ABSTRACT
Current somatic mutation callers are biased against repetitive regions, preventing the identification of potential driver alterations in these loci. We developed a mutation caller for repetitive regions, and applied it to study repetitive non protein-coding genes in more than 2200 whole-genome cases. We identified a recurrent mutation at position c.28 in the gene encoding the snRNA U2. This mutation is present in B-cell derived tumors, as well as in prostate and pancreatic cancer, suggesting U2 c.28 constitutes a driver candidate associated with worse prognosis. We showed that the GRCh37 reference genome is incomplete, lacking the U2 cluster in chromosome 17, preventing the identification of mutations in this gene. Furthermore, the 5'-flanking region of WDR74, previously described as frequently mutated in cancer, constitutes a functional copy of U2. These data reinforce the relevance of non-coding mutations in cancer, and highlight current challenges of cancer genomic research in characterizing mutations affecting repetitive genes.
ABSTRACT
Background Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumour in adults. Due to the ageing of the population, diagnosis in the elderly is becoming more common. The aim of this study was to analyse different combinations of treatments and to identify preoperative factors, including O6-methylguanine-DNA methyltransferase status, that may be associated with decreased survival among patients older than 70 years. Methods and materials We retrospectively included all patients over 70 years of age, who underwent surgery at the Department of Neurosurgery (HUCA and HUMV) and were diagnosed of GBM by pathological criteria from January 2007 to September 2014. Results Eighty-one patients were analysed, whose mean age was 75 (SD 4) and 48 were male. Karnofsky performance status (KPS) was over 70 in 61 patients and 38.3% presented with motor deficit. Sixty-three patients underwent resection, and 18 had only a diagnostic biopsy. The complication rate was 17.28% and mortality rate was 7.4%. Survival was increased in patients who received radiotherapy (n = 41) or additional chemotherapy (n = 26) (p < 0.001). KPS < 70 was an independent factor associated with low-rate survival. Patients with optimal treatment had a median survival of 8 months compared to patients with suboptimal treatment who had a median survival of 4 months (p < 0.001). Conclusions This study suggests that KPS is the most important preoperative prognostic factor. Maximal safe resection followed by radical radiotherapy and temozolomide might be the optimal treatment of choice since glioblastoma-diagnosed patients over 70 years of age showed a statistically significant survival benefit.
