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1.
Cancer Med ; 10(3): 933-943, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33350171

RESUMO

OBJECTIVES: Pancreatic cancer (PC) is one of the most lethal malignancies with an increasing death rate over the years. We performed targeted sequencing and survival analyses on 90 Chinese pancreatic cancer patients, hoping to identify genomic biomarkers associated with clinical outcomes and therapeutic options. METHOD: Genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue specimens of 90 pancreatic cancer patients and sequenced. The associations with clinicopathological factors were analyzed. RESULT: High prevalence of driver mutations in KRAS, TP53, CDKN2A, SMAD4, and ARID1A genes were found. Most mutated genes in PC belonged to cell cycle and DNA damage repair pathways. Tumors that arise from the pancreas' body and tail (BT tumors) displayed a higher ratio of mutated KRAS and TP53 than those that arise from the pancreas' head and neck (HN tumors), who showed less diverse KRAS subtypes. Patients with a KRAS p.G12R mutated tumor tended to have a prolonged disease-free survival (DFS) and overall survival (OS) than other KRAS subtypes. Those with an altered ARID1A gene and more than two mutated driver genes tended to have a shorter DFS and OS. CONCLUSION: HN and BT tumors of the pancreas displayed different mutational profiles, which had prognostic significances and indicated different potential therapeutic options.

2.
Cancer Lett ; 2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33249197

RESUMO

The gut microbiota is closely associated with colorectal neoplasia. While most metagenomics studies utilized fecal samples, circulating bacterial DNA in colorectal neoplasia patients remained unexplored. This proof-of-concept study aims to characterize alterations of circulating bacterial DNA in colorectal neoplasia patients. We performed WGS of plasma samples from 25 colorectal cancer (CRC) patients, 10 colorectal adenoma (CRA) patients and 22 healthy controls (HC). Bacterial relative abundance was measured by removing the host genome and mapping reads into bacterial genomes. By diversity analysis, we found plasma samples required less sample size to approach saturation than fecal samples, and species diversity in HC was slightly higher compared with CRC/CRA patients. The majority of circulating bacterial DNA came from bacterial genera which commonly associated with gastrointestine and oral tract. By differential analysis, a total of 127 significant species between CRC patients and HC were identified, on which basis 28 species with top predictive ability were selected and showed promise in preliminary discrimination between CRC/CRA and HC. In CRA patients, relative abundance of the selected 28 species more closely resembled those in CRC patients than HC. By comparing with fecal metagenomics studies, we found there was moderate positive correlation between fold changes of the overlapped fecal and circulating bacterial DNA. Finally, species correlation analysis revealed that CRC and HC displayed distinct patterns of species association. In conclusion, this study demonstrated alterations of circulating bacterial DNA in colorectal neoplasia patients, which had the potential to become non-invasive biomarkers for colorectal neoplasia screening and early diagnosis.

3.
Front Oncol ; 10: 1259, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32850382

RESUMO

EML4-ALK fusions are targetable oncogenic drivers in a subset of advanced non-small cell lung cancer (NSCLC) patients that can benefit from selected ALK inhibitors. Precise detection of ALK fusions may yield critical information for selection of appropriate therapy and hence improve patient survival. Analysis of circulating tumor DNA (ctDNA) in liquid biopsies using next generation sequencing (NGS) prior to or during treatment hold great promise for disease monitoring and treatment guidance of various cancers including NSCLC. Herein, we report a case of a 21-year-old advanced lung adenocarcinoma patient with a low abundance (0.03%) of EML4-ALK rearrangement identified in plasma ctDNA upon progression on two lines of chemotherapy that demonstrated long-term complete response to alectinib (>13 months) including metastatic brain tumors. Patient's clinical and pathologic characteristics, computerized tomography (CT) scans and brain magnetic resonance imaging (MRI) were reviewed retrospectively. Taken together, our report not only reinforces the translational utility of NGS-based genomic sequencing of liquid biopsy in guiding clinical practice, but also highlights the superior efficacy of alectinib than chemotherapy in ALK+ NSCLC with brain metastases, albeit at a low variant allele abundance.

