35 In addition, this study identified learn more a new subgroup characterized by polysomy of chromosome 7. Overall, there is increasing evidence that robust and clinically relevant subclassification requires integration of different technologies; future analyses will have to elaborate minimal diagnostic patterns in order to allow rational up-front testing. Although comprehensive analyses of all aspects in a representative collective of HCCs are missing and the existing data are either incomplete or biased, several

conclusions can be safely drawn. First, the vast majority of HCCs represent a classical chromosomally instable tumor (CIN-phenotype) carrying multiple genomic imbalances that is comparable to other adulthood malignancies, such as breast and sporadic colon carcinoma or pancreatic cancer. Microsatellite instability (mismatch repair deficiency) and methylator phenotypes

seem to have little, if any, overall impact. Chromosomal instability increases during tumor progression, suggesting it as a driving factor.78 Because genomic macroimbalances at some genomic loci (but not global chromosomal instability) can be observed already in premalignant Dysplastic Nodules,15 an important question is: Which processes force chromosomal instability or govern relative chromosomal stability, and at which stage during tumor progression are they altered? There is experimental evidence for p53-dependent senescence surveillance that contributes to chromosomal stability,79, 80 but it is unlikely to be the only factor. Molecular mechanisms of Roxadustat chromosomal stability governance may not only offer insights into mechanisms of HCC progression but may also be valuable therapeutic targets even in progressed, chromosomal-instable HCC. Second, somatic mutations in Teicoplanin HCCs (in addition to chromosomal imbalances) include point mutations, small/medium size insertions and deletions, and balanced chromosomal translocations. Some of the HCC mutations are of high frequency (such as codon 249 mutations in TP53 in aflatoxin-exposed

collectives),81 but the vast majority of these mutations affect only small subpopulations of HCCs, as has been demonstrated for Axin mutations.23,82 Mutational analyses of single genes in different HCC populations underscore the molecular heterogeneity of human HCCs as demonstrated also by chromosomal imbalances. Comprehensive mutational data for HCC collectives are lacking and will be collected in the frame of the International Cancer Genome Consortium.17 The first deep sequencing data have been obtained in other adulthood type cancers, such as colon, breast, and pancreatic cancer, where mutations in coding regions of cancer genomes average about 60-80 mutations and in some cases may even reach triple digits.