survival rates continue to improve with the advent of more refined treatments and better supportive care . today over 80% of children with cancer are alive for at least five years , and the majority of these are cured . as a consequence , many sufferers of childhood cancer are now living into adulthood and having families of their own . it has been estimated that about 1 in 900 adults aged 18 to 44 years is a cancer survivor . among this group , those with an inherited susceptibility to cancer will transmit their genetic fault to a proportion of their children . they are also at risk of developing a second cancer during their adult life . while the causes of the majority of childhood cancers are largely unknown , there are a number of clinical syndromes for which the evidence for an excess cancer risk in children is most persuasive . these include li - fraumeni syndrome , neurofibromatosis type i , inherited retinoblastoma mutations , familial wilms tumor , and some disorders of dna repair . these syndromes collectively account for less than 10% of all childhood cancers , however . beyond this , it is not clear if cancer in childhood increases the risk of cancer in relatives . a number of recent studies have described an association between childhood cancer and cancer in first - degree relatives [ 57 ] , particularly siblings [ 5 , 7 ] and mothers . in this study , we describe the distribution of cancers in australian children and estimate the risks of cancer in their relatives . it was established from the clinical services at the royal children 's hospital ( rch ) and the monash medical centre ( mmc ) , between which over 95% of children under 10 years of age and 83% of children aged 1015 years with cancer within the state of victoria , australia , are treated . children were eligible for inclusion if they had a diagnosis of any cancer before age 15 and when initial treatment was given at one of the participating centres between october 1998 and october 2002 . the human research ethics committee at each participating institution reviewed and approved the protocol before enrolment commenced . a total of 486 ( 422 at rch and 64 at mmc ) incident cases of childhood cancer were diagnosed during the study period . of these , 21 families were found to be ineligible ( seven non - english speaking parents , seven where the proband was aged over 15 years , six where the proband did not have their initial treatment at either service , and one where the proband was adopted ) . of the remaining 465 families , 21 were not contactable , 53 refused to participate , 6 were lost to followup , and 6 later withdrew consent . this left 379 ( 82% ) families participating ( 340 at rch and 39 at mmc ) , from which we interviewed 351 ( 92.6% ) fathers and 371 ( 97.9% ) mothers . in 343 ( 90.5% ) families , both the mother and father were interviewed , while in 28 ( 7.4% ) families only the mother was interviewed and in 8 ( 2.1% ) families only the father was interviewed . at the time of enrolment , both parents of the affected child were asked a baseline questionnaire that included information on lifestyle and environmental risk factors and a detailed family history of cancer . where half siblings were identified , the appropriate , biologically relevant family history was obtained . the family history of cancer questionnaire asked about all of the affected child 's siblings , parents , aunts , uncles , and grandparents ( i.e. , all first - degree and second - degree relatives ) . parents were asked to identify each first - degree and second - degree relative , any known cancer diagnoses with the age ( in years ) at diagnosis , and type of malignancy , together with their current age or age at the time of death . the information collected was reviewed and classified by the authors with expertise in cancer ( jah ; es ) . the world health organization 's international classification of diseases for oncology , 3rd edition ( id - o-3 ) scheme , was used for classification of site of malignancy . nonmelanoma skin cancers , nonmalignant tumours , and in situ cancerswere not included in the analyses . to address the potential contribution of known familial cancer syndromes , we examined the medical records of the 26 affected children who had a first - degree relative with cancer . in particular , we sought clinical evidence for li - fraumeni syndrome , neurofibromatosis type 1 , familial retinoblastoma , and familial wilm 's tumour syndrome . person - years at risk for the cohort of relatives were calculated as the time to date of diagnosis of cancer , date of death , or date of interview completion , whichever occurred earliest . australian population - based cancer incidence data , specific for gender , age , and year of birth , were obtained from the australian institute of health and welfare . standardised incidence ratios were used to compare the number of observed cancers in relatives with the number expected in the australian population . robust estimates for confidence intervals were calculated to account for potential clustering within a family . all statistical tests were two - sided and a p value < 0.05 was considered statistically significant . the distribution of childhood cancers diagnosed in the cohort of 379 children is summarized in table 1 . a family history for cancer was identified in 4,736 ( 1,337 first - degree and 3,399 second - degree ) relatives with a total of 211,394 person - years of followup . fourteen of the 379 ( 3.7% ) families reported a positive history for childhood cancer in any relative , with none having more than one case identified . twenty - six children with cancer ( 6.9% ) had a first - degree relative ( parent or sibling ) with a history of cancer . the results for the family history of cancer in all childhood cancer patients are summarized in table 2 . there was a higher than expected , though not statistically significant , incidence of childhood cancer among first - degree relatives ( sir 1.43 ; 95% ci 0.545.08 ) . there was also a higher than expected , though not statistically significant , incidence of cancer among first - degree relatives ( sir 1.45 ; 95% ci 0.932.1 ) . there was a statistically significant increase in cancer among female first - degree relatives ( sir 1.82 ; 95% ci 1.263.39 ) . the increased family cancer history in first - degree females was largely attributable