4.
Jpn J Clin Oncol ; 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32845005

RESUMO

Ovarian cancer is prone to recurrence and chemotherapy resistance. Ovarian tumours of some patients have been positive for anaplastic lymphoma kinase fusion gene expression (ALK+). Preclinical studies indicate that anaplastic lymphoma kinase inhibitor can suppress the growth of ovarian cancer cells and transplantation tumours. Here, we present a patient with metastatic ALK+ high-grade serous ovarian cancer that testing positive for EML4-ALK (microtubule-associated protein-like 4 gene, fused to the anaplastic lymphoma kinase gene), experienced dramatic benefit after administration of the anaplastic lymphoma kinase inhibitor alectinib. This is the first clinical evidence that treatment with alectinib may provide a personalized maximum benefit for patients with high-grade serous ovarian cancer who are positive for EML4-ALK.

5.
BMC Genomics ; 21(1): 473, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32650715

RESUMO

BACKGROUND: Previous studies found that cell-free DNA (cfDNA) generated from tumors was shorter than that from healthy cells, and selecting short cfDNA could enrich for tumor cfDNA and improve its usage in early cancer diagnosis and treatment monitoring; however, the underlying mechanism of shortened tumor cfDNA was still unknown, which potentially limits its further clinical application. RESULTS: Using targeted sequencing of cfDNA in a large cohort of solid tumor patient, sequencing reads harboring tumor-specific somatic mutations were isolated to examine the exact size distribution of tumor cfDNA. For the majority of studied cases, 166 bp remained as the peak size of tumor cfDNA, with tumor cfDNA showing an increased proportion of short fragments (100-150 bp). Less than 1% of cfDNA samples were found to be peaked at 134/144 bp and independent of tumor cfDNA purity. Using whole-genome sequencing of cfDNA, we discovered a positive correlation between cfDNA shortening and the magnitude of chromatin inaccessibility, as measured by transcription, DNase I hypersensitivity, and histone modifications. Tumor cfDNA shortening occurred simultaneously at both 5' and 3' ends of the DNA wrapped around nucleosomes. CONCLUSIONS: Tumor cfDNA shortening exhibited two distinctive modes. Tumor cfDNA purity and chromatin inaccessibility were contributing factors but insufficient to trigger a global transition from 166 bp dominant to 134/144 bp dominant phenotype.

6.
Lung Cancer ; 146: 327-334, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32623075

RESUMO

OBJECTIVES: The application of circulating tumor DNA (ctDNA) monitoring after resection in pathologic(p) stage I lung adenocarcinoma (LUAD) patients remains controversial and it is of great clinical interest to decipher the difference of genetic features between ground-glass opacity (GGO) and solid nodules (non-GGO) subgroups. We aim to assess the utility of ctDNA in tracking early recurrence or metastasis following surgery and reveal the genetic differences between GGO and non-GGO. MATERIALS AND METHODS: Tumor tissues and matched postoperative plasma samples were collected from a total of 82 (p)stage I LUAD patients. Comprehensive genomic profiling was performed using capture-based hybrid next generation sequencing by targeting 422 cancer relevant genes. RESULTS: EGFR and TP53 represent commonly mutated genes in this cohort of (p)stage I lung adenocarcinoma, followed by alterations in ALK, PIK3CA, STK11 and MYC. For a median follow-up period of 22.83 months after surgery, 65 out of 67 ctDNA-negative patients remained progression-free, while 3 out of 15 ctDNA-positive patients progressed [P = 0.040; positive predictive value = 0.20, 95 % confidence interval (CI), 0.04-0.48; negative predictive value = 0.97, 95 % CI, 0.9-1]. With time-dependent Cox regression analysis, we observed that ctDNA positivity significantly correlated with increased probability of early tumor recurrence or metastasis (P = 0.02, HR=8.5). Further comparison between GGO and non-GGO subgroups indicated the frequency of TP53 mutations in non-GGO was markedly higher than that in GGO (47 % vs 21 %, P < 0.05). Pathway analysis showed the epigenetic regulation pathway was more frequently affected in GGO subgroup, while impaired apoptosis/cell cycle pathway was more enriched in non-GGO LUADs. CONCLUSIONS: Our longitudinal ctDNA monitoring data showed that undetectable ctDNA may predict low risk of tumor recurrence or metastasis in postoperative (p)stage I LUAD patients, while it requires further investigation on how robust the positive ctDNA results could predict tumor relapse in these patients. CLINICAL REGISTRATION NUMBER: NCT03172156.

