulating tumor DNA (ctDNA) as a biomarker for prognosis prediction and disease monitoring in metastatic pancreatic adenocarcinoma (PAC).MethodsFrom 2017 to 2018, 40 patients with metastatic PAC were enrolled, and tumor tissue and blood samples were collected from 40 and 35 patients, respectively. CtDNA was sequenced by next-generation sequencing (NGS) with a 425-gene capture panel. The association of clinical characteristics, laboratory indicators, and dynamic ctDNA with patient outcomes was analyzed.ResultsMutations in KRAS (87.5%, N = 35) and TP53 (77.5%, N = 31) were most common in 40 tumor tissue. Patients’ ECOG score, CA19-9, CEA, neutrophil-lymphocyte ratio (NLR), platelet- lymphocyte ratio (PLR) levels and mutations in ≥ 3 driver genes were strongly correlated with patients’ overall survival (OS). Patients’ gender, ECOG score, CA19-9, and CEA levels were associated with progression-free survival (PFS) (P<0.05). In 35 blood samples, univariate analysis showed a significant association between ECOG score, CA19-9, KRAS or CDKN2A mutation in ctDNA and OS and between CA19-9, CDKN2A or SMAD4 mutation in ctDNA and PFS. Cox hazard proportion model showed that patients’ CDKN2A mutation in ctDNA (HR=16.1, 95% CI=4.4-59.1, P<0.001), ECOG score (HR=6.2, 95% CI=2.4-15.7, P<0.001) and tumor location (HR=0.4, 95% CI=0.1-0.9, P=0.027) were significantly associated with OS. Patients’ CDKN2A mutation in ctDNA (HR=6.8, 95% CI=2.3-19.9, P=0.001), SMAD4 mutation in ctDNA (HR=3.0, 95% CI=1.1-7.9, P=0.031) and metastatic organ (HR=0.4, 95% CI=0.2-1.0, P=0.046) were significantly associated with PFS. Longitudinal changes in gene mutation allelic frequency (MAF) value were evaluated in 24 patients. Detection of progression disease (PD) by ctDNA was 0.9 months earlier than by radiological imaging (mean PFS: 4.6m vs 5.5m, P=0.004, paired t-test).ConclusionsThe ctDNA has the potential as a specific survival predictive marker for metastatic PAC patients. Longitudinal ctDNA tracking could potentially help identify disease progression and be a valuable complement for routine clinical markers and imaging.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Evaluation of circulating tumor DNA as a prognostic biomarker for metastatic pancreatic adenocarcinoma

et al. 2022

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“…There have been several mutation profiling data of patients with pancreatic cancer in Asian populations 16 – 18 . Hong et al conducted whole-exome and RNA sequencing in 83 patients with pancreatic cancer in Korea, and they attempted to demonstrate the molecular profiles and find potential prognostic biomarkers using molecular aberrations 16 .…”

Section: Discussionmentioning

confidence: 99%

NGS-based targeted gene mutational profiles in Korean patients with pancreatic cancer

Jung

Lee

et al. 2022

Sci Rep

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According to molecular profiling studies, a considerable number of patients with pancreatic cancer harbor potentially actionable mutations. However, there are limited relevant data from the Korean population. We assessed the molecular profiles of patients with pancreatic cancer in Korea. This study collected molecular profiling data from patients with pancreatic cancer who visited Seoul National University Bundang Hospital between March 2018 and August 2020. Formalin-fixed, paraffin-embedded tumor specimens were sequenced using a targeted next-generation sequencing (NGS) platform. Cancer-associated mutations were analyzed, and potentially actionable mutations were identified. Potentially actionable mutations were classified into “highly actionable” and “modifies options” based on the Know Your Tumor registry study. In total, 87 patients with NGS tumor panel data were identified. Sixty-one patients (70.1%) had metastatic disease at the time of tissue acquisition. Tissues were obtained from the primary tumors and metastatic sites in 41 (47.1%) and 46 (52.9%) patients, respectively. At least one pathogenic mutation was reported in 86 patients (98.9%). The frequencies of four common mutations in our cohort were similar to those in The Cancer Genome Atlas data. Potentially actionable mutations were identified in 27 patients (31.0%). Of these, mutations categorized as highly actionable and modifies options were identified in 12 (13.8%) and 18 patients (20.7%), respectively. The most frequent highly actionable mutations were located in DNA damage response genes, such as BRCA1, BRCA2, or ATM (n = 6, 6.9%). Two patients with germline BRCA1 mutations received maintenance poly(adenosine diphosphate-ribose) polymerase inhibitor therapy. One patient has been receiving maintenance treatment for 18 months while remaining in radiologically complete remission. Mutational profiles using targeted NGS in Korean patients with pancreatic cancer were similar to those in Western patients. The present study supports the clinical potential and possible expanded clinical use of genetic profiling.

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“…In order to explore the underlying mechanism causing different OS between the high- and low-risk groups, three aspects including TMB, immune checkpoint and drug sensitivity were discussed. The real-world genomic characteristics of large-scale patients with pancreatic cancer showed that patients with somatic DDR gene mutations had higher TMB levels [ 23 ]. In this study, the DPRS model has the ability to distinguish high TMB and low TMB.…”

Section: Discussionmentioning

confidence: 99%

Multiple Perspectives Reveal the Role of DNA Damage Repair Genes in the Molecular Classification and Prognosis of Pancreatic Adenocarcinoma

Zhang

Peng

et al. 2022

IJMS

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Pancreatic adenocarcinoma (PAAD) is a highly heterogeneous and immunosuppressive cancer. This study investigated the diversity of DNA damage repair (DDR) and immune microenvironment in PAAD by transcriptomic and genomic analysis. Patients with PAAD were divided into two DDR-based subtypes with distinct prognosis and molecular characteristics. The differential expression genes were mostly enriched in DDR and immune-related pathways. In order to distinguish high- and low-risk groups clinically, a DDR- and immune-based 5-gene prognostic signature (termed DPRS) was established. Patients in the high-risk group had inferior prognosis, a low level of immune checkpoint gene expression and low sensitivity to DDR-associated inhibitors. Furthermore, single-cell sequencing was used to observe the performance of the DDR-based signature in a high dimension, and immunohistochemistry was used to verify the relationship between the genes we identified and the prognosis of patients with PAAD. In conclusion, the DDR heterogeneity of PAAD was demonstrated, and a novel DDR- and immune-based risk-scoring model was constructed, which indicated the feasibility of DPRS in predicting prognosis and drug response in PAAD patients.

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Characterization of the genomic landscape in large-scale Chinese patients with pancreatic cancer

Cited by 35 publications

References 49 publications

Evaluation of circulating tumor DNA as a prognostic biomarker for metastatic pancreatic adenocarcinoma

Evaluation of circulating tumor DNA as a prognostic biomarker for metastatic pancreatic adenocarcinoma

NGS-based targeted gene mutational profiles in Korean patients with pancreatic cancer

Multiple Perspectives Reveal the Role of DNA Damage Repair Genes in the Molecular Classification and Prognosis of Pancreatic Adenocarcinoma

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