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Grant Details

Grant Number: 5R01CA104666-05 Interpret this number
Primary Investigator: Boice, John
Organization: Vanderbilt University
Project Title: Genetic Consequences of Therapies for Cancer
Fiscal Year: 2009
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Abstract

Our objective is to conduct a large-scale retrospective cohort study of the offspring of survivors of childhood and earlyonset cancer and determine the extent to which curative therapies, radiation and chemotherapy that are mutagenic in test systems, contribute to adverse health outcomes or other inherited effects defined as cancer, birth defects, stillbirths, neonatal and all other premature deaths. The treatment of cancer among the young has become increasingly successful. For example, over 270,000 survivors of childhood cancer are estimated to be alive today in the United States alone and many are able to have children of their own. Consequently, the possible effects of curative treatments on inherited disorders in cancer survivors are becoming increasingly important. However, there is little understanding of the genetic consequences of these treatments or whether underlying susceptibility can be transmitted to their offspring. Further, young adults diagnosed with cancer at ages 20-34 years are often overlooked in studies of late effects. While there is little evidence that mutagenic therapies can result in transgenerational effects, few studies have looked at risk in terms of treatment dose to testes or ovaries. All persons diagnosed with cancer under age 35 after 1943 in Denmark and after 1952 in Finland will be identified, along with their siblings. Among the 10,000 children with cancer who survived to reproductive ages, 3,000 are estimated to have become the parents of 5,600 children. Among the 38,000 patients diagnosed with cancer as young adults, 25,000 survived and had 14,000 children after their cancer diagnosis. Thus, 19,600 offspring of cancer survivors can be studied. Rosters of siblings and their offspring will be developed for comparison purposes. The offspring cohorts in Denmark and Finland will be linked to outcome registries to identify cancer, birth defects, stillbirths and neonatal and other deaths. Medical records of the cancer survivors will be obtained and radiation records and chemotherapy information abstracted. Radiation doses to gonads (and uterus for female survivors) will be calculated, and the genetic consequences of curative therapies will be assessed. The gonadal exposures to radiation or chemotherapy for many cancer survivors will be high and just below the threshold for infertility. Blood samples will be collected from a sample of survivors, their spouses and their offspring to examine a number of mechanistic processes related to cancer predisposition and the effect of therapy on potential health outcomes both in the patients themselves and their offspring. 200 families will donate lymphocytes and DMA for storage and laboratory analyses that will include the G2 radiation assay to assess chromosomal radiosensitivity (that might be related to alterations of DMA damage-response/repair genes) and to determine whether such a sensitivity can be inherited; evaluation of specific repair genes, eg, XRCC1, for variant polymorphisms; and evaluation of minisatellite inheritance. A pilot study in Denmark has indicated that the proposed research approach is feasible. The study should help answer questions regarding the genetic consequences of mutagenic exposures, explore whether susceptibility states and specific genetic polymorphisms conferring susceptibility can be identified for specific cancers, and evaluate the extent to whtch-identifled genetic susceptibility or genetic damage can be transmitted to future generations.

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Publications

Very low-level heteroplasmy mtDNA variations are inherited in humans.
Authors: Guo Y, Li CI, Sheng Q, Winther JF, Cai Q, Boice JD, Shyr Y
Source: J Genet Genomics, 2013 Dec 20;40(12), p. 607-15.
EPub date: 2013 Dec 8.
PMID: 24377867
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Stillbirth, early death and neonatal morbidity among offspring of female cancer survivors.
Authors: Madanat-Harjuoja LM, Lähteenmäki PM, Dyba T, Gissler M, Boice JD Jr, Malila N
Source: Acta Oncol, 2013 Aug;52(6), p. 1152-9.
EPub date: 2013 Jan 17.
PMID: 23327340
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Intra-individual variation in G2 chromosomal radiosensitivity.
Authors: Curwen GB, Cadwell KK, Tawn EJ, Winther JF, Boice JD Jr
Source: Mutagenesis, 2012 Jul;27(4), p. 471-5.
EPub date: 2012 Mar 15.
PMID: 22422822
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The use of next generation sequencing technology to study the effect of radiation therapy on mitochondrial DNA mutation.
Authors: Guo Y, Cai Q, Samuels DC, Ye F, Long J, Li CI, Winther JF, Tawn EJ, Stovall M, Lähteenmäki P, Malila N, Levy S, Shaffer C, Shyr Y, Shu XO, Boice JD Jr
Source: Mutat Res, 2012 May 15;744(2), p. 154-60.
EPub date: 2012 Feb 24.
PMID: 22387842
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Congenital anomalies in the children of cancer survivors: a report from the childhood cancer survivor study.
