Next-Generation Sequencing of a Cohort of Pulmonary Large Cell Carcinomas Reclassified by World Health Organization 2015 Criteria

Driver, Brandon; Portier, Bryce P.; Mody, Dina R.; Deavers, Michael T.; Bernicker, Eric H.; Kim, Min P.; Teh, Bin S.; Santacruz, Jose F.; Kopas, Lisa; Munden, Reginald F.; Cagle, Philip T.

doi:10.5858/arpa.2015-0361-oa

Cited by 25 publications

(22 citation statements)

References 17 publications

(28 reference statements)

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“…Recent mutational analyses of marker-null LCLC cases have suggested that genetic profiling could further reduce the marker-null group beyond IHC scoring by detection of typical adenocarcinoma or SqCC mutations, often favoring an adenocarcinoma lineage. 3,8,14,16 Although recent NGSbased studies 14,16 have reported a notably higher frequency of (especially) adenocarcinoma-linked mutations in marker-null cases than in our cohort, it may be noted that 83% of non-marker-null cases in our marker-nullenriched gene expression cluster (cluster 8) were adenocarcinoma or LCLCs according to the WHO 2004 guidelines that have been reclassified as adenocarcinoma. This observation may lend some support to a hypothesis that marker-null LCLCs represent a variant of undifferentiated TTF1-negative adenocarcinoma.…”

Section: Discussioncontrasting

confidence: 49%

“…The reclassification frequencies observed in the discovery and validation cohorts (70% and 68%, respectively) are consistent with previous studies (59%-90%). 3,14,16,[36][37][38][39][40] Our transcriptional analysis of reclassified WHO 2004 LCLC cases demonstrates that these cases have heterogeneous profiles matching different molecular subsets/GEPs of adenocarcinoma and SqCC, providing additional biological information compared to current diagnostic immunomarkers. Generally, reclassified WHO 2004 LCLCs followed the more aggressive transcriptional phenotypes, such as proximal proliferative or proximal inflammatory in adenocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…Recent sequencing studies have demonstrated differences in oncogene mutation frequencies between WHO 2004 LCLC tumors expressing adenocarcinoma or SqCC markers and marker-null cases. 3,8,14,16 On the transcriptional level, no studies have thus far resolved the heterogeneity previously suggested for the LCLC group. Importantly, only with an improved molecular understanding can patients with marker-null LCLC benefit from the growing number of targeted treatments adopted in lung cancer.…”

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confidence: 99%

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Gene Expression Profiling of Large Cell Lung Cancer Links Transcriptional Phenotypes to the New Histological WHO 2015 Classification

Karlsson

Brunnström

Micke

et al. 2017

Journal of Thoracic Oncology

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Refined classification of LCLC has implications for diagnosis, prognostics, and therapy decisions. Our molecular analyses support the WHO 2015 classification of LCLC and LCNEC tumors, which herein follow different tumorigenic paths and can accordingly be stratified into different transcriptional subgroups, thus linking diagnostic immunohistochemical staining-driven classification with the transcriptional landscape of lung cancer.

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Section: Discussioncontrasting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Gene Expression Profiling of Large Cell Lung Cancer Links Transcriptional Phenotypes to the New Histological WHO 2015 Classification

Karlsson

Brunnström

Micke

et al. 2017

Journal of Thoracic Oncology

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“…1). Similar ‘doublet’ mutations have been recorded in other genes, such as KRAS in pilocytic astrocytoma or EGFR in lung carcinoma [16,25], but the mechanistic basis of any selective advantage that ‘doublet’ FGFR1 mutations might have is unknown. No FGFR2/3 activating mutations were identified in this study cohort; FGFR2 CNAs were seen, but were rare findings in just 2% of cases.…”

