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1.  Congenital Anomalies in the Children of Cancer Survivors: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2011;30(3):239-245.
Children with cancer receive mutagenic treatments, which raises concern about the potential transmissibility of germline damage to their offspring. This question has been inadequately studied to date because of a lack of detailed individual treatment exposure assessment such as gonadal radiation doses.
Within the Childhood Cancer Survivor Study, we performed a retrospective cohort analysis of validated cases of congenital anomalies among 4,699 children of 1,128 male and 1,627 female childhood cancer survivors. We quantified chemotherapy with alkylating agents and radiotherapy doses to the testes and ovaries and related these exposures to risk of congenital anomalies using logistic regression.
One hundred twenty-nine children had at least one anomaly (prevalence = 2.7%). For children whose mothers were exposed to radiation or alkylating agents versus neither, the prevalence of anomalies was 3.0% versus 3.5% (P = .51); corresponding figures were 1.9% versus 1.7% (P = .79) for the children of male survivors. Neither ovarian radiation dose (mean, 1.19 Gy; odds ratio [OR] = 0.59; 95% CI, 0.20 to 1.75 for 2.50+ Gy) nor testicular radiation dose (mean, 0.48 Gy; OR = 1.01; 95% CI, 0.36 to 2.83 for 0.50+ Gy) was related to risk of congenital anomalies. Treatment with alkylating agents also was not significantly associated with anomalies in the children of male or female survivors.
Our findings offer strong evidence that the children of cancer survivors are not at significantly increased risk for congenital anomalies stemming from their parent's exposure to mutagenic cancer treatments. This information is important for counseling cancer survivors planning to have children.
PMCID: PMC3269950  PMID: 22162566
2.  Genetic Disease in the Children of Danish Survivors of Childhood and Adolescent Cancer 
Journal of Clinical Oncology  2011;30(1):27-33.
Preconception radiation and chemotherapy have the potential to produce germ cell mutations leading to genetic disease in the next generation. Dose-response relationships were evaluated between cancer treatments and untoward pregnancy outcomes.
Patients and Methods
A case-cohort study was conducted involving 472 Danish survivors of childhood and adolescent cancer and their 1,037 pregnancies. Adverse outcomes included 159 congenital malformations, six chromosomal abnormalities, seven stillbirths, and nine neonatal deaths. Preconception radiation doses to the gonads, uterus, and pituitary gland and administered chemotherapy were quantified based on medical records and related to adverse outcomes using a generalized estimating equation model.
No statistically significant associations were found between genetic disease in children and parental treatment with alkylating drugs or preconception radiation doses to the testes in male and ovaries in female cancer survivors. Specifically, the risk of genetic disease was similar among the children of irradiated survivors when compared with nonirradiated survivors (relative risk [RR], 1.02; 95% CI, 0.59 to 1.44; P = .94). A statistically significant association between abdomino-pelvic irradiation and malformations, stillbirths, and neonatal deaths was not seen in the children of female survivors overall (P = .07) or in the children of mothers receiving high uterine doses (mean, 13.5 Gy; max, 100 Gy; RR, 2.3; 95% CI, 0.95 to 5.56).
Mutagenic chemotherapy and radiotherapy doses to the gonads were not associated with genetic defects in children of cancer survivors. However, larger studies need to be conducted to further explore potential associations between high-dose pelvic irradiation and specific adverse pregnancy outcomes.
PMCID: PMC3255559  PMID: 22124106
3.  Site-specific cancer risk in the Baltic cohort of Chernobyl cleanup workers, 1986–2007 
To assess site-specific cancer risk in the Baltic cohort of Chernobyl cleanup workers 1986–2007.
The Baltic cohort includes 17,040 men from Estonia, Latvia and Lithuania who participated in the environmental cleanup after the accident at the Chernobyl Nuclear Power Station in 1986–1991, and who were followed for cancer incidence until the end of 2007. Cancer cases diagnosed in the cohort and in the male population of each country were identified from the respective national cancer registers. The proportional incidence ratio (PIR) with 95% confidence interval (CI) was used to estimate the site-specific cancer risk in the cohort. For comparison and as it was possible, the site-specific standardized incidence ratio (SIR) was calculated for the Estonian sub-cohort, which was not feasible for the other countries.
Overall, 756 cancer cases were reported during 1986–2007. A higher proportion of thyroid cancers in relation to the male population was found (PIR=2.76; 95%CI 1.63–4.36), especially among those who started their mission shortly after the accident, in April–May 1986 (PIR=6.38; 95% CI 2.34–13.89). Also, an excess of oesophageal cancers was noted (PIR=1.52; 95% CI 1.06–2.11). No increased PIRs for leukaemia or radiation-related cancer sites combined were observed. PIRs and SIRs for the Estonian sub-cohort demonstrated the same site-specific cancer risk pattern.
Consistent evidence of an increase in radiation-related cancers in the Baltic cohort was not observed with the possible exception of thyroid cancer, where conclusions are hampered by known medical examination including thyroid screening among cleanup workers.