Authors: Signorello LB, Mulvihill JJ, Green DM, Munro HM, Stovall M, Weathers RE, Mertens AC, Whitton JA, Robison LL, Boice JD Jr
Source: J Clin Oncol, 2012 Jan 20;30(3), p. 239-45.
EPub date: 2011 Dec 12.
PMID: 22162566
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Genetic disease in the children of Danish survivors of childhood and adolescent cancer.
Authors: Winther JF, Olsen JH, Wu H, Shyr Y, Mulvihill JJ, Stovall M, Nielsen A, Schmiegelow M, Boice JD Jr
Source: J Clin Oncol, 2012 Jan 1;30(1), p. 27-33.
EPub date: 2011 Nov 28.
PMID: 22124106
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Long-term non-cancer mortality in pediatric and young adult cancer survivors in Finland.
Authors: Prasad PK, Signorello LB, Friedman DL, Boice JD Jr, Pukkala E
Source: Pediatr Blood Cancer, 2012 Mar;58(3), p. 421-7.
EPub date: 2011 Sep 9.
PMID: 21910209
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Hospitalizations among children of survivors of childhood and adolescent cancer: a population-based cohort study.
Authors: Winther JF, Boice JD Jr, Christensen J, Frederiksen K, Mulvihill JJ, Stovall M, Olsen JH
Source: Int J Cancer, 2010 Dec 15;127(12), p. 2879-87.
PMID: 21351267
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A study of DNA damage recognition and repair gene polymorphisms in relation to cancer predisposition and G2 chromosomal radiosensitivity.
Authors: Curwen GB, Murphy S, Tawn EJ, Winther JF, Boice JD Jr
Source: Environ Mol Mutagen, 2011 Jan;52(1), p. 72-6.
PMID: 21113933
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Germline minisatellite mutations in survivors of childhood and young adult cancer treated with radiation.
Authors: Tawn EJ, Rees GS, Leith C, Winther JF, Curwen GB, Stovall M, Olsen JH, Rechnitzer C, Schroeder H, Guldberg P, Boice JD
Source: Int J Radiat Biol, 2011 Mar;87(3), p. 330-40.
EPub date: 2010 Nov 19.
PMID: 21087171
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G2 checkpoint control and G2 chromosomal radiosensitivity in cancer survivors and their families.
Authors: Cadwell KK, Curwen GB, Tawn EJ, Winther JF, Boice JD Jr
Source: Mutagenesis, 2011 Mar;26(2), p. 291-4.
EPub date: 2010 Nov 2.
PMID: 21044988
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The heritability of G2 chromosomal radiosensitivity and its association with cancer in Danish cancer survivors and their offspring.
Authors: Curwen GB, Cadwell KK, Winther JF, Tawn EJ, Rees GS, Olsen JH, Rechnitzer C, Schroeder H, Guldberg P, Cordell HJ, Boice JD Jr
Source: Int J Radiat Biol, 2010 Nov;86(11), p. 986-95.
EPub date: 2010 Sep 1.
PMID: 20807177
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Stillbirth and neonatal death in relation to radiation exposure before conception: a retrospective cohort study.
Authors: Signorello LB, Mulvihill JJ, Green DM, Munro HM, Stovall M, Weathers RE, Mertens AC, Whitton JA, Robison LL, Boice JD Jr
Source: Lancet, 2010 Aug 21;376(9741), p. 624-30.
EPub date: 2010 Jul 23.
PMID: 20655585
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Comparison of germ line minisatellite mutation detection at the CEB1 locus by Southern blotting and PCR amplification.
Authors: Taylor M, Cieslak M, Rees GS, Oojageer A, Leith C, Bristow C, Tawn EJ, Winther JF, Boice JD Jr
Source: Mutagenesis, 2010 Jul;25(4), p. 343-9.
EPub date: 2010 Mar 12.
PMID: 20228094
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Preterm delivery among female survivors of childhood, adolescent and young adulthood cancer.
Authors: Madanat-Harjuoja LM, Malila N, Lähteenmäki PM, Boice JD Jr, Gissler M, Dyba T
Source: Int J Cancer, 2010 Oct 1;127(7), p. 1669-79.
PMID: 20054856
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Risk of cancer among children of cancer patients - a nationwide study in Finland.
Authors: Madanat-Harjuoja LM, Malila N, Lähteenmäki P, Pukkala E, Mulvihill JJ, Boice JD Jr, Sankila R
Source: Int J Cancer, 2010 Mar 1;126(5), p. 1196-205.
PMID: 19728329
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Induced abortions in Danish cancer survivors: a population-based cohort study.
