Malignant pleural mesotheliomas (MPMs) often show CDKN2A and NF2 inactivation, but other highly recurrent mutations have not been described. To identify additional driver genes, we used an integrated genomic analysis of 53 MPM tumor samples to guide a focused sequencing effort that uncovered somatic inactivating mutations in BAP1 in 23% of MPMs. The BAP1 nuclear deubiquitinase is known to target histones (together with ASXL1 as a Polycomb repressor subunit) and the HCF1 transcriptional co-factor, and we show that BAP1 knockdown in MPM cell lines affects E2F and Polycomb target genes. These findings implicate transcriptional deregulation in the pathogenesis of MPM.

At Memorial Sloan-Kettering Cancer Center, IHC incidence has increased dramatically in the last 16 years. Resection offers the best opportunity for long-term survival but is possible in the minority, and patients with large, node-positive or multifocal IHC seem to derive little benefit. Establishing and maintaining control of the intrahepatic disease remains the biggest problem for all IHC patients. The recent increase in survival seems largely because of improved nonoperative therapy for unresectable disease.

A significant number of prostate cancers have been shown to have recurrent chromosomal rearrangements resulting in the fusion of the androgen regulated TMPRSS2 promoter to a member of the ETS transcription factor family, most commonly ERG. This results in ERG overexpression which may have a direct causal role in prostate tumorigenesis or progression. However, the clinical significance of the rearrangement is unclear and, in particular, relationship to outcome has been inconsistent in recent reports. We analyzed TMPRSS2-ERG gene rearrangement status by fluorescence in situ hybridization (FISH) in 521 cases of clinically localized surgically treated prostate cancer with 95 months median follow-up and also in 40 unmatched metastases. 42% of primary tumors and 40% of metastases had rearrangements. 11% had copy number increase (CNI) of the TMPRRS2-ERG region. Rearrangement alone was associated with lower grade, but not with stage, biochemical recurrence, metastases or death. CNI with and without rearrangement was associated with high grade and advanced stage. Further, a subgroup of cancers with CNI and rearrangement by deletion, with two or more copies of the deleted locus, tended to be more clinically aggressive. DNA index assessment revealed that the majority of tumors with CNI of TMPRSS2-ERG had generalized aneuploidy/ tetraploidy in contrast to tumors without TMPRSS2-ERG CNI, which were predominantly diploid. We therefore conclude that translocation of TMPRSS2-ERG is not associated with outcome and the aggressive clinical features associated with CNI of chromosome 21 reflect generalized aneuploidy and are not due to CNI specifically of rearranged TMPRSS2-ERG.

EGFR and KRAS mutations define distinct molecular subsets of resected lung adenocarcinoma. Because EGFR and KRAS mutations also predict whether tumors are sensitive or resistant, respectively, to EGFR tyrosine kinase inhibitors, they can readily be used in clinical trials to help guide the administration of specific types of adjuvant therapy.

Background Low-grade serous (LGS) ovarian cancer (OC) is a chemoresistant disease that accounts for 10% of serous ovarian cancers. Prior studies have reported that 28–35% of serous borderline (SB)/LGS ovarian tumors harbor a BRAF mutation, suggesting that BRAF inhibitors may be a rational therapeutic approach for this disease. We sought to determine if BRAF or KRAS mutation status is associated with disease stage and/or histology in patients with SB and LGS ovarian cancer. Methods We genetically profiled 75 SB and LGS ovarian tumors for mutations in BRAF and KRAS. The incidence and identity of BRAF and KRAS mutations were defined and the results were correlated with stage, response to treatment, and overall survival. Results Of 75 samples examined, 56(75%) were SB and 19(25%) LGS histology. Fifty-seven percent of tumors harbored either a KRAS mutation (n=17) or a BRAF V600E mutation (n=26). BRAF V600E mutation was significantly associated with early stage disease (Stage I/II, P<0.001) and serous borderline histology (P=0.002). KRAS mutation was not significantly associated with stage or histology. Of the 22 (29%) patients who required treatment with chemotherapy, 20 were KRAS/BRAF wild-type (WT), 2 were KRAS mutant, and none had tumors harboring a BRAF mutation. All BRAF mutant patients were alive at a median follow-up of 3.6 years (range 1.9–129.3 months). Conclusions V600E BRAF mutations are present in 35% of SB/LGS ovarian cancers. The presence of BRAF V600E mutation in SB/LGSOC is associated with early stage disease and improved prognosis. Patients with SB/LGSOC who require systemic therapy are unlikely to have BRAF mutant tumors.