We sought to determine whether transcriptional subgroups of clinical relevance exist within EGFR-mutated, KRAS-mutated, or EGFR and KRAS-wild type (EGFRwt/KRASwt) adenocarcinomas. We identified transcriptional subgroups in EGFR-mutated and EGFRwt/KRASwt adenocarcinomas with significant differences in clinicopathological characteristics and patient outcome, not limited to a mutation specific setting.
BRAF mutations are found in a subset of non-small cell lung cancers (NSCLCs). We examined the clinical characteristics and treatment outcomes of patients with NSCLC harboring BRAF mutations. We identified five BRAF mutations not previously reported in NSCLC; two of the five were associated with increased BRAF kinase activity. BRAF mutations occur in 4% of NSCLCs and half are non-V600E. Prospective trials are ongoing to validate BRAF as a therapeutic target in NSCLC.
Here we demonstrate that a targeted genetic dependency screen is an efficient approach to identify somatic cancer alterations that are functionally important. By using this approach, we have identified three kinases with gain-of-function mutations in lung cancer, namely FGFR4, MAP3K9, and PAK5. Mutations in these kinases are activating toward the ERK pathway, and targeted depletion of the mutated kinases inhibits proliferation, suppresses constitutive activation of downstream signaling pathways, and results in specific killing of the lung cancer cells.
We report for the first time to our knowledge that V600E and non-V600E BRAF mutations affect different patients with non-small cell lung cancer. V600E mutations are significantly associated with female sex and represent a negative prognostic factor. In addition, we identified a number of other clinicopathologic parameters potentially useful for the selection of patients carrying BRAF mutations.
TP53 mutations were the most frequently observed recurrent alterations (12 patients). Tumors harbored two or more (maximum four) recurrent alterations in 10 patients. Comparative analysis of recurrent alterations between primary tumor and matched metastasis revealed a concordance rate of 94% compared with 63% for likely passenger alterations
“Mucosal melanoma displays distinct clinical and epidemiological features compared to cutaneous melanoma. Here we used whole genome and whole exome sequencing to characterize the somatic alterations and mutation spectra in the genomes of ten mucosal melanomas. We observed somatic mutation rates that are considerably lower than occur in sun-exposed cutaneous melanoma, but comparable to the rates seen in cancers not associated with exposure to known mutagens. In particular…”
“The analysis of exonic DNA from prostate cancers has identified recurrently mutated genes, but the spectrum of genome-wide alterations has not been profiled extensively in this disease. We sequenced the genomes of 57 prostate tumors and matched normal tissues to characterize somatic alterations and to study how they accumulate during oncogenesis and progression. By modeling the genesis of genomic rearrangements, we identified abundant DNA translocations and deletions that arise in a highly interdependent manner. This phenomenon, which we term “chromoplexy,” frequently accounts for…”
HER2 mutations are identified in approximately 2%of non–small-cell lung cancers (NSCLC). There are few data available that describe the clinical course of patients with HER2-mutated NSCLC.
This study, the largest to date dedicated to HER2-mutated NSCLC, reinforces the importance of screening for HER2 mutations in lung adenocarcinomas and suggests the potential efficacy of HER2-targeted drugs in this population.