PMCID: PMC3739289  PMID: 23683549
Chernobyl nuclear accident; neoplasms; incidence; radiation effects; Estonia; Latvia; Lithuania
4.  Contralateral Breast Cancer after Radiotherapy among BRCA1 and BRCA2 Mutation Carriers: A WECARE Study Report 
Women with germline BRCA1 or BRCA2 (BRCA1/BRCA2) mutations are at very high risk of developing breast cancer, including asynchronous contralateral breast cancer (CBC). BRCA1/BRCA2 genes help maintain genome stability and assist in DNA repair. We examined whether the risk of CBC associated with radiation treatment was higher among women with germline BRCA1/BRCA2 mutations than among non-carriers.
A population-based, nested case-control study was conducted within a cohort of 52,536 survivors of unilateral breast cancer (UBC). Cases were 603 women with CBC and controls were 1199 women with UBC individually matched on age at diagnosis, race, year of first diagnosis and cancer registry. All women were tested for BRCA1 and BRCA2 mutations. Radiation absorbed dose from the initial radiotherapy (RT) to the CBC location within the contralateral breast was reconstructed from measurements in a tissue-equivalent phantom and details available in the therapy records.
Among women treated with radiation, the mean radiation dose was 1.1 Gy (range=0.02-6.2 Gy). Risk of developing CBC was elevated among women who carried a deleterious BRCA1/BRCA2 mutation (rate ratio, RR=4.5, confidence interval, CI=3.0-6.8), and also among those treated with RT (RR=1.2, CI=1.0-1.6). However, among mutation carriers, an incremental increase in risk associated with radiation dose was not statistically significant.
Multiplicative interaction of RT with mutation status would be reflected by a larger association of RT with CBC among carriers than among non-carriers, but this was not apparent. Accordingly, there was no clear indication that carriers of deleterious BRCA/BRCA2 mutations were more susceptible to the carcinogenic effects of radiation than non-carriers. These findings are reassuring and have important clinical implications for treatment decisions and the clinical management of patients harboring deleterious BRCA1/BRCA2 mutations.
All work associated with this study was supported by the U.S. National Cancer Institute [R01CA097397, U01CA083178].
PMCID: PMC3755053  PMID: 23706288
Contralateral Breast Cancer; Radiotherapy; BRCA1/BRCA2
5.  Very Low-Level Heteroplasmy mtDNA Variations Are Inherited in Humans 
Little is known about the inheritance of very low heteroplasmy mitochondria DNA variations. Even with the development of new next-generation sequencing methods, the practical lower limit of measured heteroplasmy is still about 1% due to the inherent noise level of the sequencing. In this study, we sequenced the mitochondrial genome of 44 individuals using Illumina high-throughput sequencing technology and obtained high-coverage mitochondria sequencing data. Our study population contains many mother-offspring pairs. This unique study design allows us to bypass the usual heteroplasmy limitation by analyzing the correlation of mutation levels at each position in the mtDNA sequence between maternally related pairs and non-related pairs. The study showed that very low heteroplasmy variants, down to almost 0.1%, are inherited maternally and that this inheritance begins to decrease at about 0.5%, corresponding to a bottleneck of about 200 mtDNA.
PMCID: PMC4149221  PMID: 24377867
Maternal inheritance; Next-generation sequencing; High-depth sequencing; Heteroplasmy; mtDNA mutations; Bottleneck
6.  Chernobyl cleanup workers from Estonia: follow-up for cancer incidence and mortality 
This study examined cancer incidence (1986–2008) and mortality (1986–2011) among the Estonian Chernobyl cleanup workers in comparison with the Estonian male population. The cohort of 4,810 men was followed through nationwide population, mortality and cancer registries. Cancer and death risks were measured by standardized incidence ratio (SIR) and standardized mortality ratio (SMR), respectively. Poisson regression was used to analyze the effects of year of arrival, duration of stay, and time since return on cancer and death risks. The SIR for all cancers was 1.06 with 95% confidence interval 0.93–1.20 (232 cases). Elevated risks were found for cancers of pharynx, oesophagus, and the joint category of alcohol-related sites. No clear evidence of an increased risk of thyroid cancer, leukaemia, or radiation-related cancer sites combined was apparent. The SMR for all causes of death was 1.02 with 95% confidence interval 0.96–1.08 (1,018 deaths). Excess mortality was observed for mouth and pharynx cancer, alcohol-related cancer sites together, and suicide. Duration of stay rather than year of arrival was associated with increased mortality. Twenty-six years of follow-up of this cohort indicates no definite health effects attributable to radiation, but the elevated suicide risk has persisted.
PMCID: PMC3720997  PMID: 23532116
7.  Stillbirth, Early Death and Neonatal Morbidity among Offspring of Female Cancer Survivors 
Acta oncologica (Stockholm, Sweden)  2013;52(6):10.3109/0284186X.2012.758870.
Increased awareness of the adverse effects of cancer treatments has prompted the development of fertility preserving regimens for the growing population of cancer survivors who desire to have children of their own.
Materials and methods
We conducted a registry-based study to evaluate the risk of stillbirth, early death and neonatal morbidity among children of female cancer survivors (0–34 years at diagnosis) compared with children of female siblings. A total of 3,501 and 16,908 children of female cancer patients and siblings, respectively, were linked to the national medical birth and cause-of-death registers.
