On 2016 May 27, Hans Morreau commented:

Massive Chromosomal Loss with Subsequent Whole Genome Doubling is seen in a Wide Variety of Rare Tumor Types:

The authors Zheng et al. performed an impressive molecular characterization of 91 cases of adrenal cortical carcinoma (ACC). The integrated analysis is the way to understand the behaviour of this rare disease far better and hopefully will lead to better treatment options. They conclude that there is a subset of ACCs showing massive chromosomal loss with subsequent whole genome doubling (WGD). The authors state that this chromosomal loss leads to a hypodiploid karyotype. Such a phenomenon “was only matched by chromophobe renal cell carcinoma”. The latter is partly correct. In 2012 we published the occurrence near-haploidisation with or without subsequent endoreduplication (whole-genome doubling) in oncocytic follicular thyroid carcinoma (FTC-OV) and anaplastic thyroid carcinoma (ATC) derived from FTC-OV (Corver et al., 2012). In combined SNP array analysis and DNA content analysis the genomes of these lesions were seen as near-homozygous genomes (NHG) with DNA indices of 0.6-1.4 depending on the absence or presence of endoreduplication. Wagle et al. independently confirmed our observations in the New England Journal of Medicine with the description of one ATC patient who showed a spectacular treatment response upon giving the mTOR inhibitor everolimus. The patient’s ATC derived from FTC-OV and high density SNP analysis clearly identified NHG in the tumor. The phenomenon of NHG with or without endoreduplication is similar to the pattern that is seen by Zheng et al, although the terminology to describe this is slightly different. In 2014 we also showed that in a subset of ACC and parathyroid carcinoma NHG and endoreduplication can be seen, especially in tumors with oncocytic metaplasia (Corver et al., 2014). As seen by Zheng et al the “allelic states” (Corver et al., 2008) in ACC indicated the presence of more chromosomal breakpoints than seen in FTC. In fact similar observations of NHG or widespread chromosomal loss with endoreduplication of the complete genome has been described in peripheral chondrosarcomas (Bovee et al., 2000) and a subset of childhood acute lymphoblastic leukemia (Holmfeldt et al., 2013) and other uncommon cancers (Mandahl et al., 2012). It is intriguing what is eventually responsible for the widespread chromosomal loss with or without endoreduplication. In our model we proposed a stepwise process that might be related to metabolic processes, something that still needs to be proven. It might now be a step forward in understanding the underlying biology of endoreduplication/WGD with the observation of Zheng et al. that TERT expression is higher in the WGD group of ACCs. In conclusion the combined analysis of different tumor types with massive chromosomal loss with subsequent WGD might lead to further insights underlying this remarkable process.

References:

Zheng S, Cherniack AD, Dewal N, Moffitt RA, Danilova L, Murray BA, Lerario AM, Else T, Knijnenburg TA, Ciriello G, et al. (2016). Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma. Cancer Cell. 29(5):723-36.

Corver, W. E., Ruano, D., Weijers, K., den Hartog, W. C., van Nieuwenhuizen, M. P., de Miranda, N., van Eijk, R., Middeldorp, A., Jordanova, E. S., Oosting, J., et al. (2012). Genome haploidisation with chromosome 7 retention in oncocytic follicular thyroid carcinoma. PLoS ONE 7, e38287.

Wagle N, Grabiner BC, Van Allen EM, Amin-Mansour A, Taylor-Weiner A, Rosenberg M, Gray N, Barletta JA, Guo Y, Swanson SJ, et al.(2014) Response and acquired resistance to everolimus in anaplastic thyroid cancer. N Engl J Med. 371(15):1426-33.

Corver, W. E., van, W. T., Molenaar, K., Schrumpf, M., van den Akker, B., van, E. R., Ruano, N. D., Oosting, J., and Morreau, H. (2014). Near-haploidization significantly associates with oncocytic adrenocortical, thyroid, and parathyroid tumors but not with mitochondrial DNA mutations. Genes Chromosomes Cancer 53, 833-844.

Corver, W. E., Middeldorp, A., Ter Haar, N. T., Jordanova, E. S., van Puijenbroek, M., van Eijk, R., Cornelisse, C. J., Fleuren, G. J., Morreau, H., Oosting, J., and van Wezel, T. (2008). Genome-wide allelic state analysis on flow-sorted tumor fractions provides an accurate measure of chromosomal aberrations. Cancer Res 68, 10333-10340.

Bovee, J. V., van Royen, M., Bardoel, A. F., Rosenberg, C., Cornelisse, C. J., Cleton-Jansen, A. M., and Hogendoorn, P. C. (2000). Near-haploidy and subsequent polyploidization characterize the progression of peripheral chondrosarcoma. Am J Pathol 157, 1587-1595.

Holmfeldt, L., Wei, L., Diaz-Flores, E., Walsh, M., Zhang, J., Ding, L., Payne-Turner, D., Churchman, M., Andersson, A., Chen, S. C., et al. (2013). The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet 45, 242-252.

Mandahl, N., Johansson, B., Mertens, F., and Mitelman, F. (2012). Disease-associated patterns of disomic chromosomes in hyperhaploid neoplasms. Genes Chromosomes Cancer 51, 536-544.

Hans Morreau, also on behalf of Willem Corver and Tom van Wezel, Dept of Pathology, Leiden University Medical Center The Netherlands Email: j.morreau@lumc.nl.

Note: This comment was also posted on the website of Cancer Cell attached to the manuscript of Zheng et al 2016. This will however not be visible in the PubMed domain. I do not have conflicts of interest to declare.