7.
Pathol Res Pract ; 216(8): 153043, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32703503

RESUMO

Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare subtype of non-small cell lung cancer (NSCLC). There are few reported studies on the relationship between programmed death ligand-1 (PD-L1) expression and genomics features of this distinct NSCLC subtype. Our study aimed to investigate the expression levels of PD-L1 to determine their clinical value and to identify genetic alterations in PLELC. Fifty-nine PLELC patients, whose clinical information and pathology results were available, were included in this study. Immunohistochemical analysis of PD-L1 was performed in all cases. Specimens of 37 PLELCs and 3 metastatic nasopharyngeal carcinomas (NPCs) of the lung, resected within the previous 3 years, were chosen for mutation analysis, using next-generation sequencing of 425 genes. PLELC patients in the present study were mainly non-smoking females, with a high frequency of PD-L1 positivity in their tumors. Positivity rates were 96.6 %, 91.5 %, 83.1 %, and 61.0 % at tumor proportion scores (TPSs)≥ 1%, 5%, 10 %, and 50 %, respectively. Moreover, we observed that PD-L1 expression was higher in specimens stored for ≤ 3 years and in tumor cells with vesicular nucleus morphology at a TPS ≥ 50 %. Mutation analysis suggested a relatively high frequency of TP53 mutations and MCL1 copy number variation, but low tumor mutation burden (TMB) (ranging from 0 to 6.9, median of 1.1 mutation per megabase) and similarity of gene alteration with NPCs. However, no specific germline mutation was detected in PLELC patients. Additionally, survival analysis showed that patients in the early stages (stage I and II) had higher progression-free survival rates (P = 0.035) and those with tumors containing obvious stroma fibrosis tended to have worse prognosis (P =  0.008). However only stage was shown to be the independent prognostic factor (P = 0.008, HR=4.807, 95 %CI:1.508-15.323).PLELC is a subtype of lung cancer with distinct clinicopathological and genetic features, especially characterized by high PD-L1 expression and low TMB.

9.
Mol Oncol ; 14(8): 1731-1739, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32478891

RESUMO

Transmembrane domain (TMD) mutations of ERBB2 have previously been reported in lung cancer patients in addition to well-studied kinase domain (KD) mutations, which may stabilize ERBB2 heterodimerization with other EGFR family members and favor a kinase active conformation. However, the frequency and clinical significance of ERBB2 TMD mutations in Chinese population is unknown. We prospectively analyzed the next-generation sequencing data of 34 368 Chinese lung cancer patients with different sample types, including tumor tissue, plasma, cerebrospinal fluid, and pleural effusion. Patients' clinical characteristics and treatment history were retrieved from the database for further evaluation. Our findings show that ERBB2 V659/G660 mutations were detected at a frequency of 0.13% (45/34 368), of which the most frequent was V659D/E (88.9%), with a trend in nonsmokers and male. Moreover, 18% of patients (8/45) showed EGFR and/or ERBB2 amplification, whereas nine patients presented EGFR L858R or exon19 deletion. Interestingly, novel ERBB3 TMD mutation I646R was found coexisting in three patients with ERBB2 V659D and one patient with ERBB2 G660D, which might influence its heterodimerization with ERBB2 and further activate ERBB2. Four ERBB2 TMD mutation-positive patients received afatinib monotherapy or combination therapy, but showed variable responses. One patient with V659E responded well to ERBB2 inhibitor lapatinib plus capecitabine as well as subsequent afatinib treatment upon progression. Our study provides valuable insights into the distribution of ERBB2 TMD mutations by employing the largest Asian lung cancer cohort thus far. Patients with ERBB2 TMD mutations who received afatinib, a pan-ERBB inhibitor, demonstrated mixed responses, posing the urgent need to develop more effective therapeutic strategy for patients who carry ERBB2 TMD mutations.

