Mutational Profile Evaluates Response and Survival to First‐Line Chemotherapy in Lung Cancer

He, Yayi; Song, Lele; Wang, Hao; Chen, Peixin; Liu, Yu; Sun, Hui; Li, Xiaobin; Dang, Shiying; Liu, Xinyi; Chen, Shifu; Zhang, Xiaoni; Hofman, Paul; Uchino, Junichi; Park, Henry S.; Pacheco, Jose M.; Tabbò, Fabrizio; Xu, Mingyan; Dai, Jing; He, Kan; Yang, Yang; Zhou, Caicun

doi:10.1002/advs.202003263

Cited by 14 publications

(10 citation statements)

References 21 publications

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“…After that, samples from 122 qualifying advanced lung cancer patients were eligible, including 86 NSCLC and 36 SCLC participants ( Table S1 ). Tumor specimens and blood samples were collected as we previously described ( 21 ).…”

Section: Methodsmentioning

confidence: 99%

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DNA Damage Response and Repair Gene Alterations Increase Tumor Mutational Burden and Promote Poor Prognosis of Advanced Lung Cancer

Dai

Jiang

et al. 2021

Front. Oncol.

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DNA damage response and repair (DDR) gene alterations increase tumor-infiltrating lymphocytes, genomic instability, and tumor mutational burden (TMB). Whether DDR-related alterations relate to therapeutic response and prognosis in lung cancer lacking oncogenic drivers remains unknown. Pretherapeutic cancer samples of 122 patients [86 non-small cell lung cancer and 36 small cell lung cancer (SCLC)] harboring no EGFR/ALK alterations were collected. Through whole-exome sequencing, we outlined DDR mutational landscape and determined relationships between DDR gene alterations and TMB or intratumoral heterogeneity. Then, we evaluated the impacts of DDR gene alterations on therapeutic response and prognosis and established a DDR-based model for prognosis prediction. In addition, we investigated somatic interactions of DDR genes and immunomodulatory genes, immune expression patterns, immune microenvironment, and immune infiltration characteristics between DDR-deficient and DDR-proficient samples. Samples from cBioportal datasets were utilized for verification. We found that deleterious DDR gene alterations were closely associated with higher TMB than proficient-types (p < 0.001). DDR mechanisms attach great importance to the determination of patients’ prognosis after chemotherapy, and alterations of base excision repair pathway in adenocarcinoma, nucleotide excision repair in squamous carcinoma, and homologous recombination pathway in SCLC tend to associate with worse progression-free survival to first-line chemotherapy (all p < 0.05). A predictive nomogram model was constructed incorporating DDR-related alterations, clinical stage, and smoking status, with the area under curve values of 0.692–0.789 for 1- and 2-year receiver operating characteristic curves in training and testing cohorts. Furthermore, DDR-altered tumors contained enhanced frequencies of alterations in various genes of human leukocyte antigen (HLA) class I pathway including TAP1 and TAP2 than DDR-proficient samples. DDR-deficient types had lower expressions of STING1 (p = 0.01), CD28 (p = 0.020), HLA-DRB6 (p = 0.014) in adenocarcinoma, lower TNFRSF4 (p = 0.017), and TGFB1 expressions (p = 0.033) in squamous carcinoma, and higher CD40 (p = 0.012) and TNFRSF14 expressions (p = 0.022) in SCLC. DDR alteration enhanced activated mast cells in adenocarcinoma (p = 0.044) and M2 macrophage in squamous carcinoma (p = 0.004) than DDR-proficient types. Collectively, DDR gene alterations in lung cancer without oncogenic drivers are positively associated with high TMB. Specific DDR gene alterations tend to associate with worse progression-free survival to initial chemotherapy.

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Section: Methodsmentioning

confidence: 99%

“…Tissue DNA or RNA was extracted based on the manufacturer’s protocol, and reversed transcript would be performed for extracted RNA for subsequent PCR amplification. EGFR mutations and EML4-ALK fusion were detected as described ( 21 ).…”

Section: Methodsmentioning

confidence: 99%

DNA Damage Response and Repair Gene Alterations Increase Tumor Mutational Burden and Promote Poor Prognosis of Advanced Lung Cancer

Dai

Jiang

et al. 2021

Front. Oncol.

