Peculiarities of menstrual function in mothers of children with acute lymphoblastic leukemia

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Slide 1 : Peculiarities of menstrual function in mothers of children with acute lymphoblastic leukemia N. Kitsera1, H. ?k?pyan1, R. Polishchuk2, N. H?lner1 1 - ?nstitute of Hereditary Pathology ?cademy of ?edical Sciences of Ukraine, Lviv; - Lviv Regional Children’s Specialized Clinical Hospital, Lviv, Ukraine e-mail: natandi@complex.lviv.ua
Slide 2 : Summary Purpose: To analyse the peculiarities of menstrual function in a group of women having children ill with acute lymphoblastic leukemia (ALL). Patients and methods: The case – control method was used, taking into consideration the age at first menstruation, cycle regularity, duration of menstruation and discharge quantity. The case group included 160 women with children suffering from ALL and the control group included 160 women having healthy children of the corresponding age and sex. Results: It was established that alterations of the menstrual function in mothers of patients with ALL occur with statistically higher rate as compared with women having healthy children. Mothers of pediatric patients with ALL showed later menarche (= 15 years of age), reduced (to 2 days) or prolonged (over 6 days) menses duration, as well as irregularity of the menstrual cycle combined with prolonged menses duration. Conclusion: Menstrual disorders in mothers of children with ALL occur with reliably higher frequency as compared with women having healthy children. The common origin of both events (predisposition to malignancies and menstrual failure) is suggested upon the role of inherited genomic instability. Key words: acute lymphoblastic leukemia, children, menstrual function, mothers
Slide 3 : Introduction The determination of the spectrum of etiological factors influencing the initiation of a neoplastic process and determining the character of its course is one of the most important issues in modern oncology [1]. Actually, the main efforts are focused on the study of genetic markers peculiar to oncological pathology, and the most significant among them are the defects of the control mechanisms responsible for the genome stability and repair of DNA damages [2,3]. It is known that genome imbalance is often combined with hormonal imbalance. The latter can result in chromosome and genome instability and can increase the risk of tissue malignant transformation [4].
Slide 4 : The initiation of a lymphoid proliferative process in pediatric patients presupposes a certain genetic predisposition that causes genome instability, leading to cell cycle alterations and malfunction of DNA repair mechanisms and elimination of cells with abnormal karyotype. Because of the absence of phenotypic anomalies in pediatric patients with ALL, most probably there exists heterozygotic translocation of hypomorphic mutations attached to certain genes participating in these mechanisms. Since the mentioned genes are inherited from the parents, it is not inconceivable that the same genetic defects which cause a child’s predisposition to ALL development can negatively influence the maturation processes in the maternal germ cells. Menstrual dysfunction is complicated in nature and is believed to be multifactorial [5, 6]. At the same time the character of menstrual function reflects the maturation process of germ cells and the hormonal balance of the female organism. The available literature does not cover enough the peculiarities of menstrual function in mothers of pediatric patients with oncological diseases. The objective of the present work was to study the menstrual function peculiarities in women having children with ALL.
Slide 5 : Patients and methods The case-control methodology was used in this study by personal mother’s interview. The study group included 160 mothers with their children (160) undergoing medical treatment in the Hematological Department of Lviv Regional Children’s Special Clinic Hospital (RCSCH) from March 1994 to December 2006 because of ALL. Children’s age varied from 10 months to 16 years (median 3.7 years). Inclusion criteria for study entry involved all of the following: - menstrual function in mothers who had children histological confirmation of ALL; - mohers’ age on delivery – from 17 years till 39 years. The control group included 160 mothers having healthy children of the same age and sex. Their children located in school and kindergarden. The mothers of both groups resided at the territory of Lviv. We estimated the reliability of the difference between the surveyed groups with the help of Student’s coefficient.
Slide 6 : Results Table 1 gives the parameters of menstrual function and mothers’ age on delivery in mothers of pediatric patients with ALL and in mothers of the control group. The age of mothers in the study group changed from 17 till 38 years, in control group made from 17 till 39 years. Only at the statistical analysis it was possible certify that only in the age of 31 year and more, the increase in women (23 study and 12 in control groups) which have given birth to the child with ALL was observed (p<0.05). In 151 cases of the control group and in 130 cases of the study group the first menstruation began at the age of 11–15 years (94.4% and 81.3%, respectively, p>0.05). Two cases of menarche at the age of 11 years were registered in the study group and 2 cases in the control group (p>0.05). The rate of individuals with late menarche (15 and more years) was significantly higher among the mothers of children with ALL compared with the control group: 17.5% and 4.4%, respectively (p<0.01).