10.
Mol Oncol ; 14(8): 1695-1704, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32412152

RESUMO

EGFR exon 20 insertions (EGFR e20ins) account for up to 10% of EGFR mutations in lung cancer; however, tumors with EGFR e20ins had poor response rates to EGFR tyrosine kinase inhibitors (TKIs) including gefitinib, erlotinib, afatinib, and osimertinib, and the heterogeneity of EGFR e20ins further complicates the clinical studies. Here, we retrospectively screened next-generation sequencing (NGS) data from 24 468 lung cancer patients, and a total of 85 unique EGFR e20ins variants were identified in 547 cases (2.24%), with p.A767_V769dup (25.1%) and p.S768_D770dup (17.6%) being the most prevalent ones. Comprehensive genomic profiling revealed that TP53 mutations frequently coexisted with p.H773dup (77.8%, P = 0.0558) and p.A767_V769dup (62.8%, P = 0.0325), while RB1 mutations usually co-occurred with p.H773_V774insAH (33.3%, P = 0.0551), implying that different EGFR e20ins variants might require distinct genomic context for tumorigenesis and/or maintenance. Despite that treatment regimens were highly diverse for EGFR e20ins-positive patients, we observed an overall response rate of 14% and a disease control rate (DCR) of 38.4% in 65 patients who received at least one EGFR TKI. The progression-free survival (PFS) differs significantly in six representative EGFR e20ins variants (P = 0.017), and EGFR p.A763_Y764insFQEA was associated with better PFS than other EGFR e20ins when treating with various EGFR TKIs. Some EGFR e20ins variants showed at least partial response to first-generation EGFR TKIs, including p.A767_V769dup, p.S768_D770dup, p.N771_H773dup, p.A763_Y764insFQEA, and p.D770_N771insG. Poziotinib achieved higher DCR for p.S768_D770dup than for p.A767_V769dup, whereas osimertinib showed limited effects for these two insertions when used as the first-line treatment. Overall, our results demonstrated that EGFR e20ins were highly diversified in terms of insertion patterns and co-occurring mutations and these EGFR e20ins variants showed different clinical responses to various EGFR TKIs, suggesting the clinical importance of selecting proper EGFR TKI treatment based on the specific EGFR e20ins type.

