Stratification of head and neck squamous cell carcinomas (HNSCC) based on HPV16 DNA and RNA status, gene expression patterns, and mutated candidate genes may facilitate patient treatment decision. We characterize head and neck squamous cell carcinomas (HNSCC) with different HPV16 DNA and RNA (E6*I) status from 290 consecutively recruited patients by gene expression profiling and targeted sequencing of 50 genes. We show that tumors with transcriptionally inactive HPV16 (DNA+ RNA‐) are similar to HPV‐negative (DNA‐) tumors regarding gene expression and frequency ofTP53mutations (47%, 8/17 and 43%, 72/167, respectively). We also find that an immune response‐related gene expression cluster is associated with lymph node metastasis, independent of HPV16 status and that disruptiveTP53mutations are associated with lymph node metastasis in HPV16 DNA‐ tumors. We validate each of these associations in another large data set. Four gene expression clusters which we identify differ moderately but significantly in overall survival. Our findings underscore the importance of measuring the HPV16 RNA (E6*I) andTP53‐mutation status for patient stratification and identify associations of an immune response‐related gene expression cluster andTP53mutations with lymph node metastasis in HNSCC.

The prognosis of germinal center–derived B-cell (GCB) lymphomas, including follicular lymphoma and diffuse large-B-cell lymphoma (DLBCL), strongly depends on age. Children have a more favorable outcome than adults. It is not known whether this is because of differences in host characteristics, treatment protocols, or tumor biology, including the presence of chromosomal alterations. By screening for novel IGH translocation partners in pediatric and adult lymphomas, we identified chromosomal translocations juxtaposing the IRF4 oncogene next to one of the immunoglobulin (IG) loci as a novel recurrent aberration in mature B-cell lymphoma. FISH revealed 20 of 427 lymphomas to carry an IG/IRF4-fusion. Those were predominantly GCB-type DLBCL or follicular lymphoma grade 3, shared strong expression of IRF4/MUM1 and BCL6, and lacked PRDM1/BLIMP1 expression and t(14;18)/BCL2 breaks. BCL6 aberrations were common. The gene expression profile of IG/IRF4-positive lymphomas differed from other subtypes of DLBCL. A classifier for IG/IRF4 positivity containing 27 genes allowed accurate prediction. IG/IRF4 positivity was associated with young age and a favorable outcome. Our results suggest IRF4 translocations to be primary alterations in a molecularly defined subset of GCB-derived lymphomas. The probability for this subtype of lymphoma significantly decreases with age, suggesting that diversity in tumor biology might contribute to the age-dependent differences in prognosis of lymphoma.

Key Points: A subset of lymphomas with gene expression and pathological characteristics of Burkitt lymphomas but absence of MYC translocation does exist. These lymphomas carry chr 11q proximal gains and telomeric losses, suggesting co-deregulation of oncogenes and tumor suppressor genes.

Diffuse large B-cell lymphoma is the most frequent type of B-cell lymphoma in adult patients but also occurs in children. Patients are currently assigned to therapy regimens based on arbitrarily chosen age limits only (eg, 18 or 60 years) and not biologically justified limits. A total of 364 diffuse large B-cell lymphomas and related mature aggressive B-cell lymphomas other than Burkitt lymphoma from all age groups were analyzed by comprehensive molecular profiling. The probability of several biologic features previously reported to be associated with poor prognosis in diffuse large B-cell lymphoma, such as ABC subtype, BCL2 expression, or cytogenetic complexity, increases with age at diagnosis. Similarly, various genetic features, such as IRF4 translocations, gains in 1q21, 18q21, 7p22, and 7q21, as well as changes in 3q27, including gains and translocations affecting the BCL6 locus, are significantly associated with patient age, but no cut-offs between age groups could be defined. If age was incorporated in multivariate analyses, genetic complexity lost its prognostic significance, whereas the prognostic impact of ABC subtype and age were additive. Our data indicate that aging is a major determinant of lymphoma biology. They challenge current concepts regarding both prognostic biomarkers and treatment stratification based on strict age cut-offs.