Marcotte Erin L, Schraw Jeremy M, Desrosiers Tania A, Nembhard Wendy N, Langlois Peter H, Canfield Mark A, Meyer Robert E, Plon Sharon E, Lupo Philip J
Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
JNCI Cancer Spectr. 2020 Jun 11;4(5):pkaa052. doi: 10.1093/jncics/pkaa052. eCollection 2020 Oct.
There is a persistent, unexplained disparity in sex ratio among childhood cancer cases, whereby males are more likely to develop most cancers. This male predominance is also seen for most birth defects, which are strongly associated with risk of childhood cancer. We conducted mediation analysis to estimate whether the increased risk of cancer among males is partially explained by birth defect status.
We used a population-based birth cohort with linked data from birth certificates, birth defects registries, and cancer registries from Arkansas, Michigan, North Carolina, and Texas. We conducted counterfactual mediation analysis to estimate the natural direct and indirect effects of sex on cancer risk, modeling birth defect status as mediator. State; birth year; plurality; and maternal race and ethnicity, age, and education were considered confounders. We conducted separate analyses limited to cancers diagnosed younger than 1 year of age.
Our dataset included 10 181 074 children: 15 110 diagnosed with cancer, 539 567 diagnosed with birth defects, and 2124 co-occurring cases. Birth defect status mediated 38% of the association between sex and cancer overall. The proportion mediated varied by cancer type, including acute myeloid leukemia (93%), neuroblastoma (35%), and non-Hodgkin lymphoma (6%). Among children younger than 1 year of age at cancer diagnosis, the proportion mediated was substantially higher (82%).
Our results suggest that birth defects mediate a statistically significant proportion of the relationship between sex and childhood cancer. The proportion mediated varied by cancer type and diagnosis age. These findings improve our understanding of the causal pathway underlying male sex as a risk factor for childhood cancer.
儿童癌症病例的性别比例存在持续且无法解释的差异，即男性患大多数癌症的可能性更高。在大多数出生缺陷中也可见这种男性优势，而出生缺陷与儿童癌症风险密切相关。我们进行了中介分析，以估计男性患癌风险增加是否部分由出生缺陷状况所解释。
我们使用了一个基于人群的出生队列，其数据来自阿肯色州、密歇根州、北卡罗来纳州和得克萨斯州的出生证明、出生缺陷登记处和癌症登记处。我们进行了反事实中介分析，以估计性别对癌症风险的自然直接和间接影响，将出生缺陷状况作为中介进行建模。州、出生年份、胎次以及母亲的种族、民族、年龄和教育程度被视为混杂因素。我们进行了单独分析，仅限于诊断年龄小于1岁的癌症。
我们的数据集包括10181074名儿童：15110名被诊断患有癌症，539567名被诊断患有出生缺陷，2124名同时患有这两种疾病。出生缺陷状况介导了性别与总体癌症之间38%的关联。介导比例因癌症类型而异，包括急性髓系白血病（93%）、神经母细胞瘤（35%）和非霍奇金淋巴瘤（6%）。在癌症诊断时年龄小于1岁的儿童中，介导比例显著更高（82%）。
我们的结果表明，出生缺陷在性别与儿童癌症之间的关系中介导了具有统计学意义的比例。介导比例因癌症类型和诊断年龄而异。这些发现增进了我们对男性性别作为儿童癌症风险因素的潜在因果途径的理解。
