Intertumor heterogeneity of non-small-cell lung carcinomas revealed by multiplexed mutation profiling and integrative genomics
Open accessAbstract
Non-small-cell lung cancer (NSCLC) is a heterogeneous disease, with a burden of genomic alterations exceeding most other tumors. The goal of our study was to evaluate the frequencies of co-occurring mutations and copy-number aberrations (CNAs) within the same tumor and to evaluate their potential clinical impact. Mass-spectrometry based mutation profiling using a customized lung cancer panel evaluating 214 mutations across 26 key NSCLC genes was performed on 230 nonsquamous NSCLC and integrated with genome-wide CNAs and clinical variables. Among the 138 cases having at least one mutation, one-third (41, 29.7%) showed two or more mutations, either in the same gene (double mutation) or in different genes (co-mutations). In epidermal growth factor receptor (EGFR) mutant cancers, there was a double mutation in 18% and co-mutations in the following genes: TP53 (10%), PIK3CA (8%), STK11 (6%) and MET (4%). Significant relationships were detected between EGFR mutation and 1p, 7p copy gains (harboring the EGFR gene) as well as 13q copy loss. KRAS mutation was significantly related with 1q gain and 3q loss. For Stage I, tumors harboring at least one mutation or PIK3CA mutation were significantly correlated with poor prognosis (p-value = 0.02). When combining CNAs and mutational status, patients having both KRAS mutation and the highest related CNA (3q22.3 copy loss) showed a significant poorer prognosis (p-value = 0.03). Our study highlights the clinical relevance of studying tumor complexity by integrative genomic analysis and the need for developing assays that broadly screen for both "actionable" mutations and copy-number alterations to improve precision of stratified treatment approaches.
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Targeted multiplexed hotspot panels are already developed and available in CAP-accredited academic and commercial laboratories.
“Targeted multiplexed hotspot panels (e.g., Agena Oncocarta [Agena Bioscience, San Diego, CA], 47 SNaPshot [Applied Biosystems, Foster City, CA], 48 and next-generation sequencing [NGS] panels 49,50 ) have already been developed and are available in College of American Pathologists (CAP)-accredited academic and commercial laboratories.”
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“Lipidomics is an emergent “omics” science that focuses on comprehensive analyses of lipids and their interactions in biological systems.(8,9) Several studies have validated that lipidomics is a good method to further our understanding of physiological and pathological processes.”
BackgroundA Bagged, Partially Linear, Tree-Based Regression Procedure for Prediction and Variable Selection
Mbogning, C., Perdry, H., & Broët, P. (2015) · Human Heredity · doi:10.1159/000380850 · Cited by 6 · see citing works
“The bioclinical characteristics have been described in detail in previously published articles [22, 23] .”
BackgroundRecent advances in the vibrational spectroscopic diagnosis of non-small cell lung cancer
O’Dea, D., Lyng, F. M., Nicholson, S. A., O’Connell, F., Maguire, A. A., & Malkin, A. (2019) · Vibrational Spectroscopy · doi:10.1016/j.vibspec.2019.102946 · Cited by 3 · see citing works
Twenty‐One Novel EGFR Kinase Domain variants in Patients with Nonsmall Cell Lung Cancer
Hasenahuer, M. A., Parisi, G. D., Gautier, M., Lazarowski, A., Bramuglia, G. F., & Fornasari, M. S. (2015) · Annals of Human Genetics · doi:10.1111/ahg.12127 · Cited by 2 · see citing works
“Double SASs in the same protein molecule were also analyzed, regardless of their lower frequency compared with single sequence variations (Kobayashi et al., 2013; Tan et al., 2014).”
Background[Advances in Clinical Application of Liquid Biopsy in Non-small Cell Lung Cancer].