The risk of stillbirth or early death was not significantly increased among offspring of cancer survivors as compared to offspring of siblings: the risk (Odds Ratio (OR) of early neonatal death, i.e. mortality within the first week was 1.35, with a 95% confidence interval (CI) of 0.58–3.18, within 28 days 1.40, 95% CI 0.46–4.24 and within the first year of life 1.11, 95% CI 0.64–1.93 after adjustment for the main explanatory variables. All these risk estimates were reduced towards one after further adjustment for duration of pregnancy. Measures of serious neonatal morbidity were not significantly increased among the children of survivors. However, there was a significant increase in the monitoring of children of cancer survivors for neonatal conditions (OR 1.56, 95% CI 1.35–1.80), which persisted even after correcting for duration of pregnancy, that might be related to parental cancer and its treatment or increased surveillance among the children.
Offspring of cancer survivors were more likely to require monitoring or care in a neonatal intensive care unit, but the risk of early death or stillbirth was not increased after adjustment for prematurity. Due to the rarity of the mortality outcomes studied, collaborative studies may be helpful in ruling out the possibility of an increased risk among offspring of cancer survivors.
PMCID: PMC3865710  PMID: 23327340
Offspring; cancer survivor; stillbirth; neonatal deaths
8.  Cancer Mortality Following Radiotherapy for Benign Gynecologic Disorders 
Radiation research  2012;178(4):266-279.
The purpose of this study is to quantify cancer mortality in relationship to organ-specific radiation dose among women irradiated for benign gynecologic disorders. Included in this study are 12,955 women treated for benign gynecologic disorders at hospitals in the Northeastern U.S. between 1925 and 1965; 9,770 women treated by radiation and 3,186 women treated by other methods. The average age at treatment was 45.9 years (range, 13–88 years), and the average follow-up period was 30.1 years (maximum, 69.9 years). Radiation doses to organs and active bone marrow were reconstructed by medical physicists using original radiotherapy records. The highest doses were received by the uterine cervix (median, 120 Gy) and uterine corpus (median, 34 Gy), followed by the bladder, rectum and colon (median, 1.7–7.2 Gy), with other abdominal organs receiving median doses ≤1 Gy and organs in the chest and head receiving doses <0.1 Gy. Standardized mortality rate ratios relative to the general U.S. population were calculated. Radiation-related risks were estimated in internal analyses using Poisson regression models. Mortality was significantly elevated among irradiated women for cancers of the uterine corpus, ovary, bladder, rectum, colon and brain, as well as for leukemia (exclusive of chronic lymphocytic leukemia) but not for cancer of the cervix, Hodgkin or non-Hodgkin lymphoma, multiple myeloma, or chronic lymphocytic leukemia. Evidence of a dose-response was seen for cancers of the ovary [excess relative risk (ERR) 0.31/Gy, P < 0.001], bladder (ERR = 0.21/Gy, P = 0.02) and rectum (ERR = 0.23/Gy, P = 0.05) and suggested for colon (ERR = 0.09/Gy, P = 0.10), but not for cancers of the uterine corpus or brain nor for non-chronic lymphocytic leukemia. Relative risks of mortality due to cancers of the stomach, pancreas, liver and kidney were close to 1.0, with no evidence of dose-response over the range of 0–1.5 Gy. Breast cancer was not significantly associated with dose to the breast or ovary. Mortality due to cancers of heavily irradiated organs remained elevated up to 40 years after irradiation. Significantly elevated radiation-related risk was seen for cancers of organs proximal to the radiation source or fields (bladder, rectum and ovary), as well as for non-chronic lymphocytic leukemia. Our results corroborate those from previous studies that suggest that cells of the uterine cervix and lymphopoietic system are relatively resistant to the carcinogenic effects of radiation. Studies of women irradiated for benign gynecologic disorders, together with studies of women treated with higher doses of radiation for uterine cancers, provide quantitative information on cancer risks associated with a broad range of pelvic radiation exposures.
PMCID: PMC3471655  PMID: 22856888
9.  Dose to the Contralateral Breast from Radiation Therapy and Risk of Second Primary Breast Cancer in the WECARE Study 
To quantify the risk of second primary breast cancer in the contralateral breast (CB) following radiation therapy (RT) for first breast cancer.
Methods and Materials
The study population included participants in the Women’s Environmental, Cancer, and Radiation Epidemiology (WECARE) study: 708 cases (women with asynchronous bilateral breast cancer) and 1399 controls (women with unilateral breast cancer) counter-matched on radiation treatment. Participants were < 55 years of age at first breast cancer. Absorbed doses to quadrants of the CB were estimated. Rate ratios (RR) and 95% confidence intervals were calculated using multivariable-adjusted conditional logistic regression models.
Across all patients, the mean radiation dose to the specific quadrant of the CB tumor was 1.1 Gy. Women < 40 years of age who received > 1.0 Gy of absorbed dose to the specific quadrant of the CB had a 2.5-fold greater risk for CB cancer than unexposed women (RR=2.5, 95% CI= 1.4 – 4.5). No excess risk was observed in women >40 years of age. Women < 40 years of age with followup periods > 5 years had a RR of 3.0 (95% CI=1.1–8.1), and the dose response was significant (excess RR per Gy of 1.0, 95% CI=0.1–3.0).
Women < 40 years of age who received a radiation dose > 1.0 Gy to the CB had an elevated, long-term risk of developing a second primary CB cancer. The risk is inversely related to age at exposure and is dose dependent.
