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Genetic factors in childhood cancer. Associations between tumors in childhood and adulthood, and prevalence of germline TP53 mutations

Magnusson, Susanne LU (2012) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2012:24.
Abstract (Swedish)
Popular Abstract in Swedish

Varje år insjuknar omkring 300 barn i cancer. Förbättrade behandlingsmetoder under de senaste decennierna har lett till att mer än tre av fyra barn idag faktiskt botas från sin sjukdom. Tyvärr drabbas en stor andel av de som överlever sin cancer av så kallade sena komplikationer till följd av den tuffa behandling de har utsatts för. Bland annat har man sett en livslång ökad risk för att drabbas av nya cancersjukdomar. Orsaken till att barn får cancer är i de allra flesta fall okänt, men upp till 10 % av barncancer¬fallen kan förklaras av kända ärftliga orsaker. Det finns dock studier som tyder på att betydelsen av ärftliga faktorer kan vara underskattad. När barnet insjuknar i sin cancer finns i... (More)
Popular Abstract in Swedish

Varje år insjuknar omkring 300 barn i cancer. Förbättrade behandlingsmetoder under de senaste decennierna har lett till att mer än tre av fyra barn idag faktiskt botas från sin sjukdom. Tyvärr drabbas en stor andel av de som överlever sin cancer av så kallade sena komplikationer till följd av den tuffa behandling de har utsatts för. Bland annat har man sett en livslång ökad risk för att drabbas av nya cancersjukdomar. Orsaken till att barn får cancer är i de allra flesta fall okänt, men upp till 10 % av barncancer¬fallen kan förklaras av kända ärftliga orsaker. Det finns dock studier som tyder på att betydelsen av ärftliga faktorer kan vara underskattad. När barnet insjuknar i sin cancer finns i de flesta fall ingen tidigare cancer i familjen som talar för att det finns någon ärftlig bakomliggande orsak. I en del familjer förändras denna bild med tiden och en barntumör som till en början verkade vara sporadisk kan visa sig vara familjär när föräldrar och syskon blir äldre. Det har visat sig att patienter med en ärftlig benägenhet för cancer har en särskilt hög risk att drabbas av nya tumörer till följd av tidigare cancerbehandling. Ökad kunskap om ärftliga faktorers betydelse för uppkomsten av barncancer skulle kunna förbättra omhändertagandet av patienter och deras familjer genom att identifiera de patienter som är i behov av mer individualiserade behandlingsstrategier.



De fyra studier som ingår i den här avhandlingen har undersökt ärftliga faktorers betydelse vid barntumörer och eventuella samband mellan barn- och vuxentumörer i samma familj. Det har sedan länge varit känt att ärftliga faktorer ökar risken för att drabbas av cancer. Däremot vet vi betydligt mindre om hur ärftliga orsaker påverkar sjukdomsförloppet. I studie I studerades överlevnaden för bröstcancerpatienter i relation till om deras barn har haft barncancer, där barncancer användes som en markör för förekomst av ärftliga faktorer. De mödrar som har haft ett barn med cancer hade en sämre överlevnad jämfört med de andra bröstcancersjuka mödrarna. Detta tyder på att ärftliga faktorer kan ha en betydelse för patienters sjukdomsförlopp.



I studie II granskades förekomsten av barntumörer i familjer med ärftliga vuxen-cancer¬syndrom, inkluderat ärftlig bröst- och äggstockscancer, familjär malignt melanom, samt ett syndrom som orsakar ärftlig tjocktarmscancer och som kallas hereditär icke polypös kolorektalcancer (HNPCC). Familjer med HNPCC och familjär malignt melanom uppvisade en högre förekomst av barntumörer jämfört med den generella befolkningen. Ärftlig bröst- och äggstockscancer orsakas av ärftliga genetiska förändringar (mutationer) i bröstcancergen 1 och 2 (BRCA1 och BRCA2). En ökad förekomst av barntumörer identifierades hos familjer med mutationer i BRCA2 men inte i familjer med mutationer i BRCA1.



