SUMMARY We performed integrated genomic, transcriptomic and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1 and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1 and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.

PD-1 immune checkpoint inhibitors have produced encouraging results in patients with hepatocellular carcinoma (HCC). However, what determines resistance to anti-PD-1 therapies is unclear. We created a novel genetically engineered mouse model of HCC that enables interrogation of how different genetic alterations affect immune surveillance and response to immunotherapies. Expression of exogenous antigens in MYC;Trp53 −/− HCCs led to T cell-mediated immune surveillance, which was accompanied by decreased tumor formation and increased survival. Some antigen-expressing MYC;Trp53 −/− HCCs escaped the immune system by upregulating the β-catenin (CTNNB1) pathway. Accordingly, expression of exogenous antigens in MYC;CTNNB1 HCCs had no effect, demonstrating that β-catenin promoted immune escape, which involved defective recruitment of dendritic cells and consequently impaired T-cell activity. Expression of chemokine CCL5 in antigenexpressing MYC;CTNNB1 HCCs restored immune surveillance. Finally, β-catenin-driven tumors were resistant to anti-PD-1. In summary, β-catenin activation promotes immune escape and resistance to anti-PD-1 and could represent a novel biomarker for HCC patient exclusion. SIGNIFICANCE: Determinants of response to anti-PD-1 immunotherapies in HCC are poorly understood. Using a novel mouse model of HCC, we show that β-catenin activation promotes immune evasion and resistance to anti-PD-1 therapy and could potentially represent a novel biomarker for HCC patient exclusion.

Most patients with pancreatic ductal adenocarcinoma (PDAC) present with symptomatic, surgically unresectable disease. Although the goal of early detection of PDAC is laudable and likely to result in significant improvement in overall survival, the relatively low prevalence of PDAC renders general population screening infeasible. The challenges of early detection include identification of atrisk individuals in the general population who would benefit from longitudinal surveillance programs and appropriate biomarker and imaging-based modalities used for PDAC surveillance in such cohorts. In recent years, various subgroups at higher-than-average risk for PDAC have been identified, including those with familial risk due to germline mutations, a history of pancreatitis, patients with mucinous pancreatic cysts, and elderly patients with new-onset diabetes. The last 2 categories are discussed at length in terms of the opportunities and challenges they present for PDAC early detection. We also discuss current and emerging imaging modalities that are critical to identifying early, potentially curable PDAC in high-risk cohorts on surveillance.

BACKGROUND: Human papillomavirus (HPV) is a causative agent in a subset of head and neck squamous cell carcinomas (HNSCCs). These HPV-related cancers have a clinicopathologic profile that diverges from HPV-negative HNSCCs. Accordingly, HPV testing may soon become integrated into standard pathologic assessment of HNSCCs. METHODS: Data were prospectively collected for all patients with head and neck carcinomas who had undergone HPV testing at the Johns Hopkins Hospital as part of clinical care during a 57-month period. HPV testing consisted of concurrent HPV16 in situ hybridization (ISH) and p16 immunohistochemistry (IHC). Wide spectrum HPV ISH was reserved for p16-positive cases that were HPV-16 negative. RESULTS: HPV analysis was performed on 256 head and neck carcinomas in an effort to predict clinical outcomes (56%), localize primary tumor origin (21%), establish tumor classification (9%), determine patient eligibility for vaccine trials (8%), or satisfy patient curiosity (5%). A total of 182 (71%) tumors were HPV positive. HPV positivity correlated with oropharyngeal site (82% vs 9%) and male sex (77% vs 48%). p16 positivity was present in all 176 HPV16-positive cases, and in 19 of 80 (24%) cases that were HPV-16 negative. In 6 (32%) discordant cases, p16 expression was because of the presence of another HPV type. CONCLUSIONS A feasible strategy that incorporates p16 IHC and HPV ISH is able to detect HPV in a high percentage of oropharyngeal carcinomas. HPV status is frequently requested by the oncologist to estimate clinical outcome, and used by pathologists to establish tumor classification and determine site of tumor origin. Cancer 2010;116:2166-73.