PMCID: PMC3782859  PMID: 18556141
Contralateral breast; Radiation risk; Secondary breast cancer
10.  A study of DNA damage recognition and repair gene polymorphisms in relation to cancer predisposition and G2 chromosomal radiosensitivity 
The previously reported association of the APEX Asp148Glu SNP with cancer and the suggestion of associations of the XRCC3 Thr241Met and hOGG1 Ser326Cys SNP sites with G2 chromosomal radiosensitivity were investigated in a new study of 30 childhood and young adult cancer survivors, their 30 partners and 55 offspring. An additional SNP, hOGG1 Arg46Gln, was also analysed. Data on G2 chromosomal radiosensitivity was available on 29 of the families including 53 offspring. No significant associations of genotype with cancer or G2 chromosomal radiosensitivity were observed.
PMCID: PMC3779426  PMID: 21113933
Chromosome aberrations; DNA repair genes; cancer susceptibility
11.  The heritability of G2 chromosomal radiosensitivity and its association with cancer in Danish cancer survivors and their offspring 
To investigate the relationship between chromosomal radiosensitivity and early-onset cancer under age 35 years and to examine the heritability of chromosomal radiosensitivity.
Materials and methods
Peripheral blood lymphocytes were cultured for 72 hours prior to being irradiated with 0.5 Gy, 300 kV X-rays. Colcemid was added to cultures 30 minutes post-irradiation. Cultures were harvested 90 minutes post-irradiation and analysed for chromatid gaps and breaks. Heritability was estimated using Sequential Oligogenic Linkage Analysis Routines (SOLAR) software and by segregation analysis.
Elevated radiosensitivity was seen for 7 out of 29 (24.1%) cancer survivors, 3 out of 29 (10.3%) partners and 10 out of 53 (20.8%) offspring. Although the proportion of individuals displaying enhanced radiosensitivity was twice as high in both the cancer survivor and offspring groups than the partner controls, neither reached statistical significance. Heritability analysis of the radiosensitive phenotype suggested 57.9 – 78.0% of the variance could be attributed to genetic factors.
An association between G2 chromosomal radiosensitivity and childhood and young adult cancer is suggested but was not statistically significant. In contrast, there is strong evidence for heritability of the radiosensitive phenotype. The cancer survivors included a broad range of malignancies and future studies should focus on specific cancers with known or likely faults in deoxyribonucleic acid (DNA) damage recognition and repair mechanisms.
PMCID: PMC3777830  PMID: 20807177
Chromosomal radiosensitivity; heritability; cancer
12.  Germline minisatellite mutations in survivors of childhood and young adult cancer treated with radiation 
To investigate minisatellite germline mutation rates in survivors of childhood and young adult cancer who received radiotherapy.
Materials and Methods
DNA samples from 100 families, where one parent was a cancer survivor, were analysed for mutations at eight hypervariable minisatellite loci (B6.7, CEB1, CEB15, CEB25, CEB36, MS1, MS31, MS32) by Southern hybridisation.
No significant difference was observed between the paternal mutation rate of 5.6% in exposed fathers with a mean preconceptional testicular dose of 1.23 Gy (56 mutations in 998 informative alleles) and that of 5.8% in unexposed fathers (17 in 295 informative alleles). Subgrouping the exposed fathers into dose groups of <0.10 Gy, 0.10 – 0.99 Gy, 1.00 – 1.99 Gy, ≥ 2.00 Gy revealed no significant differences in paternal mutation rate in comparison with the unexposed fathers. Maternal mutation rates of 1.6% in cancer survivor mothers with a mean preconceptional ovarian dose of 0.58 Gy (five mutations in 304 informative alleles) and 2.1% in unexposed mothers (21 in 987 informative alleles) were not significantly different. There were no differences in minisatellite mutation rates associated with treatment with chemotherapeutic agents.
This study provides evidence that preconception radiotherapy for childhood or early adulthood cancer does not increase the germline minisatellite mutation rate.
PMCID: PMC3766628  PMID: 21087171
Minisatellite; germline mutation; ionising radiation; childhood and young adult cancer
13.  Intra-individual variation in G2 chromosomal radiosensitivity 
Mutagenesis  2012;27(4):471-475.
Intra-individual variation in G2 chromosomal radiosensitivity was examined by repeatedly taking blood samples from two individuals. Two healthy female volunteers provided a total of 44 blood samples, Donor 1 gave 28 samples in four time periods between 2001 and 2006 and Donor 2 gave 16 samples in two of the same time periods. Lymphocytes were cultured for 72 h prior to irradiation with 0.5 Gy, 300 kV X-rays. Colcemid was added 30 min post-irradiation. Cultures were harvested 90 min post-irradiation and analysed for chromatid gaps and breaks. Donor 1 exhibited significant intra-individual variation in G2 chromosomal radiosensitivity for two of the four time periods. Variation was not significant for Period 1 (13 samples, P = 0.111) and Period 2 (six samples, P = 0.311) but was significant for Period 3 (two samples, P = 0.030) and Period 4 (seven samples, P = 0.005). Significant intra-individual variation was observed for both time periods involving Donor 2, these being Period 2 (nine samples, P = 0.002) and Period 4 (seven samples, P < 0.001). The combined data from all time periods exhibited a significant intra-individual variation for Donor 1 (P < 0.001) and Donor 2 (P < 0.001). These findings led to the conclusion that too much reliance should not be placed on the result from a single sample when assessing individual radiosensitivity status.
