We describe the landscape of somatic genomic alterations based on multi-dimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

In the above article, we did not indicate a Sequence Read Archive (SRA) accession number for the DNA sequence data obtained to draw our conclusions. These data are available under the accession number SRP039006 at http://www.ncbi.nlm.nih.gov/sra/.

Chimeric antigen receptor (CAR) therapy targeting CD19 has yielded remarkable outcomes in patients with acute lymphoblastic leukemia. To identify potential CAR targets in acute myeloid leukemia (AML), we probed the AML surfaceome for overexpressed molecules with tolerable systemic expression. We integrated large transcriptomics and proteomics datasets from malignant and normal tissues, and developed an algorithm to identify potential targets expressed in leukemia stem cells, but not in normal CD34CD38 hematopoietic cells, T cells, or vital tissues. As these investigations did not uncover candidate targets with a profile as favorable as CD19, we developed a generalizable combinatorial targeting strategy fulfilling stringent efficacy and safety criteria. Our findings indicate that several target pairings hold great promise for CAR therapy of AML.

Targeted immunotherapy in acute myeloid leukemia (AML) is challenged by the lack of AML-specific target antigens and clonal heterogeneity, leading to unwanted on-target off-leukemia toxicity and risk of relapse from minor clones. We hypothesize that combinatorial targeting of AML cells can enhance therapeutic efficacy without increasing toxicity. To identify target antigen combinations specific for AML and leukemic stem cells, we generated a detailed protein expression profile based on flow cytometry of primary AML (n = 356) and normal bone marrow samples (n = 34), and a recently reported integrated normal tissue proteomic data set. We analyzed antigen expression levels of CD33, CD123, CLL1, TIM3, CD244 and CD7 on AML bulk and leukemic stem cells at initial diagnosis (n = 302) and relapse (n = 54). CD33, CD123, CLL1, TIM3 and CD244 were ubiquitously expressed on AML bulk cells at initial diagnosis and relapse, irrespective of genetic characteristics. For each analyzed target, we found additional expression in different populations of normal hematopoiesis. Analyzing the coexpression of our six targets in all dual combinations (n = 15), we found CD33/TIM3 and CLL1/TIM3 to be highly positive in AML compared with normal hematopoiesis and non-hematopoietic tissues. Our findings indicate that combinatorial targeting of CD33/TIM3 or CLL1/TIM3 may enhance therapeutic efficacy without aggravating toxicity in immunotherapy of AML.

Purpose Male breast cancer (MaBC) is rare and its genomic landscape has yet to be fully characterized. Lacking studies in men, treatment of MaBC patients is extrapolated from results in females with the disease (FBC). We sought to define whether MaBCs harbor somatic genetic alterations in genes frequently altered in FBCs. Experimental Design All MaBCs were estrogen receptor-positive and all but two were HER2 negative. 59 MaBCs were subtyped by immunohistochemistry and tumor-normal pairs were microdissected and subjected to massively parallel sequencing targeting all exons of 241 genes frequently mutated in FBCs or DNA-repair related. The repertoires of somatic mutations and copy number alterations of MaBCs were compared to that of subtype-matched FBCs. Results 29% and 71% of MaBCs were immunohistochemically classified as luminal A-like or luminal B-like, respectively. MaBCs displayed a heterogeneous repertoire of somatic genetic alterations that to some extent recapitulated that of estrogen receptor (ER)-positive/HER2-negative FBCs, including recurrent mutations affecting PIK3CA (20%) and GATA3 (15%). ER-positive/HER2-negative MaBCs, however, less frequently harbored 16q losses, and PIK3CA and TP53 mutations than ER-positive/HER2-negative FBCs. In addition, MaBCs were found to be significantly enriched for mutations affecting DNA repair-related genes. Conclusion MaBCs less frequently harbor somatic genetic alterations typical of ER-positive/HER2-negative FBCs, such as PIK3CA and TP53 mutations and losses of 16q, suggesting that at least a subset of MaBCs are driven by a distinct repertoire of somatic changes. Given the genomic differences, caution may be needed in the application of biological and therapeutic findings from studies of FBCs to MaBCs.