Although nearly all mammalian species are diploid, whole-genome duplications occur in select mammalian tissues as part of normal development. Such programmed polyploidization involves changes in the regulatory pathways that normally maintain the diploid state of the mammalian genome. Unscheduled whole-genome duplications, which lead primarily to tetraploid cells, also take place in a substantial fraction of human tumors and have been proposed to constitute an important step in the development of cancer aneuploidy. The origins of these polyploidization events and their consequences for tumor progression are explored in this review.

http://delangelab.rockefeller.edu/pubs/128_Davoli_AnnRevCellDevBiol_2010.pdf

The Causes and Consequences of Polyploidy in Normal Development and Cancer

A comparison of cytology and fluorescence in situ hybridization for the detection of urothelial carcinoma

Carcinogenesis is a multistep process in which new, parasitic and polymorphic cancer cells evolve from a single, normal diploid cell. This normal cell is converted to a prospective cancer cell, alias "initiated", either by a carcinogen or spontaneously. The initiated cell typically does not have a new distinctive phenotype yet, but evolves spontaneously--over months to decades--to a clinical cancer. The cells of a primary cancer also evolve spontaneously towards more and more malignant phenotypes. The outstanding genotype of initiated and cancer cells is aneuploidy, an abnormal balance of chromosomes, which increases and varies in proportion with malignancy. The driving force of the spontaneous evolution of initiated and cancerous cells to ever more abnormal phenotypes is said to be their "genetic instability". However, since neither the instability of cancer phenotypes nor the characteristically slow kinetics of carcinogenesis are compatible with gene mutation, we propose here that the driving force of carcinogenesis is the inherent instability of aneuploid karyotypes. Aneuploidy renders chromosome structure and segregation error-prone, because it unbalances mitosis proteins and the many teams of enzymes that synthesize and maintain chromosomes. Thus, carcinogenesis is initiated by a random aneuploidy, which is induced either by a carcinogen or spontaneously. The resulting karyotype instability sets off a chain reaction of aneuploidizations, which generate ever more abnormal and eventually cancer-specific combinations and rearrangements of chromosomes. According to this hypothesis the many abnormal phenotypes of cancer are generated by abnormal dosages of thousands of aneuploid, but un-mutated genes.

Multistep carcinogenesis: a chain reaction of aneuploidizations.

The complexity and diversity of cancer-specific phenotypes, including de-differentiation, invasiveness, metastasis, abnormal morphology and metabolism, genetic instability and progression to malignancy, have so far eluded explanation by a simple, coherent hypothesis. However, an adaptation of Metabolic Control Analysis supports the 100-year-old hypothesis that aneuploidy, an abnormal number of chromosomes, is the cause of cancer. The results demonstrate the currently counter-intuitive principle that it is the fraction of the genome undergoing differential expression, not the magnitude of the differential expression, that controls phenotypic transformation. Transforming the robust normal phenotype into cancer requires a twofold increase in the expression of thousands of normal gene products. The massive change in gene dose produces highly non-linear (i.e. qualitative) changes in the physiology and metabolism of cells and tissues. Since aneuploidy disrupts the natural balance of mitosis proteins, it also explains the notorious genetic instability of cancer cells as a consequence of the perpetual regrouping of chromosomes. In view of this and the existence of non-cancerous aneuploidy, we propose that cancer is the phenotype of cells above a certain threshold of aneuploidy. This threshold is reached either by the gradual, stepwise increase in the level of aneuploidy as a consequence of the autocatalysed genetic instability of aneuploid cells or by tetraploidization followed by a gradual loss of chromosomes. Thus the initiation step of carcinogenesis produces aneuploidy below the threshold for cancer, and the promotion step increases the level of aneuploidy above this threshold. We conclude that aneuploidy offers a simple and coherent explanation for all the cancer-specific phenotypes. Accordingly, the gross biochemical abnormalities, abnormal cellular size and morphology, the appearance of tumour-associated antigens, the high levels of secreted proteins responsible for invasiveness and loss of contact inhibition, and even the daunting genetic instability that enables cancer cells to evade chemotherapy, are all the natural consequence of the massive over- and under-expression of proteins.

http://terzadecade.it/download/cesare_maltoni/36%20-%20Peter%20Duesberg%20and%20David%20Rasnik%20-%20How%20Aneuploidy%20affects%20metabolic%20control%20and%20causes%20cancer%20-%201999.pdf

How aneuploidy affects metabolic control and causes cancer.

Background

Radiation-induced sarcoma of the head and neck (RISHN) is a long-term complication of treatment. The rarity of this tumour is reflected in the very few series reported in the English language medical literature. The incidence of RISHN is, however, likely to increase due to progressive aging of the population combined with improved survival in head and neck cancer patients resulting from better treatment regimes. Diagnosis and management of this problem can be extremely challenging and the overall outlook has been reported to be very bleak. As survival data from isolated case reports cannot be expected to provide reliable information on outcome, we have reviewed 69 cases reported in the English medical literature since 1966 and pooled this information with our experience in treatment of RISHN.