PMCID: PMC3382306  PMID: 22422822
14.  The use of Next Generation Sequencing Technology to Study the Effect of Radiation Therapy on Mitochondrial DNA Mutation 
Mutation Research  2012;744(2):154-160.
The human mitochondrial genome has an exclusively maternal mode of inheritance. Mitochondrial DNA (mtDNA) is particularly vulnerable to environmental insults due in part to an underdeveloped DNA repair system, limited to base excision and homologous recombination repair. Radiation exposure to the ovaries may cause mtDNA mutations in oocytes, which may in turn be transmitted to offspring. We hypothesized that the children of female cancer survivors who received radiation therapy may have an increased rate of mtDNA heteroplasmy mutations, which conceivably could increase their risk of developing cancer and other diseases. We evaluated 44 DNA blood samples from 17 Danish and 1 Finnish families (18 mothers and 26 children). All mothers had been treated for cancer as children and radiation doses to their ovaries were determined based on medical records and computational models. DNA samples were sequenced for the entire mitochondrial genome using the Illumina GAII system. Mother’s age at sample collection was positively correlated with mtDNA heteroplasmy mutations. There was evidence of heteroplasmy inheritance in that 9 of the 18 families had at least one child who inherited at least one heteroplasmy site from his or her mother. No significant difference in single nucleotide polymorphisms between mother and offspring, however, was observed. Radiation therapy dose to ovaries also was not significantly associated with the heteroplasmy mutation rate among mothers and children. No evidence was found that radiotherapy for pediatric cancer is associated with the mitochondrial genome mutation rate in female cancer survivors and their children.
PMCID: PMC3354959  PMID: 22387842
15.  Second Malignant Neoplasms and Cardiovascular Disease Following Radiotherapy 
Second malignant neoplasms (SMNs) and cardiovascular disease (CVD) are among the most serious and life-threatening late adverse effects experienced by the growing number of cancer survivors worldwide and are due in part to radiotherapy. The National Council on Radiation Protection and Measurements (NCRP) convened an expert scientific committee to critically and comprehensively review associations between radiotherapy and SMNs and CVD, taking into account radiobiology; genomics; treatment (ie, radiotherapy with or without chemotherapy and other therapies); type of radiation; and quantitative considerations (ie, dose–response relationships). Major conclusions of the NCRP include: 1) the relevance of older technologies for current risk assessment when organ-specific absorbed dose and the appropriate relative biological effectiveness are taken into account and 2) the identification of critical research needs with regard to newer radiation modalities, dose–response relationships, and genetic susceptibility. Recommendation for research priorities and infrastructural requirements include 1) long-term large-scale follow-up of extant cancer survivors and prospectively treated patients to characterize risks of SMNs and CVD in terms of radiation dose and type; 2) biological sample collection to integrate epidemiological studies with molecular and genetic evaluations; 3) investigation of interactions between radiotherapy and other potential confounding factors, such as age, sex, race, tobacco and alcohol use, dietary intake, energy balance, and other cofactors, as well as genetic susceptibility; 4) focusing on adolescent and young adult cancer survivors, given the sparse research in this population; and 5) construction of comprehensive risk prediction models for SMNs and CVD to permit the development of follow-up guidelines and prevention and intervention strategies.
PMCID: PMC3295744  PMID: 22312134
16.  Long-Term Non-Cancer Mortality in Pediatric and Young Adult Cancer Survivors in Finland 
Pediatric blood & cancer  2011;58(3):421-427.
Excess late mortality has been reported among pediatric cancer survivors, but there is a need to further establish risk profiles for non-cancer death and to examine cause-specific mortality among survivors of young adult cancers.
In a nationwide record linkage study in Finland, we identified 9,245 five-year cancer survivors diagnosed before age 35 and treated between 1966 -1999, and followed them for mortality endpoints from 1971 through 2008. Standardized mortality ratios (SMRs) and 95% confidence intervals (95% CIs) were calculated to compare the observed number of deaths with those expected in the general Finnish population. Primary endpoints included death from cardiovascular and respiratory diseases; death from malignant diseases was excluded.
Non-malignant disease mortality in the cohort was 90% higher [SMR=1.9, 95%CI 1.7-2.2] than expected, with SMRs for circulatory and respiratory disease similarly elevated [SMR=1.9, 95%CI 1.5-2.3 and SMR=2.3, 95% CI 1.3-3.8, respectively]. Important differences were noted amongst patient subgroups, with risk greatest for survivors of central nervous system (CNS) cancer, Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). The SMR’s for circulatory disease were 6.6 (95% CI 4.8-8.9) for HL and 4.8 (95% CI 2.6-8.1) for NHL for the entire population; but these risks remained elevated for survivors diagnosed between 15-34 years of age.
Previous studies have shown that there is an elevated risk of non cancer mortality in childhood cancer survivors; this is one of the first studies that show an increase in cardiovascular and respiratory mortality in long term survivors of adolescent and young adult cancers.
PMCID: PMC3237747  PMID: 21910209
cancer; mortality; pediatrics; adolescent; survival; cardiovascular diseases
17.  Variants in activators and downstream targets of ATM, radiation exposure and contralateral breast cancer risk in the WECARE Study 
Human mutation  2011;33(1):158-164.
