First-born twin has a higher risk of acute leukemia in a population-based assessment of cancer in twins in California, and lower than anticipated rate of twin concordance.

We assessed cancer concordance, cancer incidence in the healthy twin of cancer probands, and cancer risk in relation to birth order in pediatric and adolescent/young adult twins via a population-based study in California from 1982-2022. Twin subjects born in California between 1982-2017 who were diagnosed with leukemia from 0-39 years of age were identified through linked birth and California Cancer Registry (1988-2022) data. Two concordant-twin leukemias cases were identified across 255 total twin pairs with leukemia for an overall rate of leukemia concordance of 0.9%. One concordant twin pair was identified among 199 pairs with lymphoid leukemia (0.5%) and one within 34 pairs with acute myeloid leukemia (2.9%). A significant association was identified between twin plurality birth order and development of leukemia (OR 1.18, 95% CI 1-1.39, P=0.049), an effect which was strongest in lymphoid leukemias (2.21, 1.44-3.39, P=1.65e-4). Assessment of DNA methylation markers associated with birth order showed significantly reduced methylation in first-born twin cases compared to second-born (P=8.53e-12) in a subset of 41 twins discordant for lymphoid leukemia. Overall cancer concordance in twins was comparable to the lower range of previous estimates from different world regions. Concordance in lymphoid leukemias was quite lower than expected, indicating concordant leukemia is rarer than previously appreciated. We identified a strong association between twin plurality birth order and development of pediatric cancer. While the underlying cause of this finding is uncertain, we identified significant differences in DNA methylation at previously described sites associated with birth order, suggesting a similar biological mechanism.