Proteomics

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Quantitative mass spectrometry to interrogate proteomic heterogeneity in metastatic lung adenocarcinoma and validate a novel somatic mutation CDK12-G879V


ABSTRACT: 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.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung, Lymph Node

DISEASE(S): Lung Cancer

SUBMITTER: Udayan Guha  

LAB HEAD: Udayan Guha

PROVIDER: PXD010779 | Pride | 2019-01-07

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
1_LN_super-SILAC_F10_R1.raw Raw
1_LN_super-SILAC_F10_R2.raw Raw
1_LN_super-SILAC_F11_R1.raw Raw
1_LN_super-SILAC_F11_R2.raw Raw
1_LN_super-SILAC_F12_R1.raw Raw
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Publications

Quantitative Mass Spectrometry to Interrogate Proteomic Heterogeneity in Metastatic Lung Adenocarcinoma and Validate a Novel Somatic Mutation CDK12-G879V.

Zhang Xu X   Nguyen Khoa Dang KD   Rudnick Paul A PA   Roper Nitin N   Kawaler Emily E   Maity Tapan K TK   Awasthi Shivangi S   Gao Shaojian S   Biswas Romi R   Venugopalan Abhilash A   Cultraro Constance M CM   Fenyö David D   Guha Udayan U  

Molecular & cellular proteomics : MCP 20190107 4


Lung cancer is the leading cause of cancer death in both men and women. Tumor heterogeneity is an impediment to targeted treatment of all cancers, including lung cancer. Here, we sought to characterize tumor proteome and phosphoproteome changes by longitudinal, prospective collection of tumor tissue from an exceptional responder lung adenocarcinoma patient who survived with metastatic lung adenocarcinoma for over seven years while undergoing HER2-directed therapy in combination with chemotherapy  ...[more]

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