Slide 7 : Table 1. Comparative description of menstrual function in the study and control groups
Slide 8 : Menstrual irregularities were more often encountered in the study group than in the control group (25.0% and 1.3%, respectively; p<0.01). At the same time 20.6% of mothers in the study group had irregular cycle combined with menstrual duration up to 7 days, while in the control group this condition had been observed only in 2 cases (1.3%; p<0.01). 59.4% of women in the study group and 96.9% in the control group had menstruation of 3-5 days. Menses duration up to 2 days was observed only in the study group (5.6%; p<0.05). Menstrual cycle over 6 days was noted in 35.0% of cases in the study group and only in 3.1% of the cases in the control group (p<0.01). There was no significant difference of discharge quantity during the menstrual cycle between the groups (p> 0.05). Thus the alterations of the menstrual function were more frequent among the mothers of patients with ALL as compared with the control group. In particular they were characterized by later menarche (= 15 years), by short (up to 2 days) or long (> 6 days), in last case often combined by menses duration and irregular menstrual cycle.
Slide 9 : Discussion Genome instability begins with DNA double-strand breaks (DSBs), which can appear spontaneously or be caused by various genotoxic factors, and also can be the result of hormonal influence [2,3]. Absence of DSBs repair results in abnormal DNA replication and, consequently, chromosomal rearrangements can occur initiating the malignant transformation in cells, including the cases of infantile ALL. The functional insufficiency of DSBs repair mechanisms is characteristic for inherited diseases such as ataxia-telangiectasia (??) and the Nijmegen breakage syndrome (NBS), which are notable for their high sensitivity to genotoxic factors and for the predisposition to the development of lymphoreticular malignancies [7].
Slide 10 : It has been discovered that ATM and p95/nibrin encoded proteins, which show impaired function at ?? and NBS respectively, are indispensable elements of the DSBs repair during V(D)J recombination that leads to occurrence of specific chromosomal rearrangements involving 7th and 14th chromosomes. It is considered that such chromosomal rearrangements give proliferative advantages to the carrier cells and can be the reason of cells’ malignant transformation [7]. What argues for this statement is the high rate of chromosomal rearrangements with the special reference to the 7th and 14th chromosomal pairs in cases of leukemia and lymphoma in adult and pediatric patients [8]. Investigation of AT? and NBS1 genes demonstrates also some gene mutations, mainly missence mutations, which are capable to negatively influence the functional activity of the corresponding proteins. The missence mutations of AT? gene occur in patients with breast cancer and infantile acute myeloid leukemia, and NBS1 gene mutations are characteristic for ALL and for non-Hodgkin’s lymphomas in pediatric patients [9-12].
Slide 11 : It is considered that the process of meiotic chromatid crosslinking which takes place during the maturation of germ cells occurs with DSBs initiation and the activation of repair mechanisms [2]. Using animal models it has been proved that genetic impairments of meiotic chromatid crosslinking and repair mechanisms in females are realized during the ovum division in the prophase of the 1st meiosis, causing blockade of germ cells maturation and their death [2]. It is known that female patients with AT and NBS are characterized not only by functional defects of DSBs repair in lymphocytes, but also by altered maturation of germ cells with the clinical presentation of gonadal dysgenesis and hypergonadotropic hypogonadism [13,14]. The heterozygous carriers of ??? show “half” of its functional activity and reduced efficacy of cellular response to DNA damages [15,16]. Actually nothing is known about the processes connected with meiosis in heterozygous mutation carriers of genes’ repair system, but it is established that they display high sensitivity to genotoxic factors [16].
Slide 12 : Although the ALL cases in pediatric patients are sporadic and the rate of familial forms is very low, the data have been got about high incidence of premature centromere division as a prominent trait of genome instability in blood cultures of parents of sick children [17]. Of note, high rates of cells with signs of genome instability have been observed mainly in one of the parents, with mothers prevailing [17]. We suppose that the same genetic defects, which cause ALL development in pediatric patients, can negatively influence the maturation processes maternal germ cells, who probably are heterozygous carriers of hypomorphic mutations in genes responsible for the cellular repair function. It is advisable while determining the candidate genes for this role to take into consideration the current conception of cellular response to DNA damages and repair of its double-strand breaks [2,3].
Slide 13 : In our opinion, the genetic mutation carriage testing of ATM gene can be especially informative for the prognostication of cancer risk in families. This is indicated by the important role of this gene in the control mechanisms of genome stability and DNA repair, the considerable rate of heterozygous mutation carriers in populations (1% of people) and the high risk of breast cancer among them [9,13]. The next prospective candidate for genetic testing can be NBS1 gene, which is an integral element of the control program for the protection of genome stability [2,3]. The suitability of NBS1 gene mutation screening also results from its mutation prevalence in individuals of Slavonic origin, the high rate of oncological diseases in such families, and the frequent occurrence of NBS1 mutations observed in neoplastic tissues [14,18, 19].
Slide 14 : Heterozygous mutation carriage in mothers who have delivered children with ALL can lead to increased ovum genome instability, and, as a result, to disturbed maturation and intensification of misapplied processes. The objective definition of a destabilizing factor disturbing a woman’s reproductive health requires, alongside with the consideration of parameters characterizing the neuroendocrine regulation of the menstrual function, the carrying out of genetic testing for mutations of genes participating in regulation processes of the cell cycle and repair of DNA damages. Exacerbation can be provoked by the destabilizing influence of certain environmental factors (ionizing radiation and chemical pollutions) first of all by the professional activity of an individual (seamstress, accountant, teacher).
