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Circulating tumor DNA (ctDNA) provides a noninvasive approach to elucidate a patient’s genomic landscape and actionable information. Here, we design a ctDNA-based study of over 10,000 pan-cancer Chinese patients. Using parallel sequencing between plasma and white blood cells, 14% of plasma cell-free DNA samples contain clonal hematopoiesis (CH) variants, for which detectability increases with age. After eliminating CH variants, ctDNA is detected in 73.5% of plasma samples, with small cell lung cancer (91.1%) and prostate cancer (87.9%) showing the highest detectability. The landscape of putative driver genes revealed by ctDNA profiling is similar to that in a tissue-based database (R 2  = 0.87, p  < 0.001) but also shows some discrepancies, such as higher EGFR (44.8% versus 25.2%) and lower KRAS (6.8% versus 27.2%) frequencies in non-small cell lung cancer, and a higher TP53 frequency in hepatocellular carcinoma (53.1% versus 28.6%). Up to 41.2% of plasma samples harbor drug-sensitive alterations. These findings may be helpful for identifying therapeutic targets and combined treatment strategies. The detection of aberrations in circulating tumour DNA represents a non-invasive method to survey the oncogenes and tumour suppressors that are modified within a patient’s cancer. Here, the authors analysed more than 10,000 patients using a targeted sequencing panel and report on the frequencies of the mutations that they found.

The germline mutation landscape in Chinese lung cancer patients has not been well defined. In this study, sequencing data of 1,021 cancer genes of 1,794 Chinese lung cancer patients was analyzed. A total of 111 pathogenic or likely pathogenic germline mutations were identified, significantly higher than non-cancer individuals (111/1794 vs. 84/10,588, p < 2.2e-16). BRCA1/2 germline mutations are associated with earlier onset age (median 52.5 vs 60 years-old, p  = 0.008). Among 29 cancer disposition genes with germline mutations detected in Chinese cohort and/or TCGA lung cancer cohort, Only 11 from 29 genes are identified in both cohorts and BRCA2 mutations are significantly more common in Chinese cohort ( p  = 0.015). Chinese patients with germline mutations have different prevalence of somatic KRAS, MET exon 14 skipping and TP53 mutations compared to those without. Our findings suggest potential ethnic and etiologic differences between Western and Asian lung cancer patients. Germline variants that predispose to lung cancer have been mostly studied in Western populations, but data from Chinese patients is lacking. Here the authors analyze lung cancer germline variants in 1794 Chinese patients, finding exclusive variants or with different frequency compared to TCGA data.

Subclonal architecture and genomic evolution of small-cell lung cancer (SCLC) under treatment has not been well studied primarily due to lack of tumor specimens, particularly longitudinal samples acquired during treatment. SCLC is characterized by early hematogenous spread, which makes circulating cell-free tumor DNA (ctDNA) sequencing a promising modality for genomic profiling. Here, we perform targeted deep sequencing of 430 cancer genes on pre-treatment tumor biopsies, as well as on plasma samples collected prior to and during treatment from 22 SCLC patients. Similar subclonal architecture is observed between pre-treatment ctDNA and paired tumor DNA. Mean variant allele frequency of clonal mutations from pre-treatment ctDNA is associated with progression-free survival and overall survival. Pre- and post-treatment ctDNA mutational analysis demonstrate that mutations of DNA repair and NOTCH signaling pathways are enriched in post-treatment samples. These data suggest that ctDNA sequencing is promising to delineate genomic landscape, subclonal architecture, and genomic evolution of SCLC. Small cell lung cancer (SCLC) may evolve under treatment. But tumor tissues are often not available to study evolution of SCLC. Here, the authors utilize circulating tumor DNA to investigate the genomic evolution and subclonal architecture of SCLC during therapy.