Ionizing radiation is a breast carcinogen that induces DNA double strand breaks (DSBs), and variation in genes involved in the DNA DSB response has been implicated in radiation-induced breast cancer. The Women’s Environmental, Cancer and Radiation Epidemiology (WECARE) Study is a population-based study of cases with contralateral breast cancer (CBC) and matched controls with unilateral breast cancer. The location-specific radiation dose received to the contralateral breast was estimated from radiotherapy records and mathematical models. 152 SNPs in six genes (CHEK2, MRE11A, MDC1, NBN, RAD50, TP53BP1) involved in the DNA DSBs response were genotyped. No variants or haplotypes were associated with CBC risk (649 cases, 1284 controls) and no variants were found to interact with radiation dose. Carriers of a RAD50 haplotype exposed to ≥1Gy had an increased risk of CBC compared with unexposed carriers (RR=4.31 (95% CI 1.93-9.62)); with an excess relative risk (ERR)/Gy = 2.13 (95% CI 0.61-5.33)). Although the results of this study were largely null, carriers of a haplotype in RAD50 treated with radiation, had a greater CBC risk than unexposed carriers. This suggests that carriers of this haplotype may be susceptible to the DNA-damaging effects of radiation therapy associated with radiation-induced breast cancer.
PMCID: PMC3240722  PMID: 21898661
DNA repair; haplotypes; polymorphisms; radiation; contralateral breast cancer
18.  Reproductive status at first diagnosis influences risk of radiation-induced second primary contralateral breast cancer in The WECARE Study 
Our study examines whether reproductive and hormonal factors prior to, at the time of, or subsequent to, radiation treatment for a first primary breast cancer, modify the risk of radiation-induced second primary breast cancer.
Methods and Materials
The Women’s Environmental, Cancer and Radiation Epidemiology (WECARE) Study is a multi-center, population-based study of 708 women (cases) with asynchronous contralateral breast cancer (CBC) and 1,399 women (controls) with unilateral breast cancer. Radiotherapy (RT) records, coupled with anthropomorphic phantom simulations, were used to estimate quadrant-specific radiation dose to the contralateral breast for each patient. Rate ratios (RR) and 95% confidence intervals (CI) were computed to assess the relationship between reproductive factors and risk of CBC.
Women who were nulliparous at diagnosis and exposed to ≥1 gray (Gy) to the contralateral breast, had a greater risk of CBC than matched unexposed nulliparous women (RR=2.2, 95% CI 1.2–4.0). No increased risk was seen in RT-exposed parous women (RR=1.1, 95% CI 0.8–1.4). Women treated with RT who later became pregnant (n=8 cases and 9 controls) had a greater risk of CBC (RR=6.0, 95% CI 1.3, 28.4) than unexposed women (n=4 cases and 7 controls) who also became pregnant. The association of radiation with risk of CBC did not vary by number of pregnancies, history of breastfeeding or menopausal status at the time of first breast cancer diagnosis.
Nulliparous women treated with RT were at an increased risk of CBC. Although based on small numbers, women who become pregnant after first diagnosis also appear to be at an increased risk of radiation-induced CBC.
PMCID: PMC3394928  PMID: 22483700
Reproductive factors; radiation treatment; second primary contralateral breast cancer
19.  G2 checkpoint control and G2 chromosomal radiosensitivity in cancer survivors and their families 
Mutagenesis  2010;26(2):291-294.
Significant inter-individual variation in G2 chromosomal radiosensitivity, measured as radiation-induced chromatid-type aberrations in the subsequent metaphase, has been reported in peripheral blood lymphocytes of both healthy individuals and a range of cancer patients. One possible explanation for this variation is that it is driven, at least in part, by the efficiency of G2–M checkpoint control. The hypothesis tested in the current analysis is that increased G2 chromosomal radiosensitivity is facilitated by a less efficient G2–M checkpoint. The study groups comprised 23 childhood and adolescent cancer survivors, their 23 partners and 38 of their offspring (Group 1) and 29 childhood and young adult cancer survivors (Group 2). Following exposure to 0.5 Gy of 300 kV X-rays, lymphocyte cultures were assessed for both G2 checkpoint delay and G2 chromosomal radiosensitivity. In Group 1, the extent of G2 checkpoint delay was measured by mitotic inhibition. No statistically significant differences in G2 checkpoint delay were observed between the cancer survivors (P = 0.660) or offspring (P = 0.171) and the partner control group nor was there any significant relationship between G2 checkpoint delay and G2 chromosomal radiosensitivity in the cancer survivors (P = 0.751), the partners (P = 0.634), the offspring (P = 0.824) or Group 1 taken as a whole (P = 0.379). For Group 2, G2 checkpoint delay was assessed with an assay utilising premature chromosome condensation to distinguish cell cycle stage. No significant relationship between G2 checkpoint delay and G2 chromosomal radiosensitivity was found (P = 0.284). Thus, this study does not support a relationship between G2–M checkpoint efficiency and variation in G2 chromosomal radiosensitivity.