Section: Discussionmentioning

confidence: 75%

Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology

et al. 2016

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Low-grade neuroepithelial tumors (LGNTs) are diverse CNS tumors presenting in children and young adults, often with a history of epilepsy. While the genetic profiles of common LGNTs, such as the pilocytic astrocytoma and ‘adult-type’ diffuse gliomas, are largely established, those of uncommon LGNTs remain to be defined. In this study, we have used massively parallel sequencing and various targeted molecular genetic approaches to study alterations in 91 LGNTs, mostly from children but including young adult patients. These tumors comprise dysembryoplastic neuroepithelial tumors (DNETs; n=22), diffuse oligodendroglial tumors (d-OTs; n=20), diffuse astrocytomas (DAs; n=17), angiocentric gliomas (n=15), and gangliogliomas (n=17). Most LGNTs (84%) analyzed by whole-genome sequencing (WGS) were characterized by a single driver genetic alteration. Alterations of FGFR1 occurred frequently in LGNTs composed of oligodendrocyte-like cells, being present in 82% of DNETs and 40% of d-OTs. In contrast, a MYB-QKI fusion characterized almost all angiocentric gliomas (87%), and MYB fusion genes were the most common genetic alteration in DAs (41%). A BRAF:p.V600E mutation was present in 35% of gangliogliomas and 18% of DAs. Pathogenic alterations in FGFR1/2/3, BRAF, or MYB/MYBL1 occurred in 78% of the series. Adult-type d-OTs with an IDH1/2 mutation occurred in four adolescents, the youngest aged 15 years at biopsy. Despite a detailed analysis, novel genetic alterations were limited to two fusion genes, EWSR1-PATZ1 and SLMAP-NTRK2, both in gangliogliomas. Alterations in BRAF, FGFR1, or MYB account for most pathogenic alterations in LGNTs, including pilocytic astrocytomas, and alignment of these genetic alterations and cytologic features across LGNTs has diagnostic implications. Additionally, therapeutic options based upon targeting the effects of these alterations are already in clinical trials.

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“…Tumors with an original diagnosis of large cell carcinoma or NSCLC, not otherwise specified, were reclassified according to 2015 World Health Organization criteria as described in a prior study. 12 Tumors that were reclassified as large cell carcinoma with null immunohistochemical phenotype were excluded from the study.…”

Section: Tissue Microarraysmentioning

confidence: 99%

Folate Receptor α Expression Level Correlates With Histologic Grade in Lung Adenocarcinoma

Driver

Barrios²,

Ge³

et al. 2015

Archives of Pathology &Amp; Laboratory Medicine

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Context.-Folate receptor a (FRA) is a glycosylphosphatidylinositol-anchored high-affinity folate receptor that localizes to the apical surface of epithelia when it is expressed in normal tissue. Unlike normal tissues, FRA may localize to the basolateral side in tumors. These features make FRA an attractive drug target, and several FRAtargeted drugs have been developed and are in phases of clinical testing. Folate receptor a protein expression shows intertumoral variability that may correlate with response to therapy and to clinicopathologic parameters. Using immunohistochemistry, a recent study of breast carcinomas found FRA protein expression was associated with triple-negative status and high histologic grade in breast cancer. Although a prior study of lung adenocarcinomas found the expression level of the gene encoding FRA, FOLR1, was significantly increased in low-histologic-grade tumors compared to high-histologic-grade tumors, the relationship between FRA protein expression and histologic grade has not been reported for lung adenocarcinomas.Objective.-To investigate the relationship between FRA protein expression level and clinicopathologic parameters in lung adenocarcinomas, including histologic grade, by performing immunohistochemistry for FRA on a cohort of non-small cell lung carcinomas.Design.-High-density tissue microarrays constructed from 188 non-small cell lung carcinomas and used in prior studies were immunostained with FRA-specific antibody clone 26B3. Folate receptor a membranous staining intensity was given a semiquantitative score from 0 to 3þ for triplicate cores of tumor and averaged for each tumor. An average semiquantitative score from 0 to 1.4 was considered low expression, and an average semiquantitative score greater than 1.4 was considered high expression. Conclusions.-Folate receptor a protein was expressed in the majority of lung adenocarcinomas and a minority of lung squamous cell carcinomas. Folate receptor a protein expression correlated with histologic grade for lung adenocarcinomas, and the greatest difference was observed between grade 1 and grade 3. Our results indicate that poorly differentiated adenocarcinomas or focuses of poor differentiation in a heterogeneous tumor may lack FRA protein expression and be more likely to be resistant to FRA-targeting drugs.

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Next-Generation Sequencing of a Cohort of Pulmonary Large Cell Carcinomas Reclassified by World Health Organization 2015 Criteria

Cited by 25 publications

References 17 publications

Gene Expression Profiling of Large Cell Lung Cancer Links Transcriptional Phenotypes to the New Histological WHO 2015 Classification

Gene Expression Profiling of Large Cell Lung Cancer Links Transcriptional Phenotypes to the New Histological WHO 2015 Classification

Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology

Folate Receptor α Expression Level Correlates With Histologic Grade in Lung Adenocarcinoma

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