Authors: Winther JF, Boice JD Jr, Svendsen AL, Frederiksen K, Olsen JH
Source: J Natl Cancer Inst, 2009 May 6;101(9), p. 687-9.
EPub date: 2009 Apr 28.
PMID: 19401553
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Pediatric cancer survivorship research: experience of the Childhood Cancer Survivor Study.
Authors: Leisenring WM, Mertens AC, Armstrong GT, Stovall MA, Neglia JP, Lanctot JQ, Boice JD Jr, Whitton JA, Yasui Y
Source: J Clin Oncol, 2009 May 10;27(14), p. 2319-27.
EPub date: 2009 Apr 13.
PMID: 19364957
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Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the Childhood Cancer Survivor Study.
Authors: Green DM, Sklar CA, Boice JD Jr, Mulvihill JJ, Whitton JA, Stovall M, Yasui Y
Source: J Clin Oncol, 2009 May 10;27(14), p. 2374-81.
EPub date: 2009 Apr 13.
PMID: 19364956
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Radiotherapy for childhood cancer and risk for congenital malformations in offspring: a population-based cohort study.
Authors: Winther JF, Boice JD Jr, Frederiksen K, Bautz A, Mulvihill JJ, Stovall M, Olsen JH
Source: Clin Genet, 2009 Jan;75(1), p. 50-6.
EPub date: 2008 Nov 17.
PMID: 19021636
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Probability of parenthood after early onset cancer: a population-based study.
Authors: Madanat LM, Malila N, Dyba T, Hakulinen T, Sankila R, Boice JD Jr, Lähteenmäki PM
Source: Int J Cancer, 2008 Dec 15;123(12), p. 2891-8.
PMID: 18798259
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Spontaneous abortion in a Danish population-based cohort of childhood cancer survivors.
Authors: Winther JF, Boice JD Jr, Svendsen AL, Frederiksen K, Stovall M, Olsen JH
Source: J Clin Oncol, 2008 Sep 10;26(26), p. 4340-6.
PMID: 18779621
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Assessing human germ-cell mutagenesis in the Postgenome Era: a celebration of the legacy of William Lawson (Bill) Russell.
Authors: Wyrobek AJ, Mulvihill JJ, Wassom JS, Malling HV, Shelby MD, Lewis SE, Witt KL, Preston RJ, Perreault SD, Allen JW, Demarini DM, Woychik RP, Bishop JB
Source: Environ Mol Mutagen, 2007 Mar;48(2), p. 71-95.
PMID: 17295306
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Influence of polymorphisms at loci encoding DNA repair proteins on cancer susceptibility and G2 chromosomal radiosensitivity.
Authors: Wilding CS, Curwen GB, Tawn EJ, Sheng X, Winther JF, Chakraborty R, Boice JD Jr
Source: Environ Mol Mutagen, 2007 Jan;48(1), p. 48-57.
PMID: 17177211
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Female survivors of childhood cancer: preterm birth and low birth weight among their children.
Authors: Signorello LB, Cohen SS, Bosetti C, Stovall M, Kasper CE, Weathers RE, Whitton JA, Green DM, Donaldson SS, Mertens AC, Robison LL, Boice JD Jr
Source: J Natl Cancer Inst, 2006 Oct 18;98(20), p. 1453-61.
PMID: 17047194
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A pilot study examining germline minisatellite mutations in the offspring of Danish childhood and adolescent cancer survivors treated with radiotherapy.
Authors: Rees GS, Trikic MZ, Winther JF, Tawn EJ, Stovall M, Olsen JH, Rechnitzer C, Schrøder H, Guldberg P, Boice JD Jr
Source: Int J Radiat Biol, 2006 Mar;82(3), p. 153-60.
PMID: 16638712
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G(2) chromosomal radiosensitivity in Danish survivors of childhood and adolescent cancer and their offspring.
Authors: Curwen GB, Winther JF, Tawn EJ, Smart V, Whitehouse CA, Rees GS, Olsen JH, Guldberg P, Rechnitzer C, Schrøder H, Bryant PE, Sheng X, Lee HS, Chakraborty R, Boice JD
Source: Br J Cancer, 2005 Oct 31;93(9), p. 1038-45.
PMID: 16234827
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Chromosome analysis in childhood cancer survivors and their offspring--no evidence for radiotherapy-induced persistent genomic instability.
Authors: Tawn EJ, Whitehouse CA, Winther JF, Curwen GB, Rees GS, Stovall M, Olsen JH, Guldberg P, Rechnitzer C, Schrøder H, Boice JD Jr
Source: Mutat Res, 2005 Jun 6;583(2), p. 198-206.
PMID: 15914077
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