Brain metastasis (BM) is a common malignant event in lung cancer. Here, we recruited 33 lung cancer patients with brain oligo-metastasis to explore the genomic features and tumor immune microenvironment (TIME) of the lung and BM independently. For genomic profiling, targeted sequencing was performed. We found that high-frequent ZFHX3 occurred in the lung (40%) and brain tumor (28%), which might relate to brain metastasis event; the vast majority of patients had lesions-shared mutations in primary tumor and BM, confirming the common clonal events; and EGFR was the most frequently clonal gene in both lung and BM, indicating its driver capability. To characterize TIME status, we also sequenced the T cell receptor (TCR) repertoires and performed immunohistochemistry (IHC) on CD8+ tumor-infiltrating lymphocytes (TILs) and PD-L1 expression in 28 patients who had paired samples. Through the comparison, the TCR clonality of BM was higher than lung tumor, indicating the distinct pattern of the stronger oligoclonal T cell expansion in BM; the primary tumor had a higher TMB than oligo-BM (13.9 vs 8.7 mutations, p  = 0.019); CD8 + TILs of BM were significantly lower than lung tumor (10% vs 30%, p  = 0.015), revealing the lower level of cytotoxic T cell infiltration; BM showed statistically equivalent level of PD-L1 compared with lung tumor ( p  = 0.722). We further investigated the potential biomarkers associated with overall survival (OS) after brain surgery. We found that higher TCR clonality was related to prolonged OS in EGFR-treated patients (HR 0.175, p  < 0.001) but the worse outcomes in non-EGFR-treated (HR 2.623, p  = 0.034). More CD8+ TILs were an independently positive indicator for OS, in EGFR-treated (HR 0.160, p  = 0.001) and non-EGFR-treated patients (HR 0.308, p  = 0.009). These findings provide a meaningful molecular and clinical understanding of lung carcinoma and brain oligo-metastasis.

amplification relevant to malignant biological behavior exists in solid tumors. The prevalence and utility of amplification as a biomarker for the clinical response to treatment with immune checkpoint inhibitors (ICIs) are unknown. Our study is a preliminary investigation mainly focused on the predictive function of amplification in the tumor microenvironment (TME) in the aspect of genome and transcriptome. We examined the prevalence of amplification and its potential as a biomarker for the efficacy of ICI therapy for solid tumors using a local database ( = 6,536), The Cancer Genome Atlas (TCGA) database ( = 10,606), and the Memorial Sloan Kettering Cancer Center (MSKCC) database ( = 10,109). Comprehensive profiling was performed to determine the prevalence of amplification and the correlation with the prognosis and the response to ICIs. A amplification occurs in many cancer types and correlates with shorter overall survival and inferior outcomes with ICI therapy. Transcriptomic analysis showed various degrees of immune cell exclusion, including cytotoxic cells, T cells, CD8 T cells, dendritic cells (DCs), and B cells in the TME in a TCGA amplification population. The gene set enrichment analysis suggested that amplification correlates with multiple aggressive, immunosuppressive hallmarks including epithelial-mesenchymal transition, transforming growth factor (TGF)-β signaling, KRAS signaling, phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling, p53 pathway, and hypoxia signaling in solid tumors. These findings indicate that amplification may be a key point related to immunosuppression in TME and multiple malignancy hallmarks, and it hinders not only the natural host immune responses but also the efficacy of ICIs.

Pulmonary sarcomatoid carcinoma (PSC) contains carcinomatous component (CaC) and sarcomatous component (SaC). Herein, we explored the genomic origin and intratumor heterogeneity (ITH) of PSC. We collected 31 resected PSC tumors and obtained CaC and SaC by laser capture microdissection for next-generation sequencing. The majority of PSCs (97%) had component-shared alterations. Driver mutations in EGFR , KRAS , MET , PIK3CA , and EML4-ALK fusion were mostly component-shared. Twenty-seven (87%) PSCs had component-private alterations. Compared with pure lung adenocarcinoma (LUAD), adenocarcinoma component of PSC showed lower EGFR incidence. Compared with other typical sarcomas, numerous genes of SaC exhibited significant differences. CaC and SaC had equivalent and proportional tumor mutation burden (TMB), as well as PD-L1 level. Compared with LUAD, SaC had significant higher TMB and more patients with high PD-L1 expression (tumor proportion score ≥50%). PSC with lower proportion of component-shared alterations (trunk-ratio) had a prolonged disease-free survival (DFS), regardless of the influence of clinical factors. We conclude that most PSCs originate from a monoclone accompanied by genomic ITH which is a potential independent prognostic factor, and more proportion of PSCs may be beneficial from immune checkpoint inhibitors.

