Nongonadal neoplasia in Turners syndrome
TL;DR: A multi‐hospital survey of 289 cases and literature review showed a preponderance of neurogenic tumors among children and young adults, suggesting that developmental neural defects, hamartomatous growths, and susceptibility to Neurogenic tumors are related to one another as expressions of Turner's phenotype.
Abstract: Evaluation of extragonadal tumors in Turner's syndrome by a multi-hospital survey of 289 cases and literature review showed a preponderance of neurogenic tumors among children and young adults. These neoplasms occurred also in a small series of “male Turner's syndrome,” suggesting that developmental neural defects, hamartomatous growths, and susceptibility to neurogenic tumors are related to one another as expressions of Turner's phenotype.
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TL;DR: The data suggest that patients with Turner syndrome are extraordinarily prone to abnormalities constituting the metabolic syndrome (e.g., hypertension, dyslipidaemia, NIDDM, obesity, hyperinsulinemia and hyperuricemia), which may help to explain the decreased life span found in patients withTurner syndrome.
507 citations
TL;DR: The prevalence of neoplasia is increased in individuals with certain disorders of sexual differentiation and the prevalence of gonadal tumors is not increased in Klinefelter's syndrome, further indicating that gonadotropins are not carcinogenic per se.
354 citations
TL;DR: To understand the role of aneuploidy in carcinogenesis, cellular and molecular studies coupled with the cytogenetic studies will be required, and the lack of a genetic assay with mammalian cells for aneuPLoidy is a serious limitation in these studies.
Abstract: A growing body of evidence from human and animal cancer cytogenetics indicates that aneuploidy is an important chromosome change in carcinogenesis. Aneuploidy may be associated with a primary event of carcinogenesis in some cancers and a later change in other tumors. Evidence from in vitro cell transformation studies supports the idea that aneuploidy has a direct effect on the conversion of a normal cell to a preneoplastic or malignant cell. Induction of an aneuploid state in a preneoplastic or neoplastic cell could have any of the following four biological effects: a change in gene dosage, a change in gene balance, expression of a recessive mutation, or a change in genetic instability (which could secondarily lead to neoplasia). To understand the role of aneuploidy in carcinogenesis, cellular and molecular studies coupled with the cytogenetic studies will be required. There are a number of possible mechanisms by which chemicals might induce aneuploidy, including effects on microtubules, damage to essential elements for chromosome function (ie, centromeres, origins of replication, and telomeres), reduction in chromosome condensation or pairing, induction of chromosome interchanges, unresolved recombination structures, increased chromosome stickiness, damage to centrioles, impairment of chromosome alignment, ionic alterations during mitosis, damage to the nuclear membrane, and a physical disruption of chromosome segregation. Therefore, a number of different targets exist for chemically induced aneuploidy. Because the ability of certain chemicals to induce aneuploidy differs between mammalian cells and lower eukaryotic cells, it is important to study the mechanisms of aneuploidy induction in mammalian cells and to use mammalian cells in assays for potential aneuploidogens (chemicals that induce aneuploidy). Despite the wide use of mammalian cells for studying chemically induced mutagenesis and chromosome breakage, aneuploidy studies with mammalian cells are limited. The lack of a genetic assay with mammalian cells for aneuploidy is a serious limitation in these studies.
249 citations
TL;DR: In addition to having an increased risk of gonadoblastoma, women with Turner syndrome seem to be at increased risk for meningioma and childhood brain tumours, and possibly bladder cancer, melanoma, and corpus uteri cancer, but are at a decreased risk for breast cancer.