Zhang, M., & Chen, J. (2021) · Europe PMC (PubMed Central) · doi:10.3779/j.issn.1009-3419.2021.102.33 · Cited by 2 · see citing works
Li, Y., & Li, X. (2024) · PubMed Central · doi:10.3779/j.issn.1009-3419.2024.102.16 · Cited by 1 · see citing works
“…卷第 5 期 Chin J Lung Cancer, May 2024, Vol.27, No.5 肿瘤的病理学诊断和分子分型大多依赖组织活检，而 LM 病灶相对较小且脑膜活检创伤极大，几乎没有穿刺活检的 可能。此外，癌症分子会随着时间推移而不断演变，复发 时的基因组特征与首次诊断时存在差异 [4] ，单次组织活检 提供的信息有限。液体活检相较于传统组织活检创伤小、 可重复性强，有助于动态实时追踪癌症分子 [5] 。循环肿瘤 DNA （ circulating tumor DNA, ctDNA ）是其中一个新兴热 点，且广泛应用于肺癌领域 [6] 。 ctDNA 携带遗传信息和表…”
Applications of Cytogenetics and Cytogenomics Evaluation techniques in cancer diagnosis: A review
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“With advances in deep sequencing technologies, the extent of intra-and intertumoral heterogeneity has been revealed in cancers such as glioblastoma [50], non-small cell lung cancer (NSCLC) [51], breast [53], prostate [54], and ovarian cancers [44].”
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Alifano, M. (2019) · Journal of Thoracic Disease · doi:10.21037/jtd.2019.04.53 · Cited by 1 · see citing works
“The authors suggest two possible explicative mechanisms (which are merely speculative in their study and would deserve specific studies), namely a lower socio-economic status in never smokers with obstructive pulmonary disease and an increased frequency of mutated PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase…”
BackgroundFaculty Opinions recommendation of Detection of circulating tumor DNA in patients with osteosarcoma.
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Zheng, J., Cui, T., & Li, T. (2022) · European Journal of Inflammation · doi:10.1177/1721727x221145447
“Patients (10–20%) with positive EGFR-TKI mutation develop primary resistance to EGFRTKI due to tumor heterogeneity.(32) Both the 19del mutation and the 21L858 Rmutation can lead to the dominant EGFR kinase activation state and affect its downstream activity of promoting cell survival and apoptosis.”
Background
- Authors
- Tan, D. S. W., Camilleri‐Broët, S., Tan, E. H., Alifano, M., Lim, W., Bobbio, A., Zhang, S., Ng, Q., Ang, M., Iyer, N. G., Takano, A., Lim, K. H., Régnard, J., Tan, P., & Broët, P.
- Affiliations
- National Cancer Centre Singapore (SG)
- Hôpital Européen Georges-Pompidou (FR)
- Hôpital Cochin (FR)
- National University of Singapore (SG)
- Singapore General Hospital (SG)
- Université Paris-Sud (FR)
- Corresponding author
- Broët, Philippe
- ORCID
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2014-04-03
- Volume
- 135
- Issue
- 5
- Pages
- 1092-1100
- ISSN
- 0020-7136 (ISSN-L)
- 1097-0215
- OpenAlex
- W1753952636
- Cited by
- 43
- References
- 41
- Citations by year
- 2024: 1 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 6 · 2018: 6 · 2017: 3 · 2016: 7 · 2015: 8 · 2014: 2
- FWCI
- 5.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- International Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council
- National Medical Research Council
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- non-small cell lung cancer, intratumoral heterogeneity, co-occurring mutations, copy number alterations, EGFR mutation, KRAS mutation, TP53, PIK3CA, STK11, MET, 13q loss, prognostic factors, precision oncology, integrative genomics
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Prognosis, Proto-Oncogene Proteins, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), Protein Serine-Threonine Kinases, ras Proteins, Proto-Oncogene Proteins c-met, Phosphatidylinositol 3-Kinases, Genomics, DNA Copy Number Variations, Class I Phosphatidylinositol 3-Kinases, ErbB Receptors
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