Genome-Wide Association Study to Identify Susceptibility Loci That Modify Radiation-Related Risk for Breast Cancer After Childhood Cancer

Lm, Morton; Sampson, JN; Gt, Armstrong; Th, Chen; Mm, Hudson; Karlins, Eric; Cl, Dagnall; Li, Sa; Wilson, Craig M.; Dk, Srivastava; W, Liu; Kang, Guolian; Oeffinger, K; Henderson, TO; Cs, Moskowitz; Gibson, Todd M.; Dm, Merino; Wong, K.F.; Hammond, Sue; Jp, Neglia; Lm, Turcotte; Miller, Jeremy S.; Bowen, Laura; Wa, Wheeler; Wm, Leisenring; Ja, Whitton; Burdette, Laurie; Chung, Charles C.; Bd, Hicks; Jones, Kristine; Mj, Machiela; Vogt, Aurélie; Wang, Z; Yeager, Meredith; Neale, Geoffrey; Lear, Matthew; Lc, Strong; Yasui, Yutaka; Stovall, Marilyn; Re, Weathers; Smith, Stephen A.; Howell, Rebecca M.; Sm, Davies; Ga, Radloff; Onel, Kenan; A, Berrington de González; Pd, Inskip; Rajaraman, Preetha; Fraumeni, JosephF.; Bhatia, Smita; Chanock, SJ; Ma, Tenghui; Ll, Robison

doi:10.1093/jnci/djx058

Cited by 72 publications

(53 citation statements)

References 37 publications

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“…For the current report, 96 survivors were selected from the pool of ALL survivors with an available DNA sample using “extreme phenotype” sampling: 48 obese (BMI ≥ 30.0 kg/m 2 ) and 48 normal weight (18.5 ≤ BMI ≤24.9 kg/m 2 ) based on the CCSS 2007 Follow‐up survey. Specifically, eligible participants included adult (age ≥20 years at 2007 survey) survivors of ALL (with no history of bone marrow transplant, recurrence, or subsequent malignant neoplasms), genotyped as part of the CCSS and National Cancer Institute collaborative genome‐wide association study and genetically defined as being predominantly of European ancestry (ie, ≥80%) with details on therapeutic exposures . To form the obese group, we randomly selected 24 obese survivors who had CRT doses of ≥18 Gy and 24 obese survivors who did not receive CRT (ie, chemotherapy only), in order to be able to evaluate the methylation‐association differences by CRT status, one of the strongest risk factors for obesity among adult survivors of pediatric ALL .…”

Section: Methodsmentioning

confidence: 99%

DNA methylation and obesity in survivors of pediatric acute lymphoblastic leukemia: A report from the Childhood Cancer Survivor Study

Lupo

Brown

Arroyo

et al. 2018

Genes Chromosomes & Cancer

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Because survivors of pediatric acute lymphoblastic leukemia (ALL) are more likely to be obese than unaffected contemporaries, we compared DNA methylation profiles between normal-weight and obese survivors at adiposity-associated CpG sites previously-reported by epigenome-wide association studies (EWAS) of body mass index (BMI) in the general population. We selected 96 ALL survivors from the Childhood Cancer Survivor Study (CCSS): 48 obese (BMI ≥30.0 kg/m2) and 48 normal weight (BMI = 18.5–24.9 kg/m2). The Illumina HumanMethylation450 BeadChip was used to compare DNA methylation at 211 loci identified in EWAS of BMI in the general population. The false discovery rate (FDR) was used to account for multiple testing. In exploratory analyses, we also tested for interaction between cranial radiotherapy (CRT) status and selected CpG sites to evaluate differences by CRT exposure. Thirty-nine loci were associated (FDR <0.05) with obesity among survivors who only received chemotherapy (n = 49), including ABCG1 cg06500161. No loci were significantly associated with obesity among CRT-exposed survivors (n = 47). There was evidence (P-value <0.05) of interaction between CRT and methylation at six of the 39 methylation sites. Our results suggest that previously identified BMI-DNA methylation loci are associated with obesity in pediatric ALL survivors who were spared CRT, while no loci were significantly associated with obesity in survivors who received CRT. Given the obesogenic characteristics of ALL therapy, this study adds to the growing evidence of that the mechanisms underlying obesity in ALL survivors differ based on treatment exposures and may inform future intervention strategies among these individuals.

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Section: Methodsmentioning

confidence: 99%

DNA methylation and obesity in survivors of pediatric acute lymphoblastic leukemia: A report from the Childhood Cancer Survivor Study

Lupo

Brown

Arroyo

et al. 2018

Genes Chromosomes & Cancer

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“…Among childhood cancer survivors, approximately 30% of patients receiving ≥10 Gy chest RT develop breast cancer by 50 years . In a genome‐wide association study to identify loci of genetic susceptibility to breast cancer development after RT, the interaction of certain germline variants with ionizing radiation conferred a higher risk of RT‐associated breast cancer in some patients . In another study using GWAS, a genetic locus at 6q21 was associated with higher risk for RT‐associated SMNs in patients treated as adolescents .…”

Section: Survivorship and Long‐term Treatment Sequelaementioning

confidence: 99%

Adolescent and young adult Hodgkin lymphoma: Raising the bar through collaborative science and multidisciplinary care

Kahn

Kelly

2018

Pediatric Blood & Cancer

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Hodgkin lymphoma (HL) is one of the most common cancers in the adolescent and young adult (AYA) population (15-39 years). Despite continued improvements in HL outcomes, AYAs have not exhibited survival gains to the same extent as other age groups. At present, details about tumor biology, optimal therapeutic approaches, supportive care needs, and long-term toxicities in AYAs with HL remain understudied. Herein, we summarize the current state of the AYA population with HL, specifically focusing on how collaborations across the pediatric and medical oncology divide, coupled with multidisciplinary patient care, can further optimize outcomes for this group of patients.

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“…Indeed, the data from Morton et al (7) cast an element of uncertainty upon two previously reported associations detected in this setting, at 6q21 and 10q26.13 (8,9). While genetic epidemiological studies of sporadic cancer predisposition in the general population have identified and robustly validated hundreds of variants that influence the risk of most common types of the disease (10), these successes have depended on global collaborative efforts to pool vast numbers of samples for analysis (11–13).…”

mentioning

confidence: 87%

Genetic Determinants of Breast Cancer Risk in Childhood Cancer Survivors

Meier

Orr

2017

JNCI: Journal of the National Cancer Institute

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Genome-Wide Association Study to Identify Susceptibility Loci That Modify Radiation-Related Risk for Breast Cancer After Childhood Cancer

Abstract: Our study provides strong evidence that germline genetics outside high-risk syndromes could modify the effect of radiation exposure on breast cancer risk after childhood cancer.

Cited by 72 publications

References 37 publications

DNA methylation and obesity in survivors of pediatric acute lymphoblastic leukemia: A report from the Childhood Cancer Survivor Study

DNA methylation and obesity in survivors of pediatric acute lymphoblastic leukemia: A report from the Childhood Cancer Survivor Study

Adolescent and young adult Hodgkin lymphoma: Raising the bar through collaborative science and multidisciplinary care

Genetic Determinants of Breast Cancer Risk in Childhood Cancer Survivors

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