11.
Ann Surg Oncol ; 27(10): 3808-3818, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32239339

RESUMO

BACKGROUND: This study aimed to evaluate the feasibility of a wait-and-see strategy for non-small cell lung cancer (NSCLC) patients with special pleural dissemination lesions (r-pM1a and s-pM1a). Furthermore, the study characterized genomic alternations about disease progression. METHODS: For this study, 131 NSCLC patients with a diagnosis of pM1a were retrospectively selected. Survival differences were evaluated among patients treated with three different initial postoperative treatments: chemotherapy, targeted therapy, and wait-and-see strategy. Whole-exome sequencing (WES) was performed on primary and metastatic tumors of 10 patients with dramatic progression and 13 patients with gradual progression. RESULTS: The wait-and-see group showed better progression-free survival (PFS) than the chemotherapy group (p < 0.001) but PFS similar to that of targeted group (p = 0.984). This pattern persisted in epidermal growth factor receptor (EGFR)-positive patients. For patients with EGFR-negative/unknown status, PFS was longer in the wait-and-see group than in the two treatment groups. Furthermore, better overall survival (OS) was observed for the patients who received chemotherapy or targeted therapy after the wait-and-see strategy than for those who received chemotherapy or targeted therapy immediately. Lymph node status was an independent prognostic factor for PFS and OS. Finally, WES analysis showed that a high genomic instability index (GIS) and chromosome 18q loss were more common in metastatic tumors, and low GIS was significantly associated with better PFS (p = 0.016). CONCLUSIONS: The wait-and-see strategy could be considered for special pM1a patients without lymph nodes metastasis, and patients with a low GIS may be suitable for this strategy.

12.
Am J Transl Res ; 12(2): 612-617, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32194909

RESUMO

PARP inhibitor (PARPi) therapies have been approved for treating multiple germline BRCA mutated (gBRCAm) advanced cancers including metastatic pancreatic cancer. Although significantly prolonged progression-free survival was observed in gBRCAm pancreatic cancer patients, there was no improved overall survival. The underlined resistant mechanism to PARPi therapy is worth pursuing. Here, we reported a patient with advanced pancreatic cancer harboring a germline deleterious BRCA2 V1804Kfs mutation as well as somatic mutations in KRAS, TP53 and PTEN. Stable disease was achieved with the combination therapy of cisplatin and PARPi olaparib, but the disease quickly progressed after 18 weeks of treatment. Next-generation sequencing (NGS)-based genomic profiling of the liver metastasis and liquid biopsy revealed four newly acquired BRCA2 indel mutations, including two reversion mutations that could potentially restore BRCA2 function in the PARPi-resistant tumor. Our case showed that although initial response to PARPi therapy can be achieved in advanced gBRCAm pancreatic cancer patient, the tumor rapidly evolved to acquire multiple secondary BRCA2 mutations to restore the integrity of DNA repair and confer drug resistance, which may contribute to the unimproved overall survival in pancreatic cancer patients.

14.
J Immunother Cancer ; 8(1)2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31959728

RESUMO

BACKGROUND: Immunotherapy has become an important treatment option for patients with advanced non-small cell lung cancer (NSCLC). At present, none of these existing biomarkers can effectively stratify true responders and there is an urgent need for identifying novel biomarkers. Exosomes derived from the serum of patients with cancer have been proven to be reliable markers for cancer diagnosis. Here, we explored the possibility of using plasma-derived exosomal microRNAs as potential biomarkers for optimal selection of patients with advanced EGFR / ALK negative NSCLC to immunotherapy. METHODS: From June 2017 to February 2019, 30 patients with advanced EGFR / ALK wild-type (WT) NSCLC who received PD-1/PD-L1 inhibitors were enrolled. The efficacy evaluation was conducted after every three cycles of treatment according to RECIST 1.1. Plasma samples of these patients were collected before the administration of PD-1/PD-L1 inhibitors as baseline, and after every three cycles if the patients achieved partial response (PR) or complete response. Plasma from seven healthy individuals was also collected as normal control. Exosomes were prepared by ultracentrifugation followed by total RNA extraction, and exosome-derived miRNAs were profiled using small RNA next-generation sequencing followed by differential expression analysis. RESULTS: In order to identify biomarker for better response, all five patients who achieved PR and four patients with progressive disease (PD) at efficacy evaluation were included for differential expression analysis. Based on unsupervised hierarchical clustering, exosomal miRNA expression profile was significantly altered in patients with NSCLC compared with normal controls with a total of 155 differentially expressed exosomal miRNAs. Interestingly, hsa-miR-320d, hsa-miR-320c, and hsa-miR-320b were identified significantly upregulated in the PD groups compared with the PR group at baseline before the treatment. In addition, we identified that hsa-miR-125b-5p, a T-cell suppressor, showed a trend of increased expression in the PD group at baseline and was significantly downregulated in the post-treatment plasma exosomes compared with pre-treatment samples of the PR patients. CONCLUSION: Patients with NSCLC represent unique plasma exosomal miRNA profiles. Hsa-miR-320d, hsa-miR-320c, and hsa-miR-320b were identified as potential biomarkers for predicting the efficacy of immunotherapy in advanced NSCLCs. When T-cell suppressor hsa-miR-125b-5p was downregulated during the treatment, the patients may obtain increased T-cell function and respond well to immunotherapy.

