Genetic changes associated with relapse in favorable histology Wilms tumor: A Children's Oncology Group AREN03B2 study

Over the last decade, sequencing of primary tumors has clarified the genetic underpinnings of Wilms tumor but has not affected therapy, outcome, or toxicity. We now sharpen our focus on relapse samples from the umbrella AREN03B2 study. We show that over 40% of relapse samples contain mutations in SIX1 or genes of the MYCN network, drivers of progenitor proliferation. Not previously seen in large studies of primary Wilms tumors, DIS3 and TERT are now identified as recurrently mutated. The analysis of primary-relapse tumor pairs suggests that 11p15 loss of heterozygosity (and other copy number changes) and mutations in WT1 and MLLT1 typically occur early, but mutations in SIX1, MYCN, and WTX are late developments in some individuals. Most strikingly, 75% of relapse samples had gain of 1q, providing strong conceptual support for studying circulating tumor DNA in clinical trials to better detect 1q gain earlier and monitor response

Hijacked DNA repair proteins and unchained DNA polymerases

Somatic hypermutation of immunoglobulin (Ig) genes occurs at a frequency that is a million times greater than the mutation in other genes. Mutations occur in variable genes to increase antibody affinity, and in switch regions before constant genes to cause switching from IgM to IgG. Hypermutation is initiated in activated B cells when the activation-induced deaminase protein deaminates cytosine in DNA to uracil. Uracils can be processed by either a mutagenic pathway to produce mutations or a non-mutagenic pathway to remove mutations. In the mutagenic pathway, we first studied the role of mismatch repair proteins, MSH2, MSH3, MSH6, PMS2 and MLH1, since they would recognize mismatches. The MSH2–MSH6 heterodimer is involved in hypermutation by binding to U:G and other mismatches generated during repair synthesis, but the other proteins are not necessary. Second, we analysed the role of low-fidelity DNA polymerases η, ι and θ in synthesizing mutations, and conclude that polymerase η is the dominant participant by generating mutations at A:T base pairs. In the non-mutagenic pathway, we examined the role of the Cockayne syndrome B protein that interacts with other repair proteins. Mice deficient in this protein had normal hypermutation and class switch recombination, showing that it is not involved

The association between birth order and childhood brain tumors: a systematic review and meta-analysis

The incidence of childhood brain tumors (CBT) has increased worldwide, likely resulting from the improvements of early diagnostics. We conducted a systematic review and meta-analysis to clarify the association between birth order and CBT. We followed established guidelines to systematically search Ovid Medline, PubMed, and the Cochrane Library for English language studies, published before March 2018. Quality assessment was performed using the Newcastle-Ottawa Scale. Meta-analysis provided pooled risk estimates and their 95% confidence intervals (CIs) for birth order and CBT. We identified 16 case-control studies with a total sample of 32 439 cases and 166 144 controls and three prospective cohort studies (i.e. 4515 incident cases of CBTs among 5 281 558 participants). Compared with first birth order, the meta-odds ratio for second birth order in case-control studies was 1.04 (95% CI: 1.01-1.07), that for third birth order was 0.98 (95% CI: 0.90-1.06), and that for fourth order was 0.85 (95% CI: 0.78-0.92). The meta-hazard ratio for second or higher birth order compared with first birth order in cohort studies was 1.00 (95% CI: 0.96-1.05). We found no association between birth order and CBT in both case-control and cohort study designs; the small association observed for fourth birth order deserves further consideration

Timing matters: error-prone gap filling and translesion synthesis in immunoglobulin gene hypermutation

By temporarily deferring the repair of DNA lesions encountered during replication, the bypass of DNA damage is critical to the ability of cells to withstand genomic insults. Damage bypass can be achieved either by recombinational mechanisms that are generally accurate or by a process called translesion synthesis. Translesion synthesis involves replacing the stalled replicative polymerase with one of a number of specialized DNA polymerases whose active sites are able to tolerate a distorted or damaged DNA template. While this property allows the translesion polymerases to synthesize across damaged bases, it does so with the trade-off of an increased mutation rate. The deployment of these enzymes must therefore be carefully regulated. In addition to their important role in general DNA damage tolerance and mutagenesis, the translesion polymerases play a crucial role in converting the products of activation induced deaminase-catalysed cytidine deamination to mutations during immunoglobulin gene somatic hypermutation. In this paper, we specifically consider the control of translesion synthesis in the context of the timing of lesion bypass relative to replication fork progression and arrest at sites of DNA damage. We then examine how recent observations concerning the control of translesion synthesis might help refine our view of the mechanisms of immunoglobulin gene somatic hypermutation