RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer.

Tyrosine kinase inhibitors are effective treatments for non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, relapse typically occurs after an average of 1 year of continuous treatment. A fundamental histological transformation from NSCLC to small-cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of tumour samples and cell lines derived from resistant EGFR mutant patients revealed that Retinoblastoma (RB) is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC. Further, increased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared with resistant NSCLCs. Together, these findings suggest that this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC.

The prognostic impact of KRAS, its codon and amino acid specific mutations, on survival in resected stage I lung adenocarcinoma.

BACKGROUND: Despite complete surgical resection, patients with stage I non-small-cell lung cancer (NSCLC) are at risk for disease recurrence. The impact of common oncogenic driver mutations on prognosis in stage I NSCLC is limited. The pure prognostic value of KRAS mutational status was explored in resected stage I lung adenocarcinoma. METHODS: Mutation status was tested in patients who had complete resection of stage I lung adenocarcinoma without any adjuvant therapy, using a multiplex polymerase chain reaction)-based assay. Disease-free survival (DFS) and overall survival (OS) were compared between patients with KRAS-mutant (KRAS-MUT), KRAS-MUT subtypes, and KRAS wild-type (KRAS-WT) tumors. RESULTS: A total of 312 patients were included in this analysis; 127 harbored KRAS mutations and 185 had KRAS-WT tumors. When compared with KRAS-WT, KRAS-MUT was associated with significantly shorter OS (hazard ratio 4.36, 95% confidence interval 2.09-9.07; p < 0.0001) and DFS (hazard ratio 3.62, 95% confidence interval 2.11-6.22; p < 0.0001). When stratifying KRAS-WT patients based on EGFR status, KRAS-MUT patients had worse OS (p = 0.0001) and DFS (p < 0.0001) than patients with EGFR-MUT and EGFR-WT/KRAS-WT (WT/WT). Patients with codon 12 mutations had superior DFS (p = 0.0314), but there were no differences in OS compared with mutations found in codons 13 and 61 (p = 0.1772). We observed better DFS associated with G12C/G12V mutations compared with other amino acid specific KRAS mutations (p = 0.0271) with a trend towards improved OS (p = 0.0636). Multivariate analysis identified KRAS mutation as independent predictor of worse OS (p = 0.001) and DFS (p < 0.0001). CONCLUSION: KRAS is an independent prognostic marker in resected stage I lung adenocarcinoma. Differential outcomes are associated with codon and amino acid specific KRAS mutations.

Absence of chromosomal abnormalities in herniated orbital fat.

AIMS: Lipomatous tumours of the orbit are rare, and can sometimes be difficult to characterize. Herniated orbital fat is thought to be a reactive process, but its presentation can mimic a lipomatous tumour such as an atypical lipomatous tumour or spindle cell/pleomorphic lipoma. Genetic studies to determine if it is indeed a reactive process rather than an adipocytic neoplasm have not been performed. METHODS AND RESULTS: Four samples of herniated orbital fat were reviewed clinically, histopathologically and immunohistochemically. Array comparative genomic hybridization (aCGH) was used to search for genome-wide copy number alterations within the tumours. Histological evaluation revealed that all four tumours contained collections of adipocytes surrounded by fibrous septae. Lochkern cells and floret-like multinucleated giant cells were present, consistent with herniated orbital fat. CD34 was positive in all tumours. Staining for MDM2 and CDK4 was negative. ACGH analysis demonstrated no copy number alterations. CONCLUSIONS: Herniated orbital fat may share some histopathological features with lipoma and atypical lipomatous tumour, but the absence of copy number gains or losses is consistent with the impression that herniated orbital fat is a reactive process. Genetic analysis may be another method to help differentiate herniated orbital fat from a lipomatous orbital tumour when the diagnosis is in question.

Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas.

Craniopharyngiomas are epithelial tumors that typically arise in the suprasellar region of the brain. Patients experience substantial clinical sequelae from both extension of the tumors and therapeutic interventions that damage the optic chiasm, the pituitary stalk and the hypothalamic area. Using whole-exome sequencing, we identified mutations in CTNNB1 (ß-catenin) in nearly all adamantinomatous craniopharyngiomas examined (11/12, 92%) and recurrent mutations in BRAF (resulting in p.Val600Glu) in all papillary craniopharyngiomas (3/3, 100%). Targeted genotyping revealed BRAF p.Val600Glu in 95% of papillary craniopharyngiomas (36 of 39 tumors) and mutation of CTNNB1 in 96% of adamantinomatous craniopharyngiomas (51 of 53 tumors). The CTNNB1 and BRAF mutations were clonal in each tumor subtype, and we detected no other recurrent mutations or genomic aberrations in either subtype. Adamantinomatous and papillary craniopharyngiomas harbor mutations that are mutually exclusive and clonal. These findings have important implications for the diagnosis and treatment of these neoplasms.