15.
Pigment Cell Melanoma Res ; 33(4): 601-611, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31944535

RESUMO

The incidence of melanoma is rising globally including China. Comparing to Caucasians, the incidence of non-cutaneous melanomas is significantly higher in Chinese. Herein, we performed genomic profiling of 89 Chinese surgically resected primary melanomas, including acral (n = 54), cutaneous (n = 22), and mucosal (n = 13), by hybrid capture-based next-generation sequencing. We show that mucosal melanomas tended to harbor more pathogenic mutations than other types of melanoma, though the biological significance of this finding remains uncertain. Chromosomal arm-level alterations including 6q, 9p, and 10p/q loss were highly recurrent in all subtypes, but mucosal melanoma was significantly associated with increased genomic instability. Importantly, 7p gain significantly correlated with unfavorable clinical outcomes in non-cutaneous melanomas, representing an intriguing prognostic biomarker of those subtypes. Furthermore, focal amplification of 4q12 (KIT, KDR, and PDGFRα) and RAD51 deletion were more abundant in mucosal melanoma, while NOTCH2 amplification was enriched in acral melanoma. Additionally, cutaneous melanomas had higher mutation load than acral melanomas, while mucosal melanomas did not differ from other subtypes in mutation burden. Together, our data revealed important features of acral and mucosal melanomas in Chinese including distinctive driver mutation pattern and increased genomic instability. These findings highlight the possibilities of combination therapies in the clinical management of melanoma.

16.
Cancer Med ; 9(5): 1628-1637, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31851786

RESUMO

BACKGROUND: Definitive chemoradiation therapy (dCRT) is the standard treatment for patients with nonsurgical esophageal squamous cell carcinoma (ESCC), yet patients have demonstrated great variations in their responses to dCRT and inevitably progressed following treatment. METHODS: To identify prognostic biomarkers, we performed targeted next-generation sequencing of 416 cancer-related genes on primary tumors from 47 nonsurgical ESCC patients prior to dCRT treatment. The association between genetic alterations and patients' local recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS) was analyzed. RESULTS: TP53 (78% of patients), NOTCH1 (32%), ARID1A (13%), FAT1 (13%), and CDKN2A (13%) were commonly mutated in ESCC patients, while gene amplifications frequently occurred in MCL1 (36%), FGF19 (34%), MYC (32%), CCND1 (27%), ZNF217 (15%), CDKN2A (13%), and YAP1 (11%). Univariate and multivariate analyses of clinical factors and genetic alterations indicated that sex is an independent prognostic factor, with males tending to have better LRFS (hazard ratio [HR], 0.25; 95%CI, 0.08-0.77, P = .015) and progression-free survival (PFS) (HR, 0.35; 95%CI, 0.13-0.93, P = .030) following dCRT. Meanwhile, YAP1 amplification (n = 7) was an adverse prognostic factor, and patients with this alteration demonstrated a tendency toward worse outcomes with shorter LRFS (HR, 4.06; 95%CI, 1.26-13.14, P = .019) and OS (HR, 2.78; 95%CI, 0.95-8.17, P = .062). In a subgroup analysis, while sex and M-stage were controlled, a much stronger negative effect of YAP1 amplification vs wild-type in LRFS was observed (log-rank P = .0067). CONCLUSION: The results suggested that YAP1 amplification is a potentially useful biomarker for predicting treatment outcomes and identifying patients with a high risk of relapse who should be closely monitored.