PMCID: PMC3044197  PMID: 21044988
20.  Hospitalizations among children of survivors of childhood and adolescent cancer: A population-based cohort study 
Curative but potentially mutagenic cancer therapy might lead to untoward disorders and increased hospitalization among the offspring of childhood cancer survivors. Hospitalizations in childhood were evaluated in a population-based cohort of 1,920 offspring of 3,963 childhood cancer survivors, 6,394 offspring of 5,657 siblings, and 9,594 population-based comparisons. The Danish Cancer Registry, Central Population Register, and National Hospital Register were used to identify study subjects and hospitalizations. The probability for children in the offspring cohorts of being hospitalized before a given age was estimated using the Kaplan-Meier method. Hospitalization rate ratios (HRRs) were calculated using a Cox proportional hazards model with population comparisons as referent. Little differences in hospitalization histories were seen among offspring in the three cohorts. HRRs of overall hospitalization was 1.05 (95% CI, 0.98–1.12) for offspring of survivors and 1.01 (95% CI, 0.97–1.05) for offspring of siblings, neither of which was significantly different from that of population comparisons. No significant associations were seen for most of the main diagnostic groups of diseases including infections and perinatal disorders. A six-fold excess risk of hospitalization for malignant tumors in survivors’ offspring, however, could largely be explained by hereditary cancer syndromes, and part of the 2-fold excess hospitalization for benign tumors might similarly be explained by an underlying genetic susceptibility or by increased surveillance of children born to survivors. Assuming that hospitalization is an indicator of multifactorial genetic disease, the findings provide further reassurance that cancer therapies do not confer a high risk of such conditions in offspring born after treatments.
PMCID: PMC2958229  PMID: 21351267
cancer survivor; childhood cancer; germ-cell mutation; hospitalization in offspring
21.  Single nucleotide polymorphisms associated with risk for contralateral breast cancer in the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study 
Breast Cancer Research : BCR  2011;13(6):R114.
Genome-wide association studies, focusing primarily on unilateral breast cancer, have identified single nucleotide polymorphisms (SNPs) in a number of genomic regions that have alleles associated with a significantly increased risk of breast cancer. In the current study we evaluate the contributions of these previously identified regions to the risk of developing contralateral breast cancer. The most strongly disease-associated SNPs from prior studies were tested for association with contralateral breast cancer. A subset of these SNPs, selected upon their main effects on contralateral breast cancer risk was further evaluated for interaction with treatment modalities and estrogen receptor (ER) status.
We genotyped 21 SNPs in 708 women with contralateral breast cancer and 1394 women with unilateral breast cancer who serve as the cases and controls in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study. Records of treatment and ER status were available for most of WECARE Study participants. Associations of SNP genotypes and risk for contralateral breast cancer were calculated with multivariable adjusted conditional logistic regression methods.
Multiple SNPs in the FGFR2 locus were significantly associated with contralateral breast cancer, including rs1219648 (per allele rate ratio (RR) = 1.25, 95%CI = 1.08-1.45). Statistically significant associations with contralateral breast cancer were also observed at rs7313833, near the PTHLH gene (per allele RR = 1.26, 95%CI = 1.08-1.47), rs13387042 (2q35) (per allele RR = 1.19, 95%CI = 1.02-1.37), rs13281615 (8q24) (per allele RR = 1.21, 95%CI = 1.04-1.40), and rs11235127 near TMEM135 (per allele RR = 1.26, 95%CI = 1.04-1.53). The A allele of rs13387042 (2q35) was significantly associated with contralateral breast cancer in ER negative first tumors while the A allele of rs11235127 (near TMEM135) was significantly associated with contralateral breast cancer in ER positive first tumors. Although some SNP genotypes appeared to modify contralateral breast cancer risk with respect to tamoxifen treatment or particular radiation doses, trend tests for such effects were not significant.
Our results indicate that some common risk variants associated with primary breast cancer also increase risk for contralateral breast cancer, and that these risks vary with the ER status of the first tumor.
PMCID: PMC3326556  PMID: 22087758
22.  Preterm Delivery Among Female Survivors of Childhood, Adolescent and Young Adulthood Cancer 
We studied the deliveries of female cancer survivors and female siblings in a population-based setting in Finland. Nationwide cancer and birth registries were merged to identify 1309 first post-diagnosis deliveries of early onset (diagnosed under age 35) female cancer patients and 5916 first deliveries of female siblings occurring in 1987–2006. Multiple logistic regression models were used to estimate risk of preterm (<37weeks), low birth weight (LBW) (<2500g), and small-for-gestational-age (SGA) deliveries.
The risk of preterm delivery among cancer survivors compared to siblings was overall elevated (Odds ratio (OR) 1.46, 95% confidence interval (CI) 1.14–1.85), the increase in risk being visible in all diagnostic age groups. Risk of LBW was also significantly increased (OR 1.68; 95% CI 1.29–2.18) but not after adjustment for duration of pregnancy (OR 1.11; 95% CI 0.76–1.64). Neither was the risk of SGA increased. The risk of preterm delivery was most pronounced in survivors delivering ten years or more after diagnosis. Site specific analyses indicated that survivors of germ cell tumors and central nervous system (CNS) tumors were at increased risk of preterm delivery, although numbers were small. In childhood survivors, kidney tumors formed the main cause of preterm delivery.
Pediatric, adolescent and young adult cancer survivors are at risk for preterm delivery. Heightened surveillance is recommended especially for Wilms’, germ cell and CNS tumor survivors. Such adverse pregnancy outcomes can occur a decade or more after cancer diagnosis indicating a continued need for obstetric awareness, surveillance and counseling in former cancer patients.
