Genomic and evolutionary classification of lung cancer in never smokers

Zhang, Tongwu; Joubert, Philippe; Ansari-Pour, Naser; Zhao, Wei; Hoang, Phuc H.; Lokanga, Rachel; Moye, Aaron L.; Rosenbaum, Jennifer; González-Pérez, Abel; Martínez-Jiménez, Francisco; Castro, Andrea; Muscarella, Lucia Anna; Hofman, Paul L.; Consonni, Dario; Pesatori, Angela Cecilia; Kebede, Michael; Li, Mengying; Rothberg, Bonnie E. Gould; Peneva, Iliana; Schabath, Matthew B.; Poeta, Maria Luana; Costantini, Manuela; Hirsch, Daniela; Heselmeyer‐Haddad, Kerstin; Hutchinson, Amy; Olanich, Mary E.; Lawrence, Scott M.; Lenz, Petra H.; Duggan, Máire A.; Bhawsar, Praphulla; Sang, Jian; Kim, Jung; Mendoza, Laura; Saini, Natalie; Klimczak, Leszek J.; Islam, S. M. Ashiqul; Otlu, Burçak; Khandekar, Azhar; Cole, Nathan; Stewart, Douglas R.; Choi, Jiyeon; Brown, Kevin M.; Caporaso, Neil E.; Wilson, S.H.; Pommier, ﻿Yves; Lan, Qing; Rothman, Nathaniel; Almeida, Jonas S.; Carter, Hannah; Ried, Thomas; Kim, Carla F.; López‐Bigas, Núria; García-Closas, Montserrat; Shi, Jianxin; Bossé, Yohan; Zhu, Bin; Gordenin, Dmitry A.; Alexandrov, Ludmil B.; Chanock, Stephen J.; Wedge, David C.; Landi, Maria Teresa

doi:10.1038/s41588-021-00920-0

Cited by 123 publications

(116 citation statements)

References 108 publications

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“…The 61 undifferentiated sarcomas 44 and 187 high-confidence oesophageal squamous cell carcinomas 46 were downloaded from the European Genome-phenome Archive (EGAD00001004162 and EGAD00001006868, respectively). The 280 lung adenocarcinomas 45 were downloaded from dbGaP under the accession number (phs001697.v1.p1). Clustered mutations in validation samples were analysed using the same approach as the one used in the original cohort.…”

Section: Methodsmentioning

confidence: 99%

“…Kyklonic events were further investigated across 3 additional independent cohorts, including 61 sarcomas 44 , 280 lung cancers 45 and 186 oesophageal squamous cell carcinomas 46 . Comparable rates of clustered mutagenesis were found for both substitutions and indels to the rates reported in PCAWG, with a 2.4- and 5.0-fold enrichment of clustered substitutions and indels within driver events, respectively (Extended Data Fig.…”

Section: Mainmentioning

confidence: 99%

“…Genomics data for clonally expanded cell lines were downloaded from the European Genome-phenome Archive (EGAD00001004201, EGAD00001004203 and EGAD00001004583). For the three validation cohorts, datasets were downloaded as submitted by the original publications and genomics data were downloaded from their respective repositories: EGAD00001004162 for 61 undifferentiated sarcomas 44 (European Genome-phenome Archive); EGAD00001006868 for 187 high-confidence oesophageal squamous cell carcinomas 46 (European Genome-phenome Archive); and phs001697.v1.p1 for 280 lung adenocarcinomas 45 (dbGaP). Somatic mutations and metadata for the MSK-IMPACT Clinical Sequencing Cohort composed of 10,000 clinical cases 42 were downloaded from cBioPortal ( https://www.cbioportal.org/study/summary?id=msk_impact_2017 ).…”

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confidence: 99%

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Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA

Bergstrom

Luebeck

Petljak

et al. 2022

Nature

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105

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Clustered somatic mutations are common in cancer genomes and previous analyses reveal several types of clustered single-base substitutions, which include doublet- and multi-base substitutions1–5, diffuse hypermutation termed omikli6, and longer strand-coordinated events termed kataegis3,7–9. Here we provide a comprehensive characterization of clustered substitutions and clustered small insertions and deletions (indels) across 2,583 whole-genome-sequenced cancers from 30 types of cancer10. Clustered mutations were highly enriched in driver genes and associated with differential gene expression and changes in overall survival. Several distinct mutational processes gave rise to clustered indels, including signatures that were enriched in tobacco smokers and homologous-recombination-deficient cancers. Doublet-base substitutions were caused by at least 12 mutational processes, whereas most multi-base substitutions were generated by either tobacco smoking or exposure to ultraviolet light. Omikli events, which have previously been attributed to APOBEC3 activity6, accounted for a large proportion of clustered substitutions; however, only 16.2% of omikli matched APOBEC3 patterns. Kataegis was generated by multiple mutational processes, and 76.1% of all kataegic events exhibited mutational patterns that are associated with the activation-induced deaminase (AID) and APOBEC3 family of deaminases. Co-occurrence of APOBEC3 kataegis and extrachromosomal DNA (ecDNA), termed kyklonas (Greek for cyclone), was found in 31% of samples with ecDNA. Multiple distinct kyklonic events were observed on most mutated ecDNA. ecDNA containing known cancer genes exhibited both positive selection and kyklonic hypermutation. Our results reveal the diversity of clustered mutational processes in human cancer and the role of APOBEC3 in recurrently mutating and fuelling the evolution of ecDNA.