17.
Mol Genet Genomic Med ; 8(2): e1079, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31867841

RESUMO

BACKGROUND: One of the major challenges in managing invasive breast cancer (BC) is the lack of reliable biomarkers to track response. Circulating tumor DNA (ctDNA) from liquid biopsy, as a candidate biomarker, provides a valuable assessment of BC patients. In this retrospective study, we evaluated the utility of ctDNA to reflect the efficacy of treatment and to monitor resistance mechanisms. METHODS: Targeted next-generation sequencing (NGS) of 416 cancer-relevant genes was performed on 41 plasma biopsy samples of 19 HER2+ and 12 HER2- BC patients. Longitudinal ctDNA samples were analyzed in three BC patients over the treatment course for detecting acquired mutations. RESULTS: In HER2+ BC patients, ERBB2 somatic copy numbers in ctDNA samples were significantly higher in patients progressed on HER2-targeted therapy than those who were still responding to the treatment. Recurrent acquired mutations were detected in genes including ERBB2, TP53, EGFR, NF1, and SETD2, which may contribute to trastuzumab resistance. In longitudinal analyses, the observed mutation allele frequencies were tracked closely in concordance with treatment responses. A novel ERBB2 p.(Leu869Arg) mutation was acquired in one patient upon resistant to trastuzumab therapy, which was further validated as an oncogenic mutation in vitro and contributed to resistance. In HER2- BC patients with chemotherapy resistance, genetic alterations on TP53, PIK3CA, and DNA damage repair genes were frequently observed. CONCLUSIONS: In summary, ctDNA monitoring, particularly longitudinal analyses, provides valuable insights into the assessment of targeted therapy efficacy and gene alterations underlying trastuzumab resistance and chemotherapy resistance in HER2+ and HER2- BC patients, respectively.

18.
Oncogene ; 39(9): 1846-1859, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31754213

RESUMO

EGFR-mutant non-small-cell lung cancer (NSCLC) patients inevitably develop drug resistance when treated with EGFR tyrosine kinase inhibitors (TKIs). Systematic genetic analysis is important to understand drug-resistant mechanisms; however, the clinical significance of co-occurring genetic alterations at baseline, co-acquired mutations at progressive disease (PD), and the clonal evolution remain underinvestigated. We performed targeted sequencing of pre-treatment and PD tumor samples from 54 EGFR-mutant NSCLC patients. Ten additional patients were sequenced using whole-exome sequencing to infer the clonal evolution patterns. We observed a domain-dependent effect of PIK3CA mutation at baseline on patient progression-free survival (PFS). In addition, at baseline, 9q34.3/19p13.3 (NOTCH1/STK11/GNA11) showed a co-deletion pattern, which was associated with a significantly worse PFS (p = 0.00079). T790M-postive patients with other concurrent acquired oncogenic mutations had a significantly shorter PFS (p = 0.005). Besides acquired T790M mutation, chromosomal instability (CIN) related genes, including AURKA and TP53 alterations, were the most frequently acquired events. CIN significantly increased during TKI treatment in T790M-negative patients and is a candidate resistance mechanism to the first-generation TKIs. Clonal evolution analyses suggest that the composition and relationship among resistant subclones, particularly relationship with T790M subclone, affect patients' outcomes. Overall, our findings of novel co-occurring alterations and clonal evolution patterns can be served as predictive biomarkers to stratify patients and help to better understand the drug-resistant mechanism to TKIs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Resistencia a Medicamentos Antineoplásicos/genética , Evolução Molecular , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Feminino , Seguimentos , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Sequenciamento Completo do Exoma
19.
Clin Lung Cancer ; 21(3): 247-254, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31761448

