Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer

Peifer, Martin; Fernández-Cuesta, Lynnette; Sos, Martin L.; George, Julie; Seidel, Danila; Kasper, Lawryn H.; Plenker, Dennis; Leenders, Frauke; Sun, Ruping; Zander, Thomas; Menon, Roopika; Koker, Mirjam; Dahmen, Ilona; Müller, Christian; Cerbo, Vincenzo Di; Schildhaus, Hans Ulrich; Altmüller, Janine; Baessmann, Ingelore; Becker, Christian; Wilde, Bram De; Vandesompele, Jo; Böhm, Diana; Ansén, Sascha; Gabler, Franziska; Wilkening, Ines; Heynck, Stefanie; Heuckmann, Johannes M.; Lü, Xin; Carter, Scott L.; Cibulskis, Kristian; Banerji, Shantanu; Getz, Gad; Park, Kwon Sik; Rauh, Daniel; Grütter, Christian; Fischer, Matthias; Pasqualucci, Laura; Wright, Gavin; Wainer, Zoe; Russell, Prudence A.; Petersen, Iver; Chen, Yuan; Stoelben, Erich; Ludwig, Corinna; Schnabel, Philipp A.; Hoffmann, Hans; Muley, Thomas; Brockmann, Michael; Engel-Riedel, Walburga; Muscarella, Lucia Anna; Fazio, Vito Michele; Groen, Harry J.M.; Timens, Wim; Sietsma, Hannie; Thunnissen, Erik; Smit, Egbert F.; Heideman, Daniëlle A.M.; Snijders, Peter J.F.; Cappuzzo, Federico; Ligorio, Claudia; Damiani, Stefania; Field, John K.; Solberg, Steinar; Brustugun, Odd Terje; Lund‐Iversen, Marius; Sänger, Jörg; Clement, Joachim H.; Soltermann, Alex; Moch, Holger; Weder, Walter; Solomon, Benjamin; Soria, Jean Charles; Validire, Pierre; Besse, Benjamin; Brambilla, Élisabeth; Brambilla, Christian; Lantuéjoul, Sylvie; Lorimier, Philippe; Schneider, P. M.; Hallek, Michael; Pao, William; Meyerson, Matthew; Sage, Julien; Shendure, Jay; Schneider, Robert; Büttner, Reinhard; Wolf, Jürgen; Nürnberg, Peter; Perner, Sven; Heukamp, Lukas C.; Brindle, Paul K.; Haas, Stefan A.; Thomas, Roman K.

doi:10.1038/ng.2396

Cited by 1,164 publications

(1,071 citation statements)

References 85 publications

(70 reference statements)

Supporting

Mentioning

1,018

Contrasting

Unclassified

Order By: Relevance

“…2 In this context, our group systematically analyzed a large cohort of lung cancer specimens by conduction of 6.0 single-nucleotide polymorphism array analysis, exome sequencing, transcriptome sequencing and genome sequencing and identified pathogenetically relevant mutated genes. 7 In this report, we provide evidence for amplification of the FGFR1 (fibroblast growth factor receptor 1) tyrosine kinase gene in SCLC.…”

mentioning

confidence: 64%

“…The percentage is very close to data observed in a cohort analyzed by singlenucleotide polymorphism 6.0 by us (3/51, frequency 6%). 7 We identified patterns of FGFR1 gene copy numbers that appear different from other genes. Importantly, the distribution of FGFR1 copies in small-cell carcinoma is also different from the FGFR1 pattern in other tumor entities and turned out to be homogeneous in all analyzed SCLCs.…”

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential therapeutic target in small-cell lung cancer

et al. 2014

Self Cite

View full text Add to dashboard Cite

Small-cell lung cancer (SCLC) comprises about 13-15% of all lung cancers, and more than 29 400 new cases have been diagnosed in the United States in the year 2012. SCLC is a biologically complex tumor typically occurring in heavy smokers. Its medical treatment has almost remained unchanged over the last decades and selected treatment options have not been established so far, mainly due to the lack of targetable genetic alterations. In this study we analyzed a cohort of 307 SCLC samples for fibroblast growth factor receptor 1 (FGFR1) amplification using a dual color FISH probe. FGFR1 status was correlated with clinical data. FGFR1 amplifications were observed in 5.6% of evaluable pulmonary SCLCs. Most of them (93%) fulfilled the criteria for high-level amplification and only one case showed low-level amplification. Amplification patterns were homogenous in the entire tumor area without occurrence of any 'hot spot' areas. FGFR1 amplification status was not associated with age, sex, stage, smoking status or overall survival. FGFR1 amplification analysis by FISH analysis in SCLC is, under respect of certain technical issues, applicable in the routine clinical setting. However, the FGFR1 amplification patterns in SCLC differs strongly from the previously described FGFR1 amplification pattern in squamous cell carcinoma of the lung, as positive SCLC harbor mostly homogeneous high-level amplifications. We provide evidence that an estimated number of 1640 newly diagnosed FGFR1-positive SCLC cases in the United States annually could benefit from targeted therapy. Therefore, we recommend including SCLC in the screening for ongoing clinical trials with FGFR1 inhibitors.

