This is the first study in sLS patients to include the entire genomic sequence of CRC susceptibility genes. An underlying somatic or germline MMR gene defect was identified in ten of 34 sLS... Show moreThis is the first study in sLS patients to include the entire genomic sequence of CRC susceptibility genes. An underlying somatic or germline MMR gene defect was identified in ten of 34 sLS patients (29%). In the remaining sLS patients, the underlying genetic defect explaining the MMR deficiency in their tumors might be found outside the genomic regions harboring the MMR and other known CRC susceptibility genes. Show less
Surveillance of CDNK2A mutation carriers is relatively successful, detecting most PDACs at a resectable stage. The benefit of surveillance in families with FPC is less evident. (C) 2016 by American... Show moreSurveillance of CDNK2A mutation carriers is relatively successful, detecting most PDACs at a resectable stage. The benefit of surveillance in families with FPC is less evident. (C) 2016 by American Society of Clinical Oncology Show less
Boot, A.; Oosting, J.; Miranda, N.F. de; Zhang, Y.; Corver, W.E.; Water, B. van de; ... ; Wezel, T. van 2016
The genomes of a wide range of cancers, including colon, breast and thyroid cancers frequently show copy number gains of chromosome 7 and rarely show loss of heterozygosity. The molecular basis for... Show moreThe genomes of a wide range of cancers, including colon, breast and thyroid cancers frequently show copy number gains of chromosome 7 and rarely show loss of heterozygosity. The molecular basis for this phenomenon is unknown. Strikingly, oncocytic follicular thyroid carcinomas can display an extreme genomic profile, with homozygosity of all chromosomes except for chromosome 7. The observation that homozygosity of chromosome 7 is never observed suggests that retention of heterozygosity is essential for cells. We hypothesized that cell survival genes are genetically imprinted on either of two copies of chromosome 7 which thwarts loss of heterozygosity at this chromosome in cancer cells. By employing a DNA methylation screen and gene expression analysis we identified six imprinted genes that force retention of heterozygosity on chromosome 7. Subsequent knockdown of gene expression showed that CALCR, COPG2, GRB10, KLF14, MEST and PEG10 were essential for cancer cell survival resulting in reduced cell proliferation, G1 -phase arrest and increased apoptosis. We propose that imprinted cell survival genes provide a genetic basis for retention of chromosome 7 heterozygosity in cancer cells. The monoallelically expressed cell survival genes identified in this study, and the cellular pathways they are involved in, offer new therapeutic targets for the treatment of tumours showing retention of heterozygosity on chromosome 7. DNA methylation data has been submitted to GEO under accession number GSE77804. Show less
Suerink, M.; Klift, H.M. van der; Broeke, S.W. ten; Dekkers, O.M.; Bernstein, I.; Munar, G.C.; ... ; Nielsen, M. 2016