Slide 15 : Conclusions Alterations of the menstrual function in mothers of children with ALL occur with reliably higher rate as compared with women having healthy children. The particular characteristics of mothers of pediatric patients with ALL are the following: later menarche (at the age of 15 and more years), reduction (to 2 days) or prolongation (over 6 days) of menses duration, and also the irregularity of the menstrual cycle combined with prolonged menses duration. The genetic defects of the mechanisms controlling the genome stability can negatively influence both the process of germ cells maturation and blood, that can cause alterations of the menstrual function in women and all in offspring.
Slide 16 : References 1.Lilleyman JS, Hann JM, Blanchetle VS (Eds): Pediatric Hematology. London: Churchill Livigstone, 1999, p 834. 2.Jackson SP. Sensing and repairing DNA double-strand breaks. Carcinogenesis 2002; 23: 687-696. 3.Valerie K, Povirk LF. Regulation and mechanisms of mammalian double-strand break repair. Oncogene 2003; 22: 579-581. 4.McKusick VA. Mendelian inheritance in man: a catalog of human genes and genetic disordes (11th edn). Baltimore, London: The Johns Hopkins University Press, 1994, p 3009. 5.Maruna P. Gynecological aspects of thyroid disorders. A review.Ceska Gynekol 2006; 71: 332-338. [In Chech with Engl. abstract] 6.Bieniasz J, Zak T, Laskowska-Zietek A, Noczynska A. Causes of menstrual disorders in adolescent girls - a retrospective study. Endokrinol Diabetol Chor Przemiany Materii Wieku Rozw 2006; 12: 205-210. [In Polish with Engl. abstract]
Slide 17 : 7.Taylor AMR. Chromosome instability syndromes. Best Pract Res Clin Hematol 2001; 14: 631-644. 8.Gluzman DF, Sklyarenko LM, Nadgomaya VA et al. Structure of leukemias and lymphomas in children of Ukraine in post-Chernobyl period. Exp Oncol 2006; 28: 172-174. 9.Sommer SS, Jiang Z, Feng J et al. ATM missense mutations are frequent in patients with breast cancer. Cancer Genet Cytogenet 2003; 145: 115-120. 10.Oguchi K, Takagi M, Tsuchida R et al. Missense mutation and defective function of ATM in a childhood acute leukemia patient with MLL gene rearrangement. Blood 2003; 101: 3622-3627. 11.Varon R, Reis A, Henze G, Einsiedel HG, Sperling K, Seeger K. Mutations in the Nijmegen Breakage Syndrome Gene (NBS1) in Childhood Acute Lymphoblastic Leukemia (ALL). Cancer Res 2001; 61: 3570 - 3572. 12.Resnick IB, Kondratenko I, Pashanov E et al. 657del5 mutation in the gene for Nijmegen breakage syndrome (NBS1) in a cohort of Russian children with lymphoid tissue malignancies and controls. Am J Med Genet 2003; 120A: 174-179.
Slide 18 : 13.Ataxia-telangiectasia//www3.ncbi.nlm.nih.gov/htbin-post/Omim/208900.– Swift, M. R.; Sholman, L.; Perry, M.; Chase, C. : Malignant neoplasms in the families of patients with ataxia-telangiectasia. Cancer Res. 36: 209-215, 1976. 14.Hiel J.A., Weemaes C. M., van den Heuvel L. P. Nijmegen Breakage Syndrome. The International Nijmegen Breakage Syndrome Study Group. Arch Dis Child 2000; 82: 400-406. 15.Pernin D, Bay JO, Uhrhammer N, Bignon YJ. ATM heterozygote cells exhibit intermediate levels of apoptosis in response to streptonigrin and etoposide. Eur J Cancer 1999; 35: 1130-1135. 16.Bebb DG, Warrington PJ, de Jong G et al. Radiation induced apoptosis in ataxia telangiectasia homozygote, heterozygote and normal cells. Mutat Res 2001; 476: 13-20.
Slide 19 : 17.Akopyan H, Sirenko A, Polishchuk R. Forecasting of family cases of leukaemia on the basis of new cytogenetic markers of cells oncogenic transformation. Ukr Med Visti (Ukraine) 1999;3:123-124. [In Ukrainian with English abstract] 18.Tessitore A, Biordi L, Flati V et al. New mutations and protein variants of NBS1 are identified in cancer cell lines. Genes Chromosomes Cancer 2003; 36: 198-204. 19. Kitsera N., Polishchuk R., Akopyan H. et al. Clinical analysis genealogical peculiarities in families with Nijmegen breakage syndrome. Cytology and Genetics 2005; 39: 72-79

 


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