show abstract

mentioning

confidence: 64%

Section: Discussionmentioning

confidence: 98%

Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential therapeutic target in small-cell lung cancer

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, the landscape of genome aberrations differs dramatically between the most common lung cancer subtypes lung adenocarcinoma, squamous cell lung cancer, and small-cell lung cancer. Only a few therapeutically tractable genome alterations have so far been found in squamous cell lung cancer ( 3,4 ) and smallcell lung cancer ( 5 ). Of these, amplifi cations of 8p12 ( FGFR1 , WHSC1L1 ) and mutations of DDR2 have been associated with preclinical sensitivity to kinase inhibition (6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

“…Several recent studies described the 8p12 amplicon ( FGFR1 , WHSC1L1 ) as recurrently amplifi ed in lung cancer; the amplicon spans approximately 10 Mbps and contains about 50 genes in total ( 5,6 ). Here, we sought to characterize in detail the structure of the 8p12 amplicon to identify mechanisms of oncogenic transformation induced by amplifi ed FGFR1 and to determine modulators of FGFR dependency in lung cancer.…”

Section: Introductionmentioning

confidence: 99%

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer

et al. 2014

Self Cite

View full text Add to dashboard Cite

The 8p12 locus (containing the FGFR1 tyrosine kinase gene) is frequently amplifi ed in squamous cell lung cancer. However, it is currently unknown which of the 8p12-amplifi ed tumors are also sensitive to fi broblast growth factor receptor (FGFR) inhibition. We found that, in contrast with other recurrent amplifi cations, the 8p12 region included multiple centers of amplifi cation, suggesting marked genomic heterogeneity. FGFR1 -amplifi ed tumor cells were dependent on FGFR ligands in vitro and in vivo . Furthermore, ectopic expression of FGFR1 was oncogenic, which was enhanced by expression of MYC. We found that MYC was coexpressed in 40% of FGFR1 -amplifi ed tumors. Tumor cells coexpressing MYC were more sensitive to FGFR inhibition, suggesting that patients with FGFR1-amplifi ed and MYC-overexpressing tumors may benefi t from FGFR inhibitor therapy. Thus, both cell-autonomous and non-cell-autonomous mechanisms of transformation modulate FGFR dependency in FGFR1 -amplifi ed lung cancer, which may have implications for patient selection for treatment with FGFR inhibitors. SIGNIFICANCE:Amplifi cation of FGFR1 is one of the most frequent candidate targets in lung cancer. Here, we show that multiple factors affect the tumorigenic potential of FGFR1 , thus providing clinical hypotheses for refi nement of patient selection. Cancer Discov; 4(2);

show abstract

“…Peifer, et al performed SNP array analysis, exome sequencing, transcriptome analysis and whole genome sequencing in subsets of 63 SCLC tumor samples. 84 They reported that SCLC has a very high mutation rate, on the order of that observed in melanoma and squamous cell lung cancer, which is presumably because of the prevalence of this tumor among heavy smokers who have high exposure to mutagenic carcinogens in tobacco smoke. Aberrations in TP53 and RB1 were nearly universal, and derangements of histone modifiers, MYC amplification, PTEN deletion, SLIT2 mutation and FGFR1 amplification were found in 5–20% of tumors.…”

Section: Issues In Specific Tumor Typesmentioning

confidence: 99%

NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

Venook¹,

Arcila²,

Benson³

et al. 2014

J Natl Compr Canc Netw

View full text Add to dashboard Cite

Defining treatment susceptible or resistant populations of cancer patients through the use of genetically defined biomarkers has revolutionized cancer care in recent years for some disease/patient groups. Research continues to show that histologically defined diseases are diverse in their expression of unique mutations or other genetic alterations, however, which presents both opportunities for the development of personalized cancer treatments, but increased difficulty in testing these therapies because potential patient populations are divided into ever-smaller numbers. To address some of the growing challenges in biomarker development and clinical trial design, NCCN assembled a group of experts across specialties and solid tumor disease types to begin to define the problems and to consider alternate ways of designing clinical trials in the era of multiple biomarkers and targeted therapies. Results from that discussion are presented, focusing on issues of clinical trial design from the perspective of statisticians, clinical researchers, regulators, pathologists and information developers.

show abstract

Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer

Cited by 1,164 publications

References 85 publications

Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential therapeutic target in small-cell lung cancer

Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential therapeutic target in small-cell lung cancer

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer

NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

Contact Info

Product

Resources

About