to an effect in mothers ( sir 1.78 ; 95% ci 1.273.33 ) but was also observed in sisters ( sir 2.15 ; n = 1 ) . elevated cancer incidence rates were also observed in aunts ( sir 1.48 ; 95% ci 1.112.00 ) . the gender - specific association was reflected in higher than expected incidence rates of breast cancer in mothers ( sir 1.92 ; 95% ci 0.726.83 ) , aunts ( sir 1.64 ; 95% ci 0.982.94 ) and to a lesser extent grandmothers ( sir 1.04 ; 95% ci 0.781.40 ) . although numbers were small , an increased cancer incidence in relatives appeared to be most apparent in the children with sarcomas ( sir 2.58 ; 95% ci 0.998.52 ) , embryonal tumors ( sir 2.12 ; 95% ci 0.719.34 ) , and brain tumors ( sir 1.52 ; 95% ci 0.703.92 ) . of the 26 families with a history of cancer within a first - degree relative , only one met the criteria for a clinically recognizable familial cancer syndrome ( li fraumeni syndrome ) . the increased rates of cancer in female first - degree relatives ( sir 1.68 ; 95% ci 1.032.93 ) , including mothers ( sir 1.78 ; 95% ci 1.093.09 ) and aunts ( sir 1.49 ; 95% ci 1.122.02 ) , remained when this child and family were removed from the analyses . our small , population - based study suggests an increased risk of childhood cancer and some adult cancers among relatives of childhood cancer patients that are not accounted for by clinically identifiable familial cancer syndromes . these findings were seen in both first- and second - degree relatives . although some of our findings did not reach statistical significance , they are largely consistent with previously published unselected childhood cancer cohorts [ 57 , 12 ] and add to a growing body of evidence that unidentified genetic risk exists in some families . in addition to the small size of the study , other limitations include the use of family history in isolation and the absence of some parental input to family history of cancer . while we were not able to cross - reference reported history of cancer with cancer registry data , a similar study in sweden confirmed underreporting of cancer in relatives by history . furthermore , in the small minority of cases where both parents were not available to provide the relevant family history of cancer , underreporting of the family history of cancer is also likely . allowing for these two study biases towards the null hypothesis is therefore likely to strengthen the positive findings we have reported . this underreporting may also explain why a large number of apparent protective effects occurred in second - degree relatives , where direct , personal access to a family history of cancer is not always possible . overall , first - degree relatives ( siblings and parents ) had an increased incidence of childhood tumors . this is consistent with the higher occurrence of childhood cancers among siblings demonstrated in a study of 51,000 children who developed cancer under the age of 15 in the uk , even after those with a genetic etiology were excluded . it was also reported in a cohort of 13,703 childhood cancer survivors in north america ( sir 1.5 ; 95% ci 1.351.7 ) . the apparent association of childhood cancer with adult cancers in female relatives is fascinating and supports a recently published population - based study from utah , usa , where a higher risk of adult cancer was restricted to mothers and siblings ( sir 1.31 ; 95% ci 1.111.56 ) but was not observed in fathers . it is interesting to note that the effect was greatest for children younger than 5 years at diagnosis ( sir 1.48 ; 95% ci 1.131.95 ) , suggesting a strong ante- or perinatal effect . factors which may be related to maternal effects on childhood cancer risk include maternal age of pregnancies , altered in utero exposures , and birth weight . our finding of an increased prevalence of breast cancer in female relatives also supports recently published swedish data . a number of related studies have also observed higher rates of breast cancer in mothers and sisters [ 1416 ] . the potential link between breast cancer and childhood cancer is of great interest , given past reports of increased rates of childhood cancer in families carrying a brca1 or brca2 mutation [ 17 , 18 ] . our study was not designed nor powered to examine the relationship between specific childhood cancer types and family history of cancer , so it must be acknowledged that potential associations may have gone undetected . certainly , others have postulated a link between family history of cancer and the more common subtypes , childhood leukaemia , childhood lymphomas , and childhood brain tumours . the epidemiology of childhood cancer described here is the starting point for further explorations into identifying previously unrecognized genetic predisposition to childhood cancer . we are currently undertaking whole genome sequencing of these children with cancer and their affected first - degree relatives ' germline dna in order to identify the role of previously described and novel genetic mutations to account for our findings .
we determined the extent and distribution of cancers in relatives of 379 children newly diagnosed with cancer . 
 family history was collected from 1,337 first - degree and 3,399 second - degree relatives and incidence compared with national age- and gender - specific rates . 
 overall , 14 children ( 3.7% ) had a relative with a history of childhood cancer and 26 children ( 6.9% ) had a first - degree relative with a history of cancer , with only one of these having an identifiable familial cancer syndrome . 
 there was a higher than expected incidence of childhood cancer among first - degree relatives ( parents and siblings ) ( standardized incidence ratio ( sir ) 1.43 ; 95% ci 0.545.08 ) . 
 there was also a higher than expected incidence of adult cancers among first - degree relatives ( sir 1.45 ; 95% ci 0.932.21 ) , particularly in females ( sir 1.82 ; 95% ci 1.263.39 ) . 
 the increased family cancer history in first - degree females was largely attributable to an effect in mothers ( sir 1.78 ; 95% ci 1.273.33 ) . 
 the gender - specific association was reflected in higher than expected incidence rates of breast cancer in both mothers ( sir 1.92 ; 95% ci 0.726.83 ) and aunts ( sir 1.64 ; 95% ci 0.982.94 ) . 
 these findings support the hypothesis that previously undetected familial cancer syndromes contribute to childhood cancer .