Abstract: Summary Background Turner syndrome, one of the most common cytogenetic abnormalities, is characterised by complete or partial X-chromosome monosomy. Cancer risks in women with Turner syndrome have not been clearly established. We aimed to compare the risk of cancer in women with this syndrome with that of the general population. Methods We formed a national cohort of 3425 women who were cytogenetically diagnosed with Turner syndrome in Great Britain between 1959 and 2002. Identifying information for these patients was sent to the National Health Service Central Register (NHSCR) for England and Wales and to the NHSCR for Scotland. Individuals who were identified on this register were followed-up for cancer incidence. Standardised incidence ratios (SIRs) and 95% CIs were calculated on the basis of the number of cancers observed compared with that expected based on national incidence rates. Cumulative risk estimates were obtained by use of the Kaplan-Meier method. Findings A total of 58 299 person-years were accrued during the study, with a mean of 17·0 years (SD 8·6) follow-up per patient. 73 malignancies other than non-melanoma skin cancer occurred (SIR 0·9 [95% CI 0·7–1·2]). Risks were significantly increased for tumours of the CNS (n=13; 4·3 [2·3–7·4]), especially for meningioma (n=7; 12·0 [4·8–24·8]) and childhood brain tumours (n=3; 10·3 [2·1–30·1]), and for cancers of the bladder and urethra (n=5; 4·0 [1·3–9·2]) and eye (n=2; 10·5 [1·3–37·9]), compared with the general population. However, the risk of breast cancer was significantly decreased (n=10; 0·3 [0·2–0·6]). The SIR for cutaneous melanoma was 2·2 (95% CI 1·0–4·4; n=8), and one of the ocular cancers was a melanoma. The risk of corpus uteri cancer was significantly increased at ages 15–44 years (n=3; 8·0 [1·6–23·2]). During follow-up, five women, all with a Y-chromosome lineage, developed gonadoblastoma of the ovary, corresponding to a cumulative risk of 7·9% (95% CI 3·1–19·0) by age 25 years in this group. Interpretation This study shows that, in addition to having an increased risk of gonadoblastoma, women with Turner syndrome seem to be at increased risk for meningioma and childhood brain tumours, and possibly bladder cancer, melanoma, and corpus uteri cancer, but are at a decreased risk for breast cancer. Reasons for these risks might relate to genetic and hormonal factors or to the effects of hormonal treatments given to women with Turner syndrome.
168 citations
TL;DR: There is no evidence for a unique germ cell aneugen, that is a chemical that induces aneuploidy in germ cells and not in somatic cells, and an analysis of several databases indicates the proportion of chemicals which induce polyploidsy and not chromosome aberrations in vitro is low.
Abstract: Aneuploidy plays a significant role in adverse human health conditions including birth defects, pregnancy wastage and cancer. Although there is clear evidence of chemically induced aneuploidy in experimental systems, to date there are insufficient data to determine with certainty if chemically induced aneuploidy contributes to human disease. However, since there is no reason to assume that chemically induced aneuploidy will not occur in human beings, it is prudent to address the aneugenic potential of chemicals in the safety assessment process. A wide range of methods has been described for the detection of chemically induced aneuploidy including subcellular systems, tests with fungi, plants and Drosophila as well as in vitro mammalian systems and in vivo mammalian somatic and germ cell assays. However, none of these methods is sufficiently validated or widely used in routine screening. Underlying the efforts to develop aneuploidy-specific assays is the presumption that current genetic toxicology tests do not detected chemicals that have aneuploidy-inducing potential. To address this, we have critically evaluated data from standard genetic toxicology assays for 16 known or suspected aneugens. The conclusions from the review are listed below. 1. At present there are only nine chemicals that can be classified as definitive aneugens, as determined by positive results in in vivo rodent assays. 2. As expected, the majority of definitive and suspected aneugens are negative in the bacterial mutation assay. 3. The majority of definitive aneugens evaluated induce polyploidy in vitro. With few exceptions, they also induced structural chromosome aberrations in vitro. 4. All of the definitive aneugens that have been sufficiently tested induce micronuclei in rodent bone marrow cells in vivo. A number of these chemicals also induced structural chromosome aberrations in vivo. 5. There is no evidence for a unique germ cell aneugen, that is a chemical that induces aneuploidy in germ cells and not in somatic cells.
Furthermore, an analysis of several databases indicates the proportion of chemicals which induce polyploidy and not chromosome aberrations in vitro is low. Based on these conclusions, the following recommendations are made: • for screening purposes, a standard genotoxicity test battery (including an in vitro cytogenetic assay with an assessment of polyploidy and clastogenicity at the same harvest time) should be performed; • in the absence of polyploidy induction in vitro no further evaluation of aneuploidy-inducing potential is needed; • if polyploidy is observed, in vitro follow-up testing to investigate further the aneuploidy-inducing potential should be conducted; ◦ such follow-up testing will generally start with the conduct of a standard in vivo somatic cell micronucleus assay; ◦ if the in vivo somatic cell micronucleus assay is negative, with adequate evidence of exposure of the bone marrow to the test compound, no further testing of aneuploidy-inducing potential is needed; ◦ if the in vivo somatic cell micronucleus assay is positive, further information on mechanisms of micronucleus induction can be obtained by using kinetochore/centromeric staining in vitro and/or in vivo; ◦ an assessment of potential germ cell aneuploidy activity may then be considered; • aneuploidy induction which does not involve the direct interaction of a chemical or its metabolite(s) with DNA is expected to have a threshold. This must be considered in the risk assessment of such chemicals; this is not addressed by current risk assessment guidelines.
143 citations
References
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TL;DR: A new "familial" syndrome of neoplastic diseases in which heredity or oncogenic agents, or both, may have a causal role is suggested.
