Molecular Subtype Of Lung Cancer Research Articles

Abstract 2033: Identification of a novel genetic abnormality, the amplification of rictor (rapamycin-insensitive companion of mTOR), in a patient with non-small cell lung cancer.

Abstract Despite recent advances, clinically-relevant oncogenic drivers have not been identified in about half of lung adenocarcinormas. Here, we report rictor (rapamycin-insensitive companion of mTOR) amplification as a novel genetic abnormality in a young patient with non-small cell lung cancer. This male patient was a never smoker and was diagnosed with lung adenocarcinorma at the age of 18. He initially presented with refractory cough and persistent left lung lesions. Pathology was consistent with lung adenocarcinorma, poorly differentiated. Extensive molecular testing was negative for common genetic alterations in K-RAS, EGFR, ALK, HER2, RET, AKT, PIK3CA, BRAF and ROS1. His tumor was subsequently subjected to next generation DNA sequencing (FoundationOne, Foundation Medicine, Cambridge, MA) targeting a cohort of more than 180 cancer-related genes. This analysis identified rictor amplification of at least 6 copies as the sole DNA abnormality. Immunohistochemistry further documented rictor overexpression in the patient's lung tumor. The neoplastic lung tissue exhibited diffuse and strong cytoplasmic staining for rictor, compared to surrounding non-neoplastic tissues. Furthermore, the tumor tissue showed diffuse overexpression of phospho-S473 Akt, an essential downstream target of rictor. Rictor is a key component of mTORC2 complex, where it modifies actin cytoskeleton organization, cell proliferation and survival. Activation of rictor signaling has been suggested to play critical roles in regulating cancer cell migration, invasion and metastasis in breast, ovarian, and colorectal cancers and gliomas. To our knowledge, this is the first report of rictor amplification in lung cancer. Moreover, we found that blockade of the rictor-mTORC2 pathway by siRNA-mediated rictor knockdown or with pharmacological inhibitors led to decreased phosphorylation of S473-AKT and growth inhibition in lung cancer cell lines. Thus, rictor amplification may represent a potential novel target in lung cancer. We will perform further studies to determine whether rictor amplification is a unique molecular subtype of lung cancer. Further, we hope to identify which targeted drugs are active against tumors with rictor amplification and overexpression. Citation Format: Haiying Cheng, Bilal Piperdi, Edward L. Schwartz, Changcheng Zhu, Zhenfeng Zhang, Balazs Halmos, Vincent Miller, Roman Perez-Soler. Identification of a novel genetic abnormality, the amplification of rictor (rapamycin-insensitive companion of mTOR), in a patient with non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2033. doi:10.1158/1538-7445.AM2013-2033

Advances of molecular subtype and targeted therapy of lung cancer

随着肺癌发生、发展和预后相关分子机制研究的不断深入，肺癌靶向治疗取得了较大的进展，每一种分子分型的发现都会带来相应靶向药物的研究。2004年表皮生长因子受体（epidermal growth factor receptor, EGFR）基因在非小细胞肺癌中的发现，为我们带来了EGFR突变高度敏感有效的酪氨酸激酶抑制剂（tyrosine kinase inhibitor, TKI）。2007年棘皮类微管相关样蛋白-4-间变型淋巴瘤激酶（EML4-ALK）融合基因的出现为肺癌的分子发展带来了新的有效靶点。目前多个肺癌分子靶点及其靶向药物正在研究中。本文旨在回顾并总结肺癌分子分型及其靶向治疗的研究进展。

Comprehensive genomic characterization of squamous cell carcinoma of the lung.

7006 Background: A third of patients with non-small cell lung cancer are diagnosed with squamous cell carcinoma (SCC) histology. This report describes findings from the comprehensive genomic analyses of 178 SCC samples. Methods: The Cancer Genome Atlas (TCGA) is conducting DNA, RNA, and miRNA sequencing along with DNA copy number profiling, quantification of mRNA expression and promoter methylation on surgically resected samples from previously untreated patients with stage I-III SCC of the lung. Results: The demographics of 178 patients enrolled in the study: median age 68 years (range: 40-85); female 47 (26%) and history of tobacco smoking 171 (96%). Over 30 sites of significant somatic copy number alteration (SCNA) were identified. Exome sequencing of 178 lung SCC and matched normal samples revealed 13 significantly mutated genes with a False Discovery Rate (FDR) of <0.01 and high expression levels, including TP53, CDKN2A, PTEN, KEAP1, and NFE2L2. Apart from the near universal loss of TP53 and CDKN2A, alterations in the NFE2L2/KEAP1 and PI3K/AKT pathways were found in 35% and 43% of tumors analyzed. mRNA expression profiling revealed four distinct expression subtypes, each one enriched with distinct mutations and SCNAs - classical (37%): NFE2L2 and KEAP1 mutations, FGFR kinase alterations, increased global methylation and the highest rate of tobacco use; basal (24%): alterations in FGFR kinases; secretory (24%): PDGFRA alterations; primitive (15%): RB1 mutations. Rearrangements involving several known tumor suppressors were detected by whole genome shotgun sequencing of 20 tumor/normal pairs and confirmed by RNA sequencing including PTEN, RB1, NOTCH1, NF1 and CDKN2A. CDKN2A loss by one of several mechanisms (deletion, mutation, rearrangement with loss of function and methylation) was observed in 72% of specimens. Potential therapeutic targets for clinical trials with currently available drugs were identified in 127 patients (75%). Conclusions: SCC of the lung is a distinct molecular subtype of lung cancer potentially amenable to distinct molecularly targeted therapies.

Paraffin-based molecular diagnosis of lung cancer reproduces morphologic and molecular subtypes of lung cancer

7579 Background: Molecular profiling of lung cancer by gene expression analyses has documented potential to guide therapy. However, quality ‘fresh’ tissue for RNA analyses is generally unavailable in clinical practice. We introduce a (q)RT-PCR assay and analytic method for profiling lung cancers from clinically obtained formalin-fixed paraffin-embedded tissues. Methods: Approximately 1,000 DNA microarrays were analyzed to select genes distinguishing the major histological variants (adenocarcinoma, small cell carcinoma, etc) and previously described molecular subtypes of lung cancer. Based on gene expression, a classifier of 62 genes was constructed to assign each sample to its morphologic tumor type, as well as to risk stratify by molecular subtypes. A real-time qRT-PCR assay was developed to evaluate the expression of the 62 genes from paraffin-embedded samples. This assay was used to profile RNA extracted from a cohort of surgically treated lung cancer patients. Samples were procured as fresh frozen and formalin-fixed, paraffin-embedded and were archived between 1–15 years. Results: Fifty-eight of 62 genes passed performance criteria and were used for analyses. Normalized gene expression was used for sample classification. The cohort contained a broad spectrum of tumors in proportions consistent with clinical practice. Gene amplification was successful in 139 of 142 (98%) lung cancer samples. Matched frozen-paraffin and replicate paraffin samples had mean correlations of approximately 80%. Linear discriminant analysis of gene expression data agreed with morphologic classification by light microscopy in >99% of cases. More importantly, the method successfully re-identified molecular subtypes of lung cancer for the first time through the use of a paraffin-based assay. Clinical outcomes previously associated with molecular tumor subtypes, including differential survival and metastatic patterns, were again seen in our cohort. Conclusions: We describe for the first time a clinically meaningful and robust molecular diagnosis of a clinical cohort of lung cancer patients which is complementary to morphologic cancer diagnosis. This assay is easily implemented using specimens routinely collected in current patient care. No significant financial relationships to disclose.