RESUMO

BACKGROUND: Neurotrophin receptor kinase (NTRK) gene fusions (NTRK+) are rare but actionable oncogenic drivers present in a wide variety of solid tumors. However, the clinicopathologic characteristics of NTRK1 fusion-positive non-small-cell lung cancer are largely unknown. MATERIALS AND METHODS: Lung cancer tissue specimens and/or circulating cell-free DNA from patients with lung cancer who had undergone molecular profiling at a Clinical Laboratory Improvement Amendments (CLIA)-certified genomics laboratory in China were retrospectively reviewed. The laboratory performed NTRK1 fusion detection using hybridization-based targeted next-generation sequencing. The patients' clinical characteristics and treatment history were retrieved from the database for further evaluation. RESULTS: A total of 21,155 Chinese lung cancer cases had undergone molecular profiling from April 2016 to March 2019, including 13,630 adenocarcinoma cases. Of these cases, 12 were positive for NTRK1 fusion, including 10 cases of adenocarcinoma (0.073%), 1 primary sarcomatoid carcinoma, and 1 with an unknown histologic classification. Seven fusion partners (CD74, interferon regulatory factor 2 binding protein 2 [IRF2BP2], lamin A/C [LMNA], PHD finger protein 20 [PHF20], sequestosome 1 [SQSTM1], tropomyosin 3 [TPM3], TPR) were identified. Additionally, 1 unique rearrangement occurred upstream of the transcription start site of BCL9 fused to exon 12 of NTRK1 (intragenic region, BCL9-NTRK1). Of the 12 cases of NTRK1+ lung cancer, 6 had had concurrent activating EGFR mutations and/or had received previous treatment with EGFR tyrosine kinase inhibitors (TKIs), with 2 having concurrent EGFR T790M and 1 additional EGFR C797S. CONCLUSIONS: NTRK1+ lung cancer cases are extremely rare with multiple fusion partners. Additionally, emergence of NTRK1+ fusion might act as a resistance mechanism to EGFR TKIs. When performing comprehensive analysis of acquired resistance to EGFR TKIs, the ability to detect NTRK1 fusions will be important.

20.
Cancer Lett ; 472: 108-118, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31837443

RESUMO

Despite the common application and considerable efforts to achieve precision radiotherapy (RT) in several types of cancer, RT has not yet entered the era of precision medicine; the ability to predict radiosensitivity and treatment responses in tumors and normal tissues is lacking. Therefore, development of genome-based methods for individual prognosis in radiation oncology is urgently required. Traditional DNA sequencing requires tissue samples collected during invasive operations; therefore, repeated tests are nearly impossible. Intra- and inter-tumoral heterogeneity may undermine the predictive power of a single assay from tumor samples. In contrast, analysis of circulating tumor DNA (ctDNA) allows for non-invasive and near real-time sampling of tumors. By investigating the genetic composition of tumors and monitoring dynamic changes during treatment, ctDNA analysis may potentially be clinically valuable in prediction of treatment responses prior to RT, surveillance of responses during RT, and evaluation of residual disease following RT. As a biomarker for RT response, ctDNA profiling may guide personalized treatments. In this review, we will discuss approaches of tissue DNA sequencing and ctDNA detection and summarize their clinical applications in both traditional RT and in combination with immunotherapy.


Assuntos
Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/sangue , Genômica , Neoplasias/radioterapia , Biomarcadores Tumorais/efeitos da radiação , Proliferação de Células/efeitos da radiação , DNA Tumoral Circulante/efeitos da radiação , Testes Diagnósticos de Rotina , Intervalo Livre de Doença , Feminino , Genoma Humano/efeitos da radiação , Humanos , Masculino , Neoplasia Residual/sangue , Neoplasia Residual/patologia , Neoplasia Residual/radioterapia , Neoplasias/sangue , Neoplasias/patologia , Medicina de Precisão , Prognóstico , Resultado do Tratamento
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