# paper.pdf ## Metadata - PDFFormatVersion=1.7 - IsLinearized=true - IsAcroFormPresent=false - IsXFAPresent=false - IsCollectionPresent=false - IsSignaturesPresent=false - CreationDate=D:20260519135915+05'30' - Creator=PTC Arbortext Layout Developer 12.1.6202/W-x64 - Custom.EPSprocessor=PStill version 1.84.42 - Custom.WPS-ARTICLEDOI=10.1002/cncr.70458 - Custom.WPS-JOURNALDOI=10.1002/(ISSN)1097-0142 - Custom.WPS-PROCLEVEL=3 - ModDate=D:20260519165032+05'30' - Producer=PDFlib+PDI 9.3.1p6 (C++/Win64) - Title=Demographic, birth, parental characteristics, and the risk of early‐onset colorectal cancer: A population‐based nested case‐control study in California - Trapped=False - xmp:createdate=2026-05-19T13:59:15+05:30 - xmp:creatortool=PTC Arbortext Layout Developer 12.1.6202/W-x64 - xmp:modifydate=2026-05-19T16:50:32+05:30 - xmp:metadatadate=2026-05-19T16:50:32+05:30 - pdf:producer=PDFlib+PDI 9.3.1p6 (C++/Win64) - pdf:trapped=False - pdfx:wps-articledoi=10.1002/cncr.70458 - pdfx:wps-journaldoi=10.1002/(ISSN)1097-0142 - pdfx:wps-proclevel=3 - pdfx:epsprocessor=PStill version 1.84.42 - jav:journal_article_version=VoR - prism:doi=10.1002/cncr.70458 - dc:format=application/pdf - dc:title=Demographic, birth, parental characteristics, and the risk of early‐onset colorectal cancer: A population‐based nested case‐control study in California - xmpmm:documentid=uuid:ca15ac7c-8067-46d3-af04-14b2a1d48d28 - xmpmm:instanceid=uuid:54bd9337-ba3f-420f-b237-e74ad3873545 ## Contents ### Page 1 Received: 21 November 2025- Revised: 17 April 2026- Accepted: 24 April 2026 DOI: 10.1002/cncr.70458O R I G I N A L A R T I C L E Demographic, birth, parental characteristics, and the risk of early-onset colorectal cancer: A population-based nested case-control study in California Sunny Siddique MPH, PhD1 | Rong Wang PhD1 | Domenica Berardi PhD2 |Caroline H. Johnson PhD2 | Joseph L. Wiemels PhD3 | Catherine Metayer PhD4 |Xiaomei Ma PhD11Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA 2Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut, USA 3Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA 4Division of Epidemiology, School of Public Health, University of California, Berkeley, California, USACorrespondenceSunny Siddique, Department of Chronic Disease Epidemiology, Yale School of Public Health, 60 College St., New Haven, CT 06510, USA. Email: sunny.siddique@yale.eduFunding informationNational Cancer Institute, Grant/Award Number: 2T32CA250803-06Abstract Background: The incidence of early-onset colorectal cancer (EOCRC), defined as colorectal cancer diagnosed before the age of 50 years, has been increasing. The relationship between demographic, birth, and parental characteristics and risk of EOCRC has not been elucidated.Methods: This study included 1221 cases born and diagnosed with EOCRC at the age of 0 to 39 years in California during 1988 through 2021 and 61,050 frequency-matched controls based on birth year. Odds ratios (OR) and 95% CIs were esti- mated using multivariable logistic regression models.Results: Based on multivariable analysis, males had 34% higher risk of EOCRC compared to females (OR = 1.34; 95% CI, 1.20–1.51), and Hispanic ethnicity was associated with 43% higher risk of EOCRC (OR for Hispanic versus non-Hispanic White = 1.34; 95% CI, 1.20–1.51). Having a foreign-born mother was associated with a lower risk of EOCRC (OR = 0.85; 95% CI, 0.73–0.97). Among females, every 500-g increase in birthweight was associated with 10% increase in EOCRC risk (OR = 1.10; 95% CI, 1.01–1.21) and having a father aged ≥35 years was associated with higher risk of EOCRC (OR = 1.56; 95% CI, 1.08–2.25). No other demographic, birth, and parental characteristic was significantly associated with risk of EOCRC.Conclusion: High birthweight, male sex, Hispanic ethnicity, and older paternal age are potential risk factors for EOCRC. Maternal birthplace, which is associated with diet, smoking patterns, other health-promoting characteristics, may be protective against EOCRC. These factors require future research for validation and evaluation of possible mechanisms.K E Y W O R D Sbirth characteristics, birthweight, colorectal cancer risk factors, early-life exposures, early-onset colorectal cancer, Hispanic ethnicity, paternal age, parental characteristics, sex differences This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2026 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.Cancer. 2026;e70458. wileyonlinelibrary.com/journal/cncr- 1 of 12https://doi.org/10.1002/cncr.70458 ### Page 2 INTRODUCTIONColorectal cancer (CRC) is the second most common cancer and third leading cause of cancer-related mortality in the United States (US).1 Since the mid-1980s, incidence rates of CRC have declined among individuals ≥50 years of age.2–5 However, the incidence of early-onset CRC (EOCRC), defined as CRC diagnosed among individuals<50 years of age, has steadily increased over the past 2 decades.6 EOCRC is the leading cause of cancer-related mortality before the age of 50 years in the United States.7 Compared to later-onset CRC, EOCRC presents at an advanced stage (because of both aggressive pathology and delay of up to 6 months from symptom onset to diagnosis).8 EOCRC is typically found in the rectum and distal colon with high percentage of mucosal and signet cell pathology.9,10 Can- cers in the distal colon and rectum are associated with high intake of Western diet, including red and processed meat consumption and high alcohol intake across all age groups.11,12 Because of the global westernization of diet, a birth cohort effect has also been observed in EOCRC, which occurs when disease risk varies by birth year due to changes in exposure patterns.13,14 In the literature, CRC risk has been shown to differ by sever a demographic factors (e.g., individuals aged ≥65 years, males, Amer- ican Indians and Alaska Natives experiencing the highest inci- dence).15,16 However, possible variation in EOCRC risk remains understudied. Notably, steep increases in incidence and mortality have been observed among Hispanic individuals.17 The