PMCID: PMC2919618  PMID: 20054856
Preterm; Cancer survivors; Pregnancy; Late-effects
23.  Comparison of germ line minisatellite mutation detection at the CEB1 locus by Southern blotting and PCR amplification 
Mutagenesis  2010;25(4):343-349.
Identification of de novo minisatellite mutations in the offspring of parents exposed to mutagenic agents offers a potentially sensitive measure of germ line genetic events induced by ionizing radiation and genotoxic chemicals. Germ line minisatellite mutations (GMM) are usually detected by hybridizing Southern blots of unamplified size-fractionated genomic DNA with minisatellite probes. However, this consumes a relatively large amount of DNA, requires several steps and may lack sensitivity. We have developed a polymerase chain reaction (PCR)-based GMM assay, which we applied to the hypermutable minisatellite, CEB1. Here, we compare the sensitivity and specificity of this assay with the conventional Southern hybridization method using DNA from 10 spouse pairs, one parent of each pair being a survivor of cancer in childhood, and their 20 offspring. We report that both methods have similar specificity but that the PCR method uses 250 times less DNA, has fewer steps and is better at detecting GMM with single repeats provided that specific guidelines for allele sizing are followed. The PCR GMM method is easier to apply to families where the amount of offspring DNA sample is limited.
PMCID: PMC2893306  PMID: 20228094
24.  Population-Based Study of the Risk of Second Primary Contralateral Breast Cancer Associated With Carrying a Mutation in BRCA1 or BRCA2 
Journal of Clinical Oncology  2010;28(14):2404-2410.
Women with breast cancer diagnosed early in life comprise a substantial portion of those tested for BRCA1/BRCA2 mutations; however, little information is available on the subsequent risks of contralateral breast cancer in mutation carriers. This study assessed the risk of subsequent contralateral breast cancer associated with carrying a BRCA1 or BRCA2 mutation.
Patients and Methods
In this nested case-control study, patients with contralateral breast cancer diagnosed 1 year or more after a first primary breast cancer (n = 705) and controls with unilateral breast cancer (n = 1,398) were ascertained from an underlying population-based cohort of 52,536 women diagnosed with a first invasive breast cancer before age 55 years. Interviews and medical record reviews were used to collect risk factor and treatment histories. All women were tested for BRCA1/BRCA2 mutations. Relative (rate ratios) and absolute (5- and 10-year cumulative) risks of developing contralateral breast cancer following a first invasive breast cancer were computed.
Compared with noncarriers, BRCA1 and BRCA2 mutation carriers had 4.5-fold (95% CI, 2.8- to 7.1-fold) and 3.4-fold (95% CI, 2.0- to 5.8-fold) increased risks of contralateral breast cancer, respectively. The relative risk of contralateral breast cancer for BRCA1 mutation carriers increased as age of first diagnosis decreased. Age-specific cumulative risks are provided for clinical guidance.
The risks of subsequent contralateral breast cancer are substantial for women who carry a BRCA1/BRCA2 mutation. These findings have important clinical relevance regarding the assessment of BRCA1/BRCA2 status in patients with breast cancer and the counseling and clinical management of patients found to carry a mutation.
PMCID: PMC2881721  PMID: 20368571
25.  Radiation Exposure, the ATM Gene, and Contralateral Breast Cancer in the Women's Environmental Cancer and Radiation Epidemiology Study 
Ionizing radiation is a known mutagen and an established breast carcinogen. The ATM gene is a key regulator of cellular responses to the DNA damage induced by ionizing radiation. We investigated whether genetic variants in ATM play a clinically significant role in radiation-induced contralateral breast cancer in women.
The Women's Environmental, Cancer, and Radiation Epidemiology Study is an international population-based case–control study nested within a cohort of 52 536 survivors of unilateral breast cancer diagnosed between 1985 and 2000. The 708 case subjects were women with contralateral breast cancer, and the 1397 control subjects were women with unilateral breast cancer matched to the case subjects on age, follow-up time, registry reporting region, and race and/or ethnicity. All women were interviewed and underwent full mutation screening of the entire ATM gene. Complete medical treatment history information was collected, and for all women who received radiotherapy, the radiation dose to the contralateral breast was reconstructed using radiotherapy records and radiation measurements. Rate ratios (RRs) and corresponding 95% confidence intervals (CIs) were estimated by using multivariable conditional logistic regression. All P values are two-sided.
Among women who carried a rare ATM missense variant (ie, one carried by <1% of the study participants) that was predicted to be deleterious, those who were exposed to radiation (mean radiation exposure = 1.2 Gy, SD = 0.7) had a statistically significantly higher risk of contralateral breast cancer compared with unexposed women who carried the wild-type genotype (0.01–0.99 Gy: RR = 2.8, 95% CI = 1.2 to 6.5; ≥1.0 Gy: RR = 3.3, 95% CI = 1.4 to 8.0) or compared with unexposed women who carried the same predicted deleterious missense variant (0.01–0.99 Gy: RR = 5.3, 95% CI = 1.6 to 17.3; ≥1.0 Gy: RR = 5.8, 95% CI = 1.8 to 19.0; Ptrend = .044).
Women who carry rare deleterious ATM missense variants and who are treated with radiation may have an elevated risk of developing contralateral breast cancer. However, the rarity of these deleterious missense variants in human populations implies that ATM mutations could account for only a small portion of second primary breast cancers.
PMCID: PMC2902825  PMID: 20305132

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