I studie III undersöktes risken för barn- och vuxencancer hos släktingar till barncancerpatienter. En ökad risk för både barn- och vuxentumörer påvisades. I var tionde familj fanns ytterligare ett fall av barncancer, ofta hos mer avlägsna släktingar. Den ökade förekomsten av barntumörer kan inte förklaras av sedan tidigare kända ärftliga orsaker. Vuxna släktingar hade en ökad risk för bröst- och prostatacancer, och var yngre vid insjuknande än den genomsnittliga i befolkningen.



Studie IV handlar om ett ovanligt ärftligt tillstånd som kallas Li-Fraumeni syndrom, vilket orsakas av mutationer i genen TP53. Individer med detta syndrom har en mycket hög risk för att drabbas av ett flertal olika cancrar, ofta i mycket ung ålder. Man har också sett att dessa individer är känsliga för strålning och att många efter strålbehandling för en cancer med tiden drabbas av en ny tumör i det behandlade området. I familjer med Li-Fraumeni syndrom finns det oftast en stark familjehistoria av cancer hos nära släktingar, dock har man i tidigare studier sett att barn med vissa typer av tumörer ibland kan vara bärare av en mutation i TP53 utan att det finns en sjukdomsbild i familjen som talar för det. I studie IV undersöktes det vidare hur vanligt förekommande det är med medfödda mutationer i TP53 hos barncancer¬patienter med binjurebarkstumörer, plexus-tumörer (en ovanlig typ av hjärntumör) och rabdomyosarkom (tumör som utvecklas från muskelceller). Medfödda TP53 mutationer kunde identifieras hos enstaka patienter med binjurebarkstumörer och rabdomyosarkom. Detta talar för att man skulle kunna överväga att testa barn med dessa tumörformer för TP53 mutationer, för att kunna anpassa behandlingen och minska risken för nya terapirelaterade tumörer. I de allra flesta fall kunde barn¬tumörerna inte kopplas till förekomst av medfödda TP53 mutationer. En ökad förekomst av cancer påvisades dock i familjer till patienter med plexus-tumörer och rhabdomyosarkom, vilket tyder på att eventuellt andra ärftliga faktorer kan förekomma i familjerna.



Sammanfattningsvis tillför den här avhandlingen ytterligare stöd för att ärftliga faktorer kan spela en roll för uppkomsten av barntumörer. Framtida forskning bör särskilt inriktas på att studera sambandet barn- och vuxentumörer i samma familj och familjer med multipla barntumörer. (Less)
Abstract
The etiology of childhood cancer is largely unknown. Approximately 1-10% of all childhood tumors are associated with known cancer predisposition syndromes. However, the contribution may be underestimated due to the failure to detect patients with genetic susceptibility for cancer when relying on known family pattern and anomalies. Growing evidence indicates that patients with genetic susceptibility to cancer may be at higher than normal risk for therapy related cancers. Increased knowledge regarding the importance of hereditary factors in the development of childhood tumors may improve the medical care of such patients by identifying those in need of more individualized treatment. In this thesis, genetic factors, familial cancers, and... (More)
The etiology of childhood cancer is largely unknown. Approximately 1-10% of all childhood tumors are associated with known cancer predisposition syndromes. However, the contribution may be underestimated due to the failure to detect patients with genetic susceptibility for cancer when relying on known family pattern and anomalies. Growing evidence indicates that patients with genetic susceptibility to cancer may be at higher than normal risk for therapy related cancers. Increased knowledge regarding the importance of hereditary factors in the development of childhood tumors may improve the medical care of such patients by identifying those in need of more individualized treatment. In this thesis, genetic factors, familial cancers, and their associations with childhood cancer have been studied. The general aim was to investigate the importance of hereditary factors in the etiology of childhood cancer and to evaluate possible associations between childhood and adult cancers.



