PXD010779

PXD010779 is an original dataset announced via ProteomeXchange.

Title	Quantitative mass spectrometry to interrogate proteomic heterogeneity in metastatic lung adenocarcinoma and validate a novel somatic mutation CDK12-G879V
Description	Lung cancer is the leading cause of cancer death both in men and women. Tumor heterogeneity is an impediment to targeted treatment of all cancers, including lung cancer. Here, we sought to characterize changes in tumor proteome and phosphoproteome by longitudinal, prospective collection of tumor tissue of an exceptional responder lung adenocarcinoma patient who survived with metastatic lung adenocarcinoma for more than seven years with HER2-directed therapy in combination with chemotherapy. We employed “Super-SILAC” and TMT labeling strategies to quantify the proteome and phosphoproteome of a lung metastatic site and ten different metastatic progressive lymph nodes collected across a span of seven years, including five lymph nodes procured at autopsy. We identified specific signaling networks enriched in lung compared to the lymph node metastatic sites. We correlated the changes in protein abundance with changes in copy number alteration (CNA) and transcript expression. To further interrogate the mass spectrometry data, patient-specific database was built incorporating all the somatic variants identified by whole genome sequencing (WGS) of genomic DNA from the lung, one lymph node metastatic site and blood. An extensive validation pipeline was built for confirmation of variant peptides. We validated 360 spectra corresponding to 55 germline and 6 somatic variant peptides. Targeted MRM assays demonstrated expression of two novel variant somatic peptides, CDK12 G879V and FASN-R1439Q, with expression in lung and lymph node metastatic sites, respectively. CDK12 G879V mutation likely results in a nonfunctional kinase and knockdown of CDK12 in lung adenocarcinoma cells increased chemotherapy sensitivity, explaining the complete resolution of the lung metastatic sites in this patient.
HostingRepository	PRIDE
AnnounceDate	2019-01-07
AnnouncementXML	Submission_2019-01-11_01:20:45.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Udayan Guha
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2018-08-15 02:48:52	ID requested
1	2019-01-07 09:48:19	announced
⏵ 2	2019-01-11 01:20:46	announced	Updated publication reference for PubMed record(s): 30617155.

Zhang X, Nguyen KD, Rudnick PA, Roper N, Kawaler E, Maity TK, Awasthi S, Gao S, Biswas R, Venugopalan A, Cultraro CM, Feny, ö D, Guha U, Quantitative Mass Spectrometry to Interrogate Proteomic Heterogeneity in Metastatic Lung Adenocarcinoma and Validate a Novel Somatic Mutation CDK12-G879V. Mol Cell Proteomics, 18(4):622-641(2019) [pubmed]

curator keyword: Biomedical

submitter keyword: proteomic heterogeneity, lung adenocarcinoma, quantitative mass spectrometry

Udayan Guha
contact affiliation	Thoracic and Gastrointestinal Oncology Branch, CCR , NCI, NIH
contact email	udayan.guha@nih.gov
lab head
Udayan Guha
contact affiliation	NCI/NIH
contact email	udayan.guha@nih.gov
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD010779
     1. Label: PRIDE project
     2. Name: Quantitative mass spectrometry to interrogate proteomic heterogeneity in metastatic lung adenocarcinoma and validate a novel somatic mutation CDK12-G879V