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“…For DNA extraction and quantification, we used QIAamp DNA Tissue Kit (Qiagen, Valencia, USA), RelaxGene Blood DNA system (Tiangen, Beijing, China), Fluorometer (Qubit 2.0), and the Qubit dsDNA HS assay kit (Thermo Fisher Scientific, CA, USA). Once we obtained fragmented genomic DNA by particular instrument and reagents ( 28 , 29 ), we constructed DNA library by Kapa Biossystems (MA, USA). Then, fragments with poor quality were excluded, while remaining reads were amplified by a certain circulation of polymerase chain reaction.…”

Section: Methodsmentioning

confidence: 99%

“…With the help of Genome Analysis ToolKit (V 4.1) and Mutect2, DNA fragments were aligned to hg19 reference genome (GRch37), thus detecting somatic mutation, single nucleotide variants, and insertion-deletion mutations. Eventually, according to conventional formula for TMB calculation ( 28 ), the somatic TMB value of each case was obtained.…”

Section: Methodsmentioning

confidence: 99%

Immune Checkpoints OX40 and OX40L in Small-Cell Lung Cancer: Predict Prognosis and Modulate Immune Microenvironment

et al. 2021

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BackgroundOX40 and OX40 ligand (OX40L), as essential immune checkpoint (IC) modulators, are highly correlated with cancer immunity regulation as well as tumor microenvironment (TME). Immunotherapy showed outstanding advantages in small-cell lung cancer (SCLC) therapy. However, functions and clinical significance of OX40 and OX40L in SCLC were not clear yet.Materials and MethodsSCLC samples of 143 patients were collected for immunohistochemistry (IHC) or whole-exome sequencing (WES). We comprehensively explored the expression and mutation of OX40/OX40L in SCLC, and systematically linked OX40/OX40L with TME.ResultsThe expression of OX40/OX40L on tumor cells and tumor-infiltrating lymphocytes (TILs) was found in the IHC cohort and verified in other cohorts with SCLC tissues and cell lines. The results showed co-expression patterns among OX40/OX40L, other ICs, and T-cell markers. The WES data suggested that OX40/OX40L mutation is rare in SCLC (<5%). Patients with positive OX40 protein expression on TILs showed substantially higher recurrence-free survival than those with negative expression (p=0.009). The external dataset also indicated that high OX40/OX40L expression was correlated with better prognosis [overall survival: OX40, p<0.001; OX40L, p=0.019]. Importantly, activation of immunity and high infiltration of CD4(+) and CD8(+) T cells were observed in the high OX40/OX40L expression group.ConclusionsCollectively, this work highlighted the significance of OX40 and OX40L in prognosis and TME cell infiltration characterization of SCLC. Evaluating the OX40/OX40L-expression levels of individual patients with SCLC might contribute to guiding more precise therapy.

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“…The therapeutic response and survival of lung cancer patients without EGFR or anaplastic lymphoma kinase (ALK) driver gene alterations receiving first-line chemotherapy are difficult to predict. Recently, He et al [9] showed that molecular signatures could only provide limited information. In this study, NSCLC patients were classified into four subtypes based on genomic alteration characteristics, however, no survival difference between the subtypes were observed.…”

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confidence: 99%

Clinical characteristics and outcomes of Chinese patients with KRAS‐mutant non‐small cell lung cancer after chemotherapy

Lai

Zhao

et al. 2021

Cancer Communications

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Dear Editor,The RAS gene is one of the most frequent oncogenes in human cancers, with significantly different mutation frequencies. The RAS family contains three isoforms: KRAS, HRAS and NRAS, with the KRAS mutations being more common than the other two. The KRAS mutation rate varies in non-small cell lung cancer (NSCLC) patients of different races: 27% in Caucasians [1] and approximately 10% in Asians [2,3]. Recently, the U.S. Food and Drug Administration (FDA) approved sotorasib (AMG510) and adagrasib (MRTX849) for the treatment of metastatic NSCLC harboring KRAS G12C mutations. In the face of novel treatment choices for KRAS-mutated NSCLC, it is indispensable to learn more about the systemic treatment of these patients. Clinical studies have shown that Caucasian patients with KRAS-mutated NSCLC had poor outcomes following first-line chemotherapy [4,5]. However, studies on treatment outcomes of Asian patients with KRAS-mutated NSCLC are lacking. As the overwhelming majority of cases are diagnosed with lung adenocarcinoma, the standard first-line treatment for metastatic disease is pemetrexed-based doublet chemotherapy in combination with bevacizumab and/or immunotherapy in China. Herein, we investigated the clinical characteristics of KRAS mutation subtypes, co-occurring genomic alterations, and efficacy of first-line pemetrexed-platinum chemotherapy in Chinese KRAS-mutated NSCLC patients.The data of 5180 patients with NSCLC (either de novo or relapsed) who underwent genetic testing at Shandong Cancer Hospital between

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Mutational Profile Evaluates Response and Survival to First‐Line Chemotherapy in Lung Cancer

Cited by 14 publications

References 21 publications

DNA Damage Response and Repair Gene Alterations Increase Tumor Mutational Burden and Promote Poor Prognosis of Advanced Lung Cancer

DNA Damage Response and Repair Gene Alterations Increase Tumor Mutational Burden and Promote Poor Prognosis of Advanced Lung Cancer

Immune Checkpoints OX40 and OX40L in Small-Cell Lung Cancer: Predict Prognosis and Modulate Immune Microenvironment

Clinical characteristics and outcomes of Chinese patients with KRAS‐mutant non‐small cell lung cancer after chemotherapy

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