Abstract: c Four families were identified in SUMMARY w h i c h a p a j [ r o f c h i l d r e n h a d s o f t . tissue sarcomas: three sets of sibs and one set of cousins. One parent of each affected child developed cancer; carcinoma of the breast occurred in three mothers under 30 years of age. Other young adults in these families had a high frequency of cancer, with no evidence of underlying genetic disorders known to carry a high risk of neoplasia. The increased familial susceptibility to cancer was manifested not only by the large number of members affected but by a seeming excess of multiple primary neoplasms. These findings suggest a new \"familial\" syndrome of neoplastic diseases in which heredity or oncogenic agents, or both, may have a causal role.
1,357 citations
TL;DR: A perspective of current knowledge concerning the excessive coexistence of these diseases as determined by study of individuals, families or communities is presented.
Abstract: WHEN diseases are found to occur together more often than can be attributed to chance, each can be studied in the light of what is known of the other for clues to etiology Particularly informative in this regard has been a series of recent observations linking certain cancers with specific malformations Presented here is a perspective of current knowledge concerning the excessive coexistence of these diseases as determined by study of individuals, families or communities Concurrence of Cancer and Congenital Defects in Individuals Cancer and Down's Syndrome Pediatricians generally knew from clinical experience that in children with Down's syndrome (mongolism)
166 citations
TL;DR: The authors point to the danger of gonadal neoplasm in patient with female phenotype, primary amenorrhea, signs of masculinization and presence of a negative sex chromatin pattern and a Y chromosome.
Abstract: The occurrence of gonadal tumors was studied in 51 patients with gonadal dysgenesis. The patients have female legal sex and complained of primary amenorrhea. They were classified into two main groups: Turner's syndrome—25 cases; and gonadal dysgenesis (without somatic malformations)—26 cases. Of 25 cases of Turner's syndrome two cases of gonadal tumors were found—one gonadoblastoma and one interstitioma. Of 26 cases of gonadal dysgenesis without somatic malformations eight tumors were found—dysgerminoma (seminoma) in four cases, gonadoblastoma in three cases and a Brenner tumor in one. In all ten cases with gonadal tumors a negative sex chromatin pattern was found. Cytogenetic analysis revealed a normal male 46/XY karyotype in seven cases and in one case a 45/XO//46/XY mosaic was present. In all ten cases high secretion of gonadotrophins was encountered. The authors conclude that persistent germ cells from the embryonic stage, within malformed testicular elements or within so-called bisexual formations play an important role in pathogenesis. The authors point to the danger of gonadal neoplasm in patient with female phenotype, primary amenorrhea, signs of masculinization and presence of a negative sex chromatin pattern and a Y chromosome.
147 citations
128 citations
TL;DR: It is indicated that greater accuracy and completeness in filling out death certificates would greatly aid research and the clinical benefits derived from it, and that, contrary to popular opinion, myelogenous leukemia is not significantly more common than usual in Down's syndrome.
Abstract: Extract: Study was made of the death certificates for all 29,457 children under 15 years of age who died of cancer in the United States during 1960–1966. Congenital defects were greatly underreported, but from the anomalies that were recorded, some new understanding of the relation between oncogenesis and teratogenesis may be derived. On 146 death certificates, Down's syndrome was listed with leukemia, an 11-fold excess over normal expectation. The peak mortality occurred at two years of age. In the general population, the peak occurs two years later and is due to an increase in the rates for acute lymphocytic leukemia. This study and others indicate that, contrary to popular opinion, myelogenous leukemia is not significantly more common than usual in Down's syndrome. The association of Wilms' tumor with aniridia or renal anomalies, unknown when the death certificates were made out, was nevertheless apparent. There were previously unreported cases of leukemia with osteogenesis imperfecta, Marfan's syndrome, Treacher-Collins syndrome, and Ollier's syndrome. These cases, and others described in the literature, raise the possibility that certain genetically induced disorders of bone or connective tissue may predispose to leukemia. There were also four new cases of leukemia-lymphoma with immunological abnormality (two with myasthenia gravis; one each with ataxia-telangiectasia and agammaglobulinemia), and two with leukemia and congenital granulocytic abnormalities (one each with agranulocytosis and familial granulomatosis). Other concurrences of possible etiologic significance included two of phenylketonuria and leukemia-lymphoma, three of tetralogy of Fallot and glioma and one of cleidocranial dysostosis and medulloblastoma. Clarification of these relations may come from studies of susceptibility to viral transformation in vitro of skin fibroblasts from children with the anomalies noted above. This study indicates that greater accuracy and completeness in filling out death certificates would greatly aid research and the clinical benefits derived from it. Speculation: Although imperfect, diagnoses recorded on death certificates may provide clues to as yet unknown relations between cancer and congenital defects.
121 citations