Increased Burden of Familial-associated Early-onset Cancer Risk among Latino Americans Compared to non-Latino Whites.

The role of race/ethnicity in genetic predisposition of early-onset cancers can be estimated by comparing family-based cancer concordance rates among ethnic groups. We used linked California health registries to evaluate the relative cancer risks for first degree relatives of patients diagnosed between ages 0-26, and the relative risks of developing distinct second malignancies (SPMs). From 1989-2015, we identified 29,631 cancer patients and 62,863 healthy family members. Given probands with cancer, there were increased relative risks of any cancer for siblings and mothers [standardized incidence ratio (SIR)=3.32;95% confidence interval (CI):2.54-4.35;P<0.001)]and of SPMs (SIR=7.12;95%CI:5.46-9.28;P<0.001). Higher relative risk of any cancer in siblings and mothers (P=0.001) was observed for Latinos (SIR=3.36;95%CI:2.24-5.05) compared to non-Latino White subjects (SIR=2.60;95%CI:1.66-4.06). Latinos had higher relative risks in first degree relatives and higher SPM risk compared to non-Latino Whites for most cancers, supporting a need for increased attention to the genetics of early-onset cancer predisposition in Latinos.

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The copyright holder for this this version posted December 14, 2020. ; https://doi.org/10.1101/2020.12.11.20247866 doi: medRxiv preprint groups and subgroups as defined by the International Classification of Childhood Cancer, Third 121 edition (ICCC-3, November 2012) (https://seer.cancer.gov/iccc/iccc3.html). The abbreviations 122 for cancer types are included in Table 1. We also grouped the cancers into hematologic or solid 123 categories in the analyses. Hematologic cancers were defined as leukemias and lymphomas.

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We quantified the relative risks for siblings and mothers, and the relative risks of SPMs by 130 calculating the standardized incident ratios (SIRs) of a given cancer or of SPMs among the cancer. We compared the SIRs across race/ethnic groups with approximate Chi-squared tests.

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The approximate chi-square method compares the probability of occurrence of events in one 150 group to another, based on a binomial distribution. This comparison is not related to the 95% 151 confidence intervals for the SIRs which are based on a Poisson distribution and may overlap 152 between two groups that are significantly different by approximate chi-square comparison. We 153 designated that all events occurred right at the middle point of each calendar year. We also 154 stratified the analysis by 5-year age groups. The 95% confidence intervals (CIs) and p-values 155 were calculated assuming a Poisson distribution. Statistical analyses were performed using R 156 software (v 3.6.0). Any two-sided p-value less than 0.05 was considered statistically significant.

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A supplement is included with this manuscript with more information on the statistical tests and 158 computational codes used. Please access this supplement "Statistics and coding supplement:

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From 1989 to 2015, we identified a total of 29 249 pediatric and AYA patients with a primary 164 malignancy, comprising 29 072 probands, 112 affected siblings (from 110 families) and 65 165 affected mothers. All siblings were diagnosed after the proband's diagnosis as defined, and 56 166 (86.15%) of the 65 mothers were diagnosed after the proband's diagnosis. We also identified 167 387 SPMs among all pediatric and AYA probands ( Table 2).

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Familial relative risks of early-onset cancers 170 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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For the relative risk of specific cancer types, we found a 2.68-fold

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When stratified by more finely defined cancer subtypes, increased relative risks of any cancer 191 for siblings and mothers were observed given a proband with lymphoid leukemia, acute myeloid   Table 4).

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The copyright holder for this this version posted December 14, 2020. ; https://doi.org/10.1101/2020.12.11.20247866 doi: medRxiv preprint with an early-onset cancer. Likewise, the relative risks for SPMs were elevated among 236 children/AYAs who contracted a first primary cancer. The findings were consistent across 237 race/ethnic groups; however, the magnitude was different. Latinos had higher sibling/maternal 238 relative risks as well as risks for SPMs compared to NLWs for most cancers.

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The copyright holder for this this version posted December 14, 2020. ; https://doi.org/10.1101/2020.12.11.20247866 doi: medRxiv preprint non-Latino Whites. This familial concordance is likely due to both shared genetic and 258 environmental causes and is accompanied by a clearly higher incidence of some cancer types.

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Latinos are an admixed population, comprising an ancestral mixture from Native American,

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For some tumor types the germline predisposition was readily noted in this cohort, for example 281 ten of the fourteen affected relatives who had a proband with retinoblastoma were diagnosed 282 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this this version posted December 14, 2020. ; https://doi.org/10.1101/2020.12.11.20247866 doi: medRxiv preprint with the same cancer, an unsurprising finding given that germline RB1 mutations account for a 283 significant proportion of retinoblastoma are highly penetrant and those tumors tend to be 284 diagnosed young. We also observed increased relative risks for sarcomas given a proband with   preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this this version posted December 14, 2020. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The axis for SIR was natural log-transformed. SIR and 95% CI were not calculatable for cancers 516 with zero observed case.

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P was calculated assuming a Poisson distribution.

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Standardized incidence ratios greater than 10 were recoded to 10.

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Siblings and mothers of a proband were diagnosed with cancer from 1989 to 2015 at 0 to 26 526 years of age.  All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this this version posted December 14, 2020. ; https://doi.org/10.1101/2020.12.11.20247866 doi: medRxiv preprint All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this this version posted December 14, 2020. ; https://doi.org/10.1101/2020.12.11.20247866 doi: medRxiv preprint All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.