On 2016 May 27, Hans Morreau commented:

Massive Chromosomal Loss with Subsequent Whole Genome Doubling is seen in a Wide Variety of Rare Tumor Types:

The authors Zheng et al. performed an impressive molecular characterization of 91 cases of adrenal cortical carcinoma (ACC). The integrated analysis is the way to understand the behaviour of this rare disease far better and hopefully will lead to better treatment options. They conclude that there is a subset of ACCs showing massive chromosomal loss with subsequent whole genome doubling (WGD). The authors state that this chromosomal loss leads to a hypodiploid karyotype. Such a phenomenon “was only matched by chromophobe renal cell carcinoma”. The latter is partly correct. In 2012 we published the occurrence near-haploidisation with or without subsequent endoreduplication (whole-genome doubling) in oncocytic follicular thyroid carcinoma (FTC-OV) and anaplastic thyroid carcinoma (ATC) derived from FTC-OV (Corver et al., 2012). In combined SNP array analysis and DNA content analysis the genomes of these lesions were seen as near-homozygous genomes (NHG) with DNA indices of 0.6-1.4 depending on the absence or presence of endoreduplication. Wagle et al. independently confirmed our observations in the New England Journal of Medicine with the description of one ATC patient who showed a spectacular treatment response upon giving the mTOR inhibitor everolimus. The patient’s ATC derived from FTC-OV and high density SNP analysis clearly identified NHG in the tumor. The phenomenon of NHG with or without endoreduplication is similar to the pattern that is seen by Zheng et al, although the terminology to describe this is slightly different. In 2014 we also showed that in a subset of ACC and parathyroid carcinoma NHG and endoreduplication can be seen, especially in tumors with oncocytic metaplasia (Corver et al., 2014). As seen by Zheng et al the “allelic states” (Corver et al., 2008) in ACC indicated the presence of more chromosomal breakpoints than seen in FTC. In fact similar observations of NHG or widespread chromosomal loss with endoreduplication of the complete genome has been described in peripheral chondrosarcomas (Bovee et al., 2000) and a subset of childhood acute lymphoblastic leukemia (Holmfeldt et al., 2013) and other uncommon cancers (Mandahl et al., 2012). It is intriguing what is eventually responsible for the widespread chromosomal loss with or without endoreduplication. In our model we proposed a stepwise process that might be related to metabolic processes, something that still needs to be proven. It might now be a step forward in understanding the underlying biology of endoreduplication/WGD with the observation of Zheng et al. that TERT expression is higher in the WGD group of ACCs. In conclusion the combined analysis of different tumor types with massive chromosomal loss with subsequent WGD might lead to further insights underlying this remarkable process.

References:

Zheng S, Cherniack AD, Dewal N, Moffitt RA, Danilova L, Murray BA, Lerario AM, Else T, Knijnenburg TA, Ciriello G, et al. (2016). Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma. Cancer Cell. 29(5):723-36.

Corver, W. E., Ruano, D., Weijers, K., den Hartog, W. C., van Nieuwenhuizen, M. P., de Miranda, N., van Eijk, R., Middeldorp, A., Jordanova, E. S., Oosting, J., et al. (2012). Genome haploidisation with chromosome 7 retention in oncocytic follicular thyroid carcinoma. PLoS ONE 7, e38287.

Wagle N, Grabiner BC, Van Allen EM, Amin-Mansour A, Taylor-Weiner A, Rosenberg M, Gray N, Barletta JA, Guo Y, Swanson SJ, et al.(2014) Response and acquired resistance to everolimus in anaplastic thyroid cancer. N Engl J Med. 371(15):1426-33.

Corver, W. E., van, W. T., Molenaar, K., Schrumpf, M., van den Akker, B., van, E. R., Ruano, N. D., Oosting, J., and Morreau, H. (2014). Near-haploidization significantly associates with oncocytic adrenocortical, thyroid, and parathyroid tumors but not with mitochondrial DNA mutations. Genes Chromosomes Cancer 53, 833-844.

Corver, W. E., Middeldorp, A., Ter Haar, N. T., Jordanova, E. S., van Puijenbroek, M., van Eijk, R., Cornelisse, C. J., Fleuren, G. J., Morreau, H., Oosting, J., and van Wezel, T. (2008). Genome-wide allelic state analysis on flow-sorted tumor fractions provides an accurate measure of chromosomal aberrations. Cancer Res 68, 10333-10340.

Bovee, J. V., van Royen, M., Bardoel, A. F., Rosenberg, C., Cornelisse, C. J., Cleton-Jansen, A. M., and Hogendoorn, P. C. (2000). Near-haploidy and subsequent polyploidization characterize the progression of peripheral chondrosarcoma. Am J Pathol 157, 1587-1595.

Holmfeldt, L., Wei, L., Diaz-Flores, E., Walsh, M., Zhang, J., Ding, L., Payne-Turner, D., Churchman, M., Andersson, A., Chen, S. C., et al. (2013). The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet 45, 242-252.

Mandahl, N., Johansson, B., Mertens, F., and Mitelman, F. (2012). Disease-associated patterns of disomic chromosomes in hyperhaploid neoplasms. Genes Chromosomes Cancer 51, 536-544.

Hans Morreau, also on behalf of Willem Corver and Tom van Wezel, Dept of Pathology, Leiden University Medical Center The Netherlands Email: j.morreau@lumc.nl.

Note: This comment was also posted on the website of Cancer Cell attached to the manuscript of Zheng et al 2016. This will however not be visible in the PubMed domain. I do not have conflicts of interest to declare.