• Childhood cancer survival in Europe 1999-2007: results of EUROCARE-5--a population-based study.

      Gatta, Gemma; Botta, Laura; Rossi, Silvia; Aareleid, Tiiu; Bielska-Lasota, Magdalena; Clavel, Jacqueline; Dimitrova, Nadya; Jakab, Zsuzsanna; Kaatsch, Peter; Lacour, Brigitte; et al. (Elsevier Science Inc, 2014-01)
      Survival and cure rates for childhood cancers in Europe have greatly improved over the past 40 years and are mostly good, although not in all European countries. The EUROCARE-5 survival study estimates survival of children diagnosed with cancer between 2000 and 2007, assesses whether survival differences among European countries have changed, and investigates changes from 1999 to 2007.
    • A common variant at 8q24.21 is associated with renal cell cancer.

      Gudmundsson, Julius; Sulem, Patrick; Gudbjartsson, Daniel F; Masson, Gisli; Petursdottir, Vigdis; Hardarson, Sverrir; Gudjonsson, Sigurjon A; Johannsdottir, Hrefna; Helgadottir, Hafdis Th; Stacey, Simon N; et al. (Nature Publishing Group, 2013)
      Renal cell carcinoma (RCC) represents between 80 and 90% of kidney cancers. Previous genome-wide association studies of RCC have identified five variants conferring risk of the disease. Here we report the results from a discovery RCC genome-wide association study and replication analysis, including a total of 2,411 patients and 71,497 controls. One variant, rs35252396[CG] located at 8q24.21, is significantly associated with RCC after combining discovery and replication results (OR=1.27, P(combined)=5.4 × 10(-11)) and has an average risk allele frequency in controls of 46%. rs35252396[CG] does not have any strongly correlated variants in the genome and is located within a region predicted to have regulatory functions in several cell lines, including six originating from the kidney. This is the first RCC variant reported at 8q24.21 and it is largely independent (r(2)≤0.02) of the numerous previously reported cancer risk variants at this locus.
    • Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

      Kuchenbaecker, Karoline B; Ramus, Susan J; Tyrer, Jonathan; Lee, Andrew; Shen, Howard C; Beesley, Jonathan; Lawrenson, Kate; McGuffog, Lesley; Healey, Sue; Lee, Janet M; et al. (Nature Publishing Group, 2015-02)
      Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
    • No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer.

      Hollestelle, Antoinette; van der Baan, Frederieke H; Berchuck, Andrew; Johnatty, Sharon E; Aben, Katja K; Agnarsson, Bjarni A; Aittomäki, Kristiina; Alducci, Elisa; Andrulis, Irene L; Anton-Culver, Hoda; et al. (Academic Press Inc Elsevier Science, 2016-05)
      Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370.
    • Processed pseudogenes acquired somatically during cancer development.

      Cooke, Susanna L; Shlien, Adam; Marshall, John; Pipinikas, Christodoulos P; Martincorena, Inigo; Tubio, Jose M C; Li, Yilong; Menzies, Andrew; Mudie, Laura; Ramakrishna, Manasa; et al. (Nature, 2014)
      Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5' truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context.