BACKGROUND BRAF V600 mutations occur in various nonmelanoma cancers. We undertook a histology-independent phase 2 “basket” study of vemurafenib in BRAF V600 mutation–positive nonmelanoma cancers. METHODS We enrolled patients in six prespecified cancer cohorts; patients with all other tumor types were enrolled in a seventh cohort. A total of 122 patients with BRAF V600 mutation–positive cancer were treated, including 27 patients with colorectal cancer who received vemurafenib and cetuximab. The primary end point was the response rate; secondary end points included progression-free and overall survival. RESULTS In the cohort with non–small-cell lung cancer, the response rate was 42% (95% confidence interval [CI], 20 to 67) and median progression-free survival was 7.3 months (95% CI, 3.5 to 10.8). In the cohort with Erdheim–Chester disease or Langerhans’-cell histiocytosis, the response rate was 43% (95% CI, 18 to 71); the median treatment duration was 5.9 months (range, 0.6 to 18.6), and no patients had disease progression during therapy. There were anecdotal responses among patients with pleomorphic xanthoastrocytoma, anaplastic thyroid cancer, cholangiocarcinoma, salivary-duct cancer, ovarian cancer, and clear-cell sarcoma and among patients with colorectal cancer who received vemurafenib and cetuximab. Safety was similar to that in prior studies of vemurafenib for melanoma. CONCLUSIONS BRAF V600 appears to be a targetable oncogene in some, but not all, nonmelanoma cancers. Preliminary vemurafenib activity was observed in non–small-cell lung cancer and in Erdheim–Chester disease and Langerhans’-cell histiocytosis. The histologic context is an important determinant of response in BRAF V600–mutated cancers. (Funded by F. Hoffmann–La Roche/Genentech; ClinicalTrials.gov number, NCT01524978.)

To determine the role of the FHIT gene, which encompasses the fragile site at 3p14.2, we analyzed 59 tumors of the small cell and non-small cell type by reverse transcription of FHIT mRNA, followed by PCR amplification and sequencing of products. Allelic losses affecting the gene were evaluated by microsatellite polymorphism analysis and genomic alterations by hybridization using cDNA and genomic probes. Small cell lung tumors (80%) and non-small cell lung cancers (40%) showed abnormalities in RNA transcripts of FHIT, and 76% of the tumors exhibited loss of FHIT alleles. Abnormal lung tumor transcripts lack two or more exons of the FHIT gene. Small cell lung cancer tumors and cell lines were analyzed by Southern blotting and showed rearranged BamHI fragments. These data suggest a critical role of the FHIT gene in lung carcinogenesis.

Treatment with BAY 43-9006 is associated with a significant and sustained increase in BP. The lack of significant change in circulating factors suggests that these humoral factors had little role in the increase in BP.

To determine whether the FHIT gene at 3pl4.2 is altered in head and neck squamous cell carcinomas (HNSCC), we examined 26 HNSCC cell lines for deletions within the FHIT locus by Southern analysis, for allelic losses of specific exons FHIT by fluorescence in situ hybridization (FISH) and for integrity of FHIT transcripts. Three cell lines exhibited homozygous deletions within the FHIT gene, 55% (15/25) showed the presence of aberrant transcripts, and 65% (13/20) Head and neck cancers represent 3% of all cancer in Western countries (1), and in some geographical regions such as India, the incidence is as high as 45% (2); 90-95% of these tumors are head and neck squamous cell carcinomas (HNSCC). HNSCC has a high mortality rate with a 5 year survival of 40%. Tobacco and alcohol have been recognized as etiological factors of these carcinomas, and the reported increase in the incidence of HNSCC by epidemiological studies is probably due to changes in consumption of these agents (2).Several regions of loss of heterozygosity (LOH) have been identified in HNSCC recently, including regions of 3p, 9p, llq, 13q, and 17p (3, 4). Among these loci, the 9p region presents the highest rate of genetic alteration at 75%, followed by alterations of 3p ranging between 45% and 55% (4, 5). LOH of 9p has been linked to the tumor suppressor gene, CDKN2 (6-8), whereas LOH on 3p has not yet been associated with specific genes.Deletions of the short arm of chromosome 3 are common in many human cancers, including sporadic and hereditary renal carcinomas, small-cell lung carcinomas (SCLC) (9, 10) and non-small-cell lung carcinomas (NSCLC) (11, 12) and carcinomas of the breast and cervix (13,14). In this regard, it is interesting to note that the most common fragile site in humans, FRA3B, is at 3pl4.2 (for reviews, see refs. 15 Recently, we have cloned the FHIT gene, at 3pl4.2, which encompasses the FRA3B fragile site, is disrupted by the t(3;8) chromosomal translocation observed in a family with renal cell carcinoma, and spans a region commonly deleted in cancer cell lines (20,21). We have also shown that "80% of SCLC and 40% of NSCLC express aberrant FHIT transcripts (22), suggesting that the FHIT gene is a frequent target for alteration in lung tumors. SCLC and HNSCC present the same type of histology, share major etiological factors such as tobacco (23,24), and exhibit similar regions of LOH of the short arm of chromosome 3. To determine whether the FHIT gene is also disrupted and aberrantly transcribed in HNSCCs, we studied 26 early passage HNSCC-derived cell lines. MATERIALS AND METHODS RNA Extraction and Reverse Transcription-PCR (RT-PCR). Total RNA was extracted from cell lines using RNAzol (Tel-Test, Friendswood, TX) and cDNA synthesized from 1 ,ug of total RNA. RT was performed in a 20 ,ul volume of 1 x first strand buffer (GIBCO), 10 mM DTT, 500 mM of each dNTP, 0.3 mg/ml random primers (GIBCO), and 300 units of SuperScript II (GIBCO) reverse transcriptase. The samples were first incubated 5 min at 65°C and then at 37°C ...

We have identified a gene at 11q23, telomeric to MLL, that encodes a guanine nucleotide exchange factor (GEF). This gene is transcribed into a 9.5-kb mRNA containing a 4.6-kb ORF. By Northern analysis, it was found to be expressed in all human tissues examined including peripheral blood leukocytes, spleen, prostate, testis, ovary, small intestine, colon, and minimally in thymus. Analysis of the predicted protein sequence indicates that it has strong homology to several members of the family of Rho GEFs that includes such oncogenes as Dbl, Vav, Tiam, and Bcr. A patient with primary acute myeloid leukemia (AML) and a karyotype of 51,XY,؉8,؉19,؉3mar was found to have the 5 end of MLL at exon 6 fused in-frame with the 3 end of almost the entire ORF of this gene, which we named LARG for leukemia-associated Rho GEF. Transcriptional orientation of both genes at 11q23 is from centromere to telomere, consistent with other data that suggest the MLL-LARG fusion resulted from an interstitial deletion rather than a balanced translocation. LARG does not appear to have any homology with other MLL partner genes reported thus far. Thus, LARG represents an additional member of the GEF family and a novel MLL fusion partner in acute myeloid leukemia.LARG ͉ Dbl protein ͉ gene rearrangements