Patients and Methods

Ten patients with features of a RISHN were treated at the Royal Marsden Hospital between 1944 and 1997. The features of RISHN, treatment, and outcome were analysed in these patients. Additionally, 61 eligible patients with RISHN reported in the literature between 1966 and 1997 were pooled with nine of our patients to form the RISHN group (n = 70). This group was then compared for survival with 124 patients with a diagnosis of head and neck sarcoma registered on the Head and Neck Sarcoma database at the Royal Marsden Hospital (SHN group). Lifetables were constructed using the Kaplan-Meier method and compared using the log-rank test.



Results

There was no site of predilection for RISHN, but malignant fibrous histiocytoma (MFH) was the commonest pathological diagnosis. The period of latency between initial radiation therapy and diagnosis of RISHN ranged from 9 to 45 years with a median of 17 years. Surgery was the mainstay of treatment and follow-up ranged from 6 months to 15 years with a median of 48 months. The actuarial five-year disease free survival in these patients was 60%.



Conclusion

There is at present little or no prospect for effective prevention of RISHN and therefore, a high index of suspicion based on the patient's symptoms assumes great importance in the outcome of these patients. Although surgical management of RISHN is challenging because of the close proximity of the tumour to important regional structures and the technical difficulties of operating in an irradiated area, complete surgical excision appears to offer the best means for palliation and the only realistic chance for long-term survival. © 1999 John Wiley & Sons, Inc. Head Neck 21: 346–354, 1999.

Radiation induced sarcoma of the head and neck.

Cytogenetic and flow cytometric studies in a variety of human solid tumors have suggested that gross aneuploidy may arise by a process of abrupt chromosome complement doubling followed by gradual chromosome loss. However, this sequence has not been demonstrated directly in serial studies in individual patients in vivo. The purpose of this study was to search for evidence of chromosome complement doubling and subsequent chromosome loss in flow cytometric ploidy patterns in serial bladder washings and/or biopsies from individual patients with early bladder cancer. Fifty-two patients with noninvasive bladder cancer were followed with serial flow cytometric DNA studies for periods ranging from 5.1 to 42.7 months (median 15.1 months). Serial changes in DNA ploidy and S phase fractions were recorded and correlated with histologic and/or cytologic findings, response to treatment and clinical outcome. The data suggest a series of genetic evolutionary changes in early bladder cancer that include the initial development of peridiploid aneuploidy and repeated rounds of DNA content doubling with chromosome loss in patients with progressive disease. It is likely that gross DNA aneuploidy, and more specifically, DNA multiploidy and DNA hypertetraploidy, all arise by this mechanism. The sequence of DNA diploidy, peridiploid aneuploidy, near-tetraploidy, hypotetraploidy and hypertetraploidy is associated with a progressive increase in S phase fraction, and with increasing tumor grade; late steps in this ploidy sequence were often present in tumors that were refractory to local therapeutic measures and tumors that developed deep tumor invasion and/or distant metastases. We conclude that DNA multiploidy and hypertetraploidy are markers of advanced stages of genetic evolution in human bladder cancer.

Origins and clinical implications of aneuploidy in early bladder cancer.

Complete response of carcinosarcoma of the ovary to therapy with doxorubicin, ifosfamide, and dacarbazine

A patient with a pleomorphic intravascular leiomyosarcoma of the great vessels of the neck and mediastinum presented clinically with a superior vena cava syndrome. A latent period of 29 years elapsed between receiving orthovoltage radiation to the neck and right side of chest to treat recurrent ganglioneuroblastoma, and the appearance of a leiomyosarcoma and subsequent recurrences. The patient underwent partial resection of the tumor, received adjunct chemotherapy, and was shown to be free of disease by clinical tests and by magnetic resonance imaging (MRI) 17 months after completion of chemotherapy. The criteria for the diagnosis of radiation-induced sarcomas are reviewed in relation to the present case. The critical role of magnetic resonance imaging in both the diagnosis and continued follow-up of the patient is described. This would appear to be the first reported case of radiation-induced intravascular leiomyosarcoma of the great vessels of the neck and mediastinum presenting as a superior vena cava syndrome.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%2819870915%2960%3A6%3C1238%3A%3AAID-CNCR2820600613%3E3.0.CO%3B2-V

Radiation-induced leiomyosarcoma of the great vessels presenting as superior vena cava syndrome.

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Origins and clinical implications of aneuploidy in early bladder cancer.

Complete response of carcinosarcoma of the ovary to therapy with doxorubicin, ifosfamide, and dacarbazine

Radiation-induced leiomyosarcoma of the great vessels presenting as superior vena cava syndrome.