In paper I, a national registry-based cohort of parous women with breast cancer was used to study whether the occurrence of childhood cancer in children affects the survival of mothers with breast cancer. Women who had a child with childhood cancer were found to have shorter survival compared to other parous patients with breast cancer, suggesting that hereditary factors may affect prognosis.



In paper II, the occurrence of childhood cancer in families with hereditary adult cancer syndromes was investigated. Families with BRCA2-associated hereditary breast and ovarian cancer, mismatch repair gene-associated hereditary non-polyposis colorectal cancer and CDKN2A-associated malignant melanoma were found to have a higher occurrence of childhood cancer compared to the general population. No increased occurrence of childhood cancer was found in families with BRCA1-associated breast and ovarian cancers.



In paper III, the incidence of childhood and adult cancer was evaluated in the extended families of patients with childhood cancer, and the frequency of germline TP53 mutations in families with multiple childhood tumors was investigated. The relatives of patients with childhood cancer were found to have an increased incidence of childhood and adult cancers, particularly of the breast and prostate. Breast and prostate cancers were observed at earlier than average ages. No germline TP53 mutations were found in families with multiple childhood tumors, which exclude TP53 mutations as a contributor to the observed excess of childhood tumors.



In paper IV, a population-based material was used to confirm the prevalence of germline TP53 mutations in children with adrenocortical tumors, choroid plexus tumors and early childhood rhabdomyosarcomas and investigate whether these may be early manifestations of Li-Fraumeni syndrome (LFS). Germline TP53 mutations were found in few children with adrenocortical tumors and rhabdomyosarcomas. No mutations were found in children with choroid plexus tumors. Furthermore, neither the family history nor the observed tumor spectra in the relatives of most children with these rare tumors were suggestive of LFS. These data suggest that most children, particularly those with choroid plexus tumors or rhabdomyosarcomas, do not present early manifestations of LFS. Nevertheless, an increased cancer incidence, particularly for certain adult tumors, was found in the relatives of children with choroid plexus tumors and rhabdomyosarcomas, which suggests that other syndromes or predisposing factors may exist.



