Mutational signatures and increased retrotransposon insertions in xeroderma pigmentosum variant skin tumors.

Xeroderma pigmentosum variant (XP-V) is an autosomal recessive disease with an increased risk of developing cutaneous neoplasms in sunlight-exposed regions. These cells are deficient in the translesion synthesis (TLS) DNA polymerase eta, responsible for bypassing different types of DNA lesions. From the exome sequencing of 11 skin tumors of a genetic XP-V patients' cluster, classical mutational signatures related to sunlight exposure, such as C>T transitions targeted to pyrimidine dimers, were identified. However, basal cell carcinomas also showed distinct C>A mutation spectra reflecting a mutational signature possibly related to sunlight-induced oxidative stress. Moreover, four samples carry different mutational signatures, with C>A mutations associated with tobacco chewing or smoking usage. Thus, XP-V patients should be warned of the risk of these habits. Surprisingly, higher levels of retrotransposon somatic insertions were also detected when the tumors were compared with non-XP skin tumors, revealing other possible causes for XP-V tumors and novel functions for the TLS polymerase eta in suppressing retrotransposition. Finally, the expected high mutation burden found in most of these tumors renders these XP patients good candidates for checkpoint blockade immunotherapy.

Alterations in Molecular Profiles Affecting Glioblastoma Resistance to Radiochemotherapy: Where Does the Good Go?

Glioblastoma multiforme (GBM) is a brain tumor characterized by high heterogeneity, diffuse infiltration, aggressiveness, and formation of recurrences. Patients with this kind of tumor suffer from cognitive, emotional, and behavioral problems, beyond exhibiting dismal survival rates. Current treatment comprises surgery, radiotherapy, and chemotherapy with the methylating agent, temozolomide (TMZ). GBMs harbor intrinsic mutations involving major pathways that elicit the cells to evade cell death, adapt to the genotoxic stress, and regrow. Ionizing radiation and TMZ induce, for the most part, DNA damage repair, autophagy, stemness, and senescence, whereas only a small fraction of GBM cells undergoes treatment-induced apoptosis. Particularly upon TMZ exposure, most of the GBM cells undergo cellular senescence. Increased DNA repair attenuates the agent-induced cytotoxicity; autophagy functions as a pro-survival mechanism, protecting the cells from damage and facilitating the cells to have energy to grow. Stemness grants the cells capacity to repopulate the tumor, and senescence triggers an inflammatory microenvironment favorable to transformation. Here, we highlight this mutational background and its interference with the response to the standard radiochemotherapy. We discuss the most relevant and recent evidence obtained from the studies revealing the molecular mechanisms that lead these cells to be resistant and indicate some future perspectives on combating this incurable tumor.

Large deletions in immunoglobulin genes are associated with a sustained absence of DNA Polymerase η.

Somatic hypermutation of immunoglobulin genes is a highly mutagenic process that is B cell-specific and occurs during antigen-driven responses leading to antigen specificity and antibody affinity maturation. Mutations at the Ig locus are initiated by Activation-Induced cytidine Deaminase and are equally distributed at G/C and A/T bases. This requires the establishment of error-prone repair pathways involving the activity of several low fidelity DNA polymerases. In the physiological context, the G/C base pair mutations involve multiple error-prone DNA polymerases, while the generation of mutations at A/T base pairs depends exclusively on the activity of DNA polymerase η. Using two large cohorts of individuals with xeroderma pigmentosum variant (XP-V), we report that the pattern of mutations at Ig genes becomes highly enriched with large deletions. This observation is more striking for patients older than 50 years. We propose that the absence of Pol η allows the recruitment of other DNA polymerases that profoundly affect the Ig genomic landscape.