Small-cell carcinoma of the esophagus (SCCE) is a rare and aggressive cancer. Although several consistent genomic changes were observed previously between SCCE and small-cell lung cancer (SCLC), detailed mutational landscapes revealing discrepancies in genetic underpinnings of tumorigenesis between these two cancers are scarce, and little attention has been paid to answer whether these genetic alterations were related to the prognosis. Herein by performing whole-exome sequencing of 48 SCCE and 64 SCLC tumor samples, respectively we have shown that the number of driver mutations in SCCE was significantly lower than in SCLC ( p  = 0.0042). In SCCE, 46% of recurrent driver mutations were clonal, which occurred at an early stage during tumorigenesis, while 16 driver mutations were found clonal in SCLC. NOTCH1/3 , PIK3CA , and ATM were specifically clonal in SCCE, while TP53 was clonal in SCLC. The total number of clonal mutations differed between two cancers and presented lower in SCCE compared to SCLC ( p  = 0.0036). Moreover, overall survival (OS) was shorter in patients with higher numbers of clonal mutations for both cancers. In summary, SCCE showed distinct mutational background and clonal architecture compared with SCLC. Organ-specific clonal events revealed different molecular mechanisms underlying tumorigenesis, tumor development, patients’ prognosis, and possible variations in therapeutic outcomes to candidate treatments.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21285-2

Gracilariopsis lemaneiformis has a high economic value and is one of the most important aquaculture species in China. Despite it is economic importance, it has remained largely unstudied at the genomic level. In this study, we conducted a genome survey of Gp. lemaneiformis using next-generation sequencing (NGS) technologies. In total, 18.70 Gb of high-quality sequence data with an estimated genome size of 97 Mb were obtained by HiSeq 2000 sequencing for Gp. lemaneiformis. These reads were assembled into 160,390 contigs with a N50 length of 3.64 kb, which were further assembled into 125,685 scaffolds with a total length of 81.17 Mb. Genome analysis predicted 3490 genes and a GC% content of 48%. The identified genes have an average transcript length of 1,429 bp, an average coding sequence size of 1,369 bp, 1.36 exons per gene, exon length of 1,008 bp, and intron length of 191 bp. From the initial assembled scaffold, transposable elements constituted 54.64% (44.35 Mb) of the genome, and 7737 simple sequence repeats (SSRs) were identified. Among these SSRs, the trinucleotide repeat type was the most abundant (up to 73.20% of total SSRs), followed by the di- (17.41%), tetra- (5.49%), hexa- (2.90%), and penta- (1.00%) nucleotide repeat type. These characteristics suggest that Gp. lemaneiformis is a model organism for genetic study. This is the first report of genome-wide characterization within this taxon.

Understanding of intratumor heterogeneity (ITH) among different non-small cell lung cancer (NSCLC) subtypes is necessary. Whether circulating tumor DNA (ctDNA) profile could represent these ITH is still an open question. We performed 181 multi-region tumor tissues sequencing and matched ctDNA sequencing from 32 operative NSCLC to compare ITH among different NSCLC subtypes, including EGFR-mutant lung adenocarcinoma (LUAD), KRAS-mutant LUAD, EGFR&KRAS-wild-type LUAD, and lung squamous cell carcinoma (LUSC), and examine potential value of ctDNA for ITH analysis. ITH is evaluated by ITH index (ITHi). If the somatic genetic alteration is shared by all the tissue regions, it is defined as trunk mutation. Otherwise, it is called branch mutation. The ITHi will be higher, if the tumor has less trunk mutations. We found EGFR-mutant LUAD showed significantly higher ITHi than KRAS-mutant LUAD/wild-type LUAD ( P  = 0.03) and numerically higher ITH than LUSC. For trunk mutations, driver mutations were identified at a higher proportion than passenger mutations (60% vs. 40%, P  = 0.0023) in overall, especially in EGFR-mutant LUAD (86% vs. 14%, P  = 0.0004), while it was opposite in KRAS-mutant LUAD (40% vs. 60%, P  = 0.18). For branch mutations, the proportions of driver mutations and passenger mutations were similar for each NSCLC subtype. ctDNA analysis showed unsatisfactory detections of tumor-derived trunk and branch mutations (43% vs. 23%, P  = 4.53e-6) among all NSCLC subtypes. In summary, EGFR-mutant LUAD has the highest ITH than other NSCLC subtypes, offering further understanding of tumorigenesis mechanisms among different NSCLC subtypes. Besides, ctDNA maybe not an appropriate method to reflect ITH.