Hispanic population is expanding at a substantially faster rate than the non-Hispanic (NH) population.18 In 2014, nearly 60% of the US Hispan- ic population were millennials or younger (i.e., younger than 33 years), compared to 40% of NH Whites who belong to the same age group.19 Given the relatively younger age distribution and distinct dietary and health behavioral factors, risk factors for EOCRC may differ among Hispanic individuals.20,21 Prior studies elucidating risk factors at the time of cancer diag- nosis often overlook birth characteristics, a key set of early life risk factors that are indicative of health outcomes throughout the life- span.22 Furthermore, those that do consider early life factors focus on a limited set of factors (e.g., birthweight, birth size, maternal obesity).23–27 Birthweight and maternal obesity have been shown to be positively associated with risk of CRC, perhaps because of fetal growth restrictions and intrauterine alterations in pregnancy hor- mones (e.g., growth hormones, steroid hormones, insulin).24–26 Furthermore, one study has identified birth by cesarean delivery as a risk factor for CRC among female offspring in later life.28 These observations suggest that intrauterine factors may be important predictors of CRC, but there has been a paucity of research evalu- ating demographic, birth, and parental characteristics in relation to the risk of EOCRC, particularly among growing minority groups such as Hispanics. To fill these knowledge gaps, we conducted a large population-based nested case-control study evaluating the association be- tween a comprehensive set of demographic, birth, parental charac- teristics, and risk of EOCRC among individuals born in the state of California. To identify potential differences in EOCRC etiology based on demographic factors, we further conducted stratified analysis based on sex and age at diagnosis.29 We also stratified our results based on Hispanic ethnicity because they represented the largest birth population impacted by EOCRC in the study sample and constitute the fastest growing minority groups in the US because of their highest birth rates.18METHODS Study populationThe California Linkage Study of Early-Onset Cancers is a population-based nested case-control study joining California birth records maintained by the Center for Health Statistics and Informatics at the California Department of Public Health (for the birth years 1982–2021), with statewide cancer diagnosis data from the Cali- fornia Cancer Registry for the years 1988–2021.30,31 First primary malignant CRC was classified according to the following International Classification of Diseases for Oncology, 3rd edition, site codes: 21040-21041, 21043-21052. Individuals with unknown information for the following variables were excluded: maternal age (n = 1), birthweight (n = 0), birth order (n = 3), birth plurality (n = 0), mother’s place of birth (n = 1), delivery mode (n = 3), history of miscarriage or stillbirth (n = 1), and congenital abnormality (n = 15). One case whose mother resided outside of California at the time of delivery was also excluded. Fifty times as many control subjects were randomly selected from the statewide birth records and frequency-matched to the cases on year of birth; the controls had not been diagnosed with any cancer based on the absence of cancer report data from the California Cancer Registry. The same exclusion criteria for cases were applied to potential controls. Since the rising incidence of EOCRC is characterized by a birth cohort effect, we frequency-matched on year of birth while retaining other biological variables (e.g., sex, age) as potential confounders in our models. The study protocol was approved by the institutional review boards at the California Health and Human Services Agency, the University of California, Berkeley, and Yale University.Variables of interestWe abstracted child, maternal, and paternal characteristics from birth records. Child demographic characteristics included sex, age, race and ethnicity, and child birth characteristics included birth- weight (separately as both continuous [i.e., every 500 g] and cate- gorical variables [i.e., <2500 g, 2500–2999 g, 3000–3499 g, 3500–3999 g, ≥4000 g]), gestational age (≤36 weeks [preterm], 37–41 weeks [full term], >41 weeks [postterm], unknown), birth or- der (first, second, third or higher), mode of delivery (vaginal, cesar- ean), and birth plurality (singleton, multiple). Maternal characteristics included: maternal age (<20, 20–24, 25–29, 30–34, ≥35 years),2 of 12 - RISK FACTORS OF EOCRC ### Page 3 maternal education (high school or below, at least some college, unknown), maternal history of miscarriage or stillbirth (yes/no), maternal birthplace (US, foreign), maternal history of complications during pregnancy (yes/no), and maternal history of cesarean delivery (cesarean section, yes/no). Paternal characteristics included: paternal age (<20, 20–24, 25–29, 30–34, ≥35 years, unknown) and paternal education (high school or below, at least some college, unknown).Statistical analysisWe used Pearson’s chi-squared and Fisher’s exact tests to evaluate differences in categorical variables, and two-sided t-tests to evaluate differences in continuous variables between cases and controls. Odds ratios (ORs) and 95% CIs were obtained from unconditional logistic regression models. Because controls were frequency matched to cases based on year of birth, this variable was simultaneously included in all models to account for matching. Crude and adjusted ORs and 95% CIs were obtained for all variables. Adjusted models included sex, race and ethnicity, birthweight, gestational age, birth order, mode of delivery, birth plurality, maternal age, maternal edu- cation, maternal history of miscarriage or stillbirth, maternal history of complications during pregnancy, maternal history of cesarean section, maternal birthplace, paternal age, and paternal education. To account for multiple comparisons, we also considered a Bonferroni corrected α = 0.003. We tested for interaction by sex