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Section: Methodsmentioning

confidence: 99%

Section: Mainmentioning

confidence: 99%

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confidence: 99%

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Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA

Bergstrom

Luebeck

Petljak

et al. 2022

Nature

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105

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show abstract

“…Previous research revealed that mutations in TP53 lead to genetic instability and result in focal high‐amplitude amplifications that occur late during the evolution of lung cancer. 34 Zhang et al 35 also reported that EGFR copy number gains occurred relatively late compared with EGFR mutation and TP53 mutation in molecular time scale. In our search, the presence of EGFR amplification was correlated with TP53 mutation in both two cohorts, which indicated EGFR amplification arise relatively late and toward the end of the evolution of EGFR ‐mutated adenocarcinoma, resulting in aggressive pathological characteristics (e.g., high‐grade‐component predominance and lymphatic metastases).…”

Section: Discussionmentioning

confidence: 97%

The clinicopathological and molecular characteristics of resected EGFR‐mutant lung adenocarcinoma

et al. 2022

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Background Epidermal growth factor receptor (EGFR) mutations were frequently found with concomitant genetic alterations in lung adenocarcinoma (LUAD). This study aimed to investigate the profile of concomitant alterations of EGFR‐mutant LUAD ≤3 cm in size and its prognostic effect on recurrence. Methods From January 2018 to December 2018, patients with resected LUAD ≤3 cm in size in Shanghai Chest Hospital were identified. All patients underwent capture‐based targeted next‐generation sequencing (NGS) with a panel of 68 lung cancer‐related genes and were found with EGFR mutation. Clinicopathological and molecular characteristics and recurrence‐free survival (RFS) were analyzed. Results A total of 637 patients were enrolled in this study. The top three frequent co‐mutational genes were TP53 (179 of 637, 28.1%), PIK3CA (27 of 637, 4.2%), and ATM (22 of 637, 3.5%). The most common amplified genes were EGFR (37 of 637, 5.8%), followed by CDK4 (37 of 637, 5.8%) and MYC (12 of 637, 2.0%). Only TP53 mutation and EGFR amplification were adverse prognostic factors for RFS (all p < 0.001) in univariate analysis. Multivariable analysis further demonstrated that TP53 mutation and EGFR amplification were independent risk factors for RFS [(hazard ratio (HR) 2.07, 95% confidence interval (CI) 1.07–4.00, p = 0.030; HR 3.09, 95% CI 1.49–6.40, p = 0.002, respectively]. Conclusions Concomitant TP53 mutation and EGFR amplification were poor prognostic factors for RFS in patients with EGFR‐mutant resected LUAD. Our findings provide valuable understanding of the impact of concurrent alterations and implication for better implementation of precision therapy for patients.

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“…Although smoking is a well-known risk factor associated with lung cancer, 10–25% of people who develop lung cancer are never-smokers and its cause cannot be definitively associated with environmental risk factors such as exposure to secondhand tobacco smoke, radon, air pollution, and asbestos, or with having had lung disease previously or an inherited genetic susceptibility [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Understanding the lived experience of lung cancer: a European social media listening study

et al. 2022

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Background Social media platforms are increasingly being used by stakeholders to generate, access, and share health-related information and experiences. Lung cancer is the most common cancer, impacting > 2 million patients globally. This observational study utilized a social listening approach to analyze social media trends and gain insights into stakeholder perceptions of lung cancer. Methods This social media study retrospectively collated data from open access blogs, forums, and social networking sites. Social media posts were collected between June 2019–May 2020 from 14 European countries. Using social media aggregator tools, posts comprising lung cancer and non-small cell lung cancer-specific terms were extracted. Manual and automated relevancy algorithms filtered the extracted information to provide the relevant dataset. This contextualized dataset was further mined to generate the final data for analysis. Results Of 1360 conversations analyzed, 42% were generated by patients/caregivers and 14% by healthcare professionals (HCPs). A majority of patients were 51–70 years old (approximately 50%) and 91% (n = 500/550) had late-stage cancer. Treatment (35%) and disease awareness (30%) were among the most discussed topic of the patient journey. Although the overall treatment sentiment was neutral, chemotherapy was the treatment type with the highest associated negative sentiment (28%); fewer negative sentiments were associated with immunotherapy (9%) and targeted therapy (2%), due to perceptions of longer survival outcomes and fewer side effects. In conversations that discussed clinical endpoints, “survivability” and “overall survival” (47 and 30%, respectively; n = 539) were most frequently mentioned by stakeholders. HCPs mostly used technical terms, whereas patients and caregivers used colloquial terms such as “getting rid of cancer”. Emotional wellness was identified to have a huge impact on quality of life in lung cancer. Delay or treatment cancellations due to COVID-19, lack of effective treatments and funding, and lack of empathy by physicians emerged as the key unmet needs among patients/caregivers. Conclusions Social listening proved to be an effective tool to explore stakeholders’ perceptions and their key unmet needs, typically not available in published literature or databases, and provides HCPs with valuable insights into the distress, doubts, and needs of lung cancer patients and caregivers.

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Genomic and evolutionary classification of lung cancer in never smokers

Cited by 123 publications

References 108 publications

Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA

Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA

The clinicopathological and molecular characteristics of resected EGFR‐mutant lung adenocarcinoma

Understanding the lived experience of lung cancer: a European social media listening study

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