In summary, this thesis adds new data suggesting that hereditary factors play a role in the development of childhood tumors. In addition, these factors may also increase the risk for adult tumors, modify the onset age of common adult tumors, and affect breast cancer prognosis. Our findings further support the need for future studies regarding the importance of genetic susceptibility to childhood cancer, particularly in families with multiple childhood tumors. Also the associations between tumors of childhood and adulthood in the same family should be further studied. (Less)
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author
supervisor
opponent
  • Melin, Beatrice, Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Childhood cancer, hereditary factors, breast cancer, survival, hereditary breast and ovarian cancer, hereditary non-polyposis colorectal cancer, familial malignant melanoma, BRCA1, BRCA2, mismatch repair, CDKN2A, familial risk, multiple childhood tumors, Li-Fraumeni syndrome, TP53, adrenocortical carcinoma, choroid plexus tumors, rhabdomyosarcoma
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2012:24
pages
135 pages
publisher
Department of Oncology, Clinical Sciences, Lund University
defense location
Alwall Lecture Hall, Barngatan 2, Lund
defense date
2012-03-23 09:00
ISSN
1652-8220
ISBN
978-91-86871-86-4
language
English
LU publication?
yes
id
8682214a-aa36-4dc6-80b7-5cff301681e1 (old id 2364386)
date added to LUP
2012-03-07 09:38:31
date last changed
2016-09-19 08:44:49
@phdthesis{8682214a-aa36-4dc6-80b7-5cff301681e1,
  abstract     = {The etiology of childhood cancer is largely unknown. Approximately 1-10% of all childhood tumors are associated with known cancer predisposition syndromes. However, the contribution may be underestimated due to the failure to detect patients with genetic susceptibility for cancer when relying on known family pattern and anomalies. Growing evidence indicates that patients with genetic susceptibility to cancer may be at higher than normal risk for therapy related cancers. Increased knowledge regarding the importance of hereditary factors in the development of childhood tumors may improve the medical care of such patients by identifying those in need of more individualized treatment. In this thesis, genetic factors, familial cancers, and their associations with childhood cancer have been studied. The general aim was to investigate the importance of hereditary factors in the etiology of childhood cancer and to evaluate possible associations between childhood and adult cancers. <br/><br>
<br/><br>
In paper I, a national registry-based cohort of parous women with breast cancer was used to study whether the occurrence of childhood cancer in children affects the survival of mothers with breast cancer. Women who had a child with childhood cancer were found to have shorter survival compared to other parous patients with breast cancer, suggesting that hereditary factors may affect prognosis.<br/><br>
<br/><br>
In paper II, the occurrence of childhood cancer in families with hereditary adult cancer syndromes was investigated. Families with BRCA2-associated hereditary breast and ovarian cancer, mismatch repair gene-associated hereditary non-polyposis colorectal cancer and CDKN2A-associated malignant melanoma were found to have a higher occurrence of childhood cancer compared to the general population. No increased occurrence of childhood cancer was found in families with BRCA1-associated breast and ovarian cancers. <br/><br>
<br/><br>
In paper III, the incidence of childhood and adult cancer was evaluated in the extended families of patients with childhood cancer, and the frequency of germline TP53 mutations in families with multiple childhood tumors was investigated. The relatives of patients with childhood cancer were found to have an increased incidence of childhood and adult cancers, particularly of the breast and prostate. Breast and prostate cancers were observed at earlier than average ages. No germline TP53 mutations were found in families with multiple childhood tumors, which exclude TP53 mutations as a contributor to the observed excess of childhood tumors. <br/><br>
<br/><br>
In paper IV, a population-based material was used to confirm the prevalence of germline TP53 mutations in children with adrenocortical tumors, choroid plexus tumors and early childhood rhabdomyosarcomas and investigate whether these may be early manifestations of Li-Fraumeni syndrome (LFS). Germline TP53 mutations were found in few children with adrenocortical tumors and rhabdomyosarcomas. No mutations were found in children with choroid plexus tumors. Furthermore, neither the family history nor the observed tumor spectra in the relatives of most children with these rare tumors were suggestive of LFS. These data suggest that most children, particularly those with choroid plexus tumors or rhabdomyosarcomas, do not present early manifestations of LFS. Nevertheless, an increased cancer incidence, particularly for certain adult tumors, was found in the relatives of children with choroid plexus tumors and rhabdomyosarcomas, which suggests that other syndromes or predisposing factors may exist.<br/><br>
<br/><br>
In summary, this thesis adds new data suggesting that hereditary factors play a role in the development of childhood tumors. In addition, these factors may also increase the risk for adult tumors, modify the onset age of common adult tumors, and affect breast cancer prognosis. Our findings further support the need for future studies regarding the importance of genetic susceptibility to childhood cancer, particularly in families with multiple childhood tumors. Also the associations between tumors of childhood and adulthood in the same family should be further studied.},
  author       = {Magnusson, Susanne},
  isbn         = {978-91-86871-86-4},
  issn         = {1652-8220},
  keyword      = {Childhood cancer,hereditary factors,breast cancer,survival,hereditary breast and ovarian cancer,hereditary non-polyposis colorectal cancer,familial malignant melanoma,BRCA1,BRCA2,mismatch repair,CDKN2A,familial risk,multiple childhood tumors,Li-Fraumeni syndrome,TP53,adrenocortical carcinoma,choroid plexus tumors,rhabdomyosarcoma},
  language     = {eng},
  pages        = {135},
  publisher    = {Department of Oncology, Clinical Sciences, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Genetic factors in childhood cancer. Associations between tumors in childhood and adulthood, and prevalence of germline TP53 mutations},
  volume       = {2012:24},
  year         = {2012},
}