Dataset Information

Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas.

ABSTRACT: To compare lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SqCC) and to identify new drivers of lung carcinogenesis, we examined the exome sequences and copy number profiles of 660 lung ADC and 484 lung SqCC tumor-normal pairs. Recurrent alterations in lung SqCCs were more similar to those of other squamous carcinomas than to alterations in lung ADCs. New significantly mutated genes included PPP3CA, DOT1L, and FTSJD1 in lung ADC, RASA1 in lung SqCC, and KLF5, EP300, and CREBBP in both tumor types. New amplification peaks encompassed MIR21 in lung ADC, MIR205 in lung SqCC, and MAPK1 in both. Lung ADCs lacking receptor tyrosine kinase-Ras-Raf pathway alterations had mutations in SOS1, VAV1, RASA1, and ARHGAP35. Regarding neoantigens, 47% of the lung ADC and 53% of the lung SqCC tumors had at least five predicted neoepitopes. Although targeted therapies for lung ADC and SqCC are largely distinct, immunotherapies may aid in treatment for both subtypes.

SUBMITTER: Campbell JD

PROVIDER: S-EPMC4884143 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas.

Campbell Joshua D JD Alexandrov Anton A Kim Jaegil J Wala Jeremiah J Berger Alice H AH Pedamallu Chandra Sekhar CS Shukla Sachet A SA Guo Guangwu G Brooks Angela N AN Murray Bradley A BA Imielinski Marcin M Hu Xin X Ling Shiyun S Akbani Rehan R Rosenberg Mara M Cibulskis Carrie C Ramachandran Aruna A Collisson Eric A EA Kwiatkowski David J DJ Lawrence Michael S MS Weinstein John N JN Verhaak Roel G W RG Wu Catherine J CJ Hammerman Peter S PS Cherniack Andrew D AD Getz Gad G Artyomov Maxim N MN Schreiber Robert R Govindan Ramaswamy R Meyerson Matthew M

Nature genetics 20160509 6

To compare lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SqCC) and to identify new drivers of lung carcinogenesis, we examined the exome sequences and copy number profiles of 660 lung ADC and 484 lung SqCC tumor-normal pairs. Recurrent alterations in lung SqCCs were more similar to those of other squamous carcinomas than to alterations in lung ADCs. New significantly mutated genes included PPP3CA, DOT1L, and FTSJD1 in lung ADC, RASA1 in lung SqCC, and KLF5, EP300, and CREBBP in bot ...[more]

PMID: 27158780

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Project description:BACKGROUND:Targeted therapy for non-small cell lung cancer is histology dependent. However, histological classification by routine pathological assessment with hematoxylin-eosin staining and immunostaining for poorly differentiated tumors, particularly those from small biopsies, is still challenging. Additionally, the effectiveness of immunomarkers is limited by technical inconsistencies of immunostaining and lack of standardization for staining interpretation. RESULTS:Using gene expression profiles of pathologically-determined lung adenocarcinomas and squamous cell carcinomas, denoted as pADC and pSCC respectively, we developed a qualitative transcriptional signature, based on the within-sample relative gene expression orderings (REOs) of gene pairs, to distinguish ADC from SCC. The signature consists of two genes, KRT5 and AGR2, which has the stable REO pattern of KRT5 > AGR2 in pSCC and KRT5 < AGR2 in pADC. In the two test datasets with relative unambiguous NSCLC types, the apparent accuracy of the signature were 94.44 and 98.41%, respectively. In the other integrated dataset for frozen tissues, the signature reclassified 4.22% of the 805 pADC patients as SCC and 12% of the 125 pSCC patients as ADC. Similar results were observed in the clinical challenging cases, including FFPE specimens, mixed tumors, small biopsy specimens and poorly differentiated specimens. The survival analyses showed that the pADC patients reclassified as SCC had significantly shorter overall survival than the signature-confirmed pADC patients (log-rank p = 0.0123, HR = 1.89), consisting with the knowledge that SCC patients suffer poor prognoses than ADC patients. The proliferative activity, subtype-specific marker genes and consensus clustering analyses also supported the correctness of our signature. CONCLUSIONS:The non-subjective qualitative REOs signature could effectively distinguish ADC from SCC, which would be an auxiliary test for the pathological assessment of the ambiguous cases.

Dataset Information

Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas.

Publications

Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas.

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