Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Stem cell dynamics and pretumor progression in the intestinal tract

Colorectal carcinogenesis is a process that follows a stepwise cascade that goes from the normal to an invisible pretumor stage ultimately leading to grossly visible tumor progression. During pretumor progression, an increasing accumulation of genetic alterations occurs, by definition without visible manifestations. It is generally thought that stem cells in the crypt base are responsible for this initiation of colorectal cancer progression because they are the origin of the differentiated epithelial cells that occupy the crypt. Furthermore, they are characterized by a long life span that enables them to acquire these cumulative mutations. Recent studies visualized the dynamics of stem cells both in vitro and in vivo. Translating this work into clinical applications will contribute to the evaluation of patients’ predisposition for colorectal carcinogenesis and may help in the design of preventive measures for high-risk groups. In this review, we outline the progress made in the research into tracing stem cell dynamics. Further, we highlight the importance and potential clinical value of tracing stem cell dynamics in pretumor progression

Age estimation based on Willems method versus new country-specific method in South African black children

AIM : The aims of our study were to develop new maturity scores for dental age estimation in South African black children according to the Willems method, which was developed based on Belgian Caucasian (BC) reference data (Willems et al. J Forensic Sci 46(4):893–895, 2001), and to compare age prediction performance of both methods. SUBJECTS AND METHODS : A total of 986 panoramic radiographs of healthy South African black (SAB) children (493 males and 493 females) in the age range of 4.14 to 14.99 years (mean age 10.06 years) were selected for obtaining developmental staging scores (according to Demirjian et al. Hum Biol 45(2):211–227, 1973). Willems BC methodology was applied to develop new country-specific maturity scores (Willems SAB). Age prediction performance of Willems BC and Willems SAB was compared. RESULTS : On average, Willems BC renders acceptable results with an overestimation of chronological age of 0.06 years (SD 0.88 years) in SAB children. Compared to Willems SAB, the overall mean absolute error was slightly higher with Willems BC (0.62 and 0.68 years, respectively), but this was not significant in males. Also, the root mean squared error was marginally higher in Willems BC. CONCLUSION : The new age prediction method developed in South African black children was found to be better compared to Willems BC, although the difference seems to be small and clinically not relevant, especially in males.http://link.springer.com/journal/4142019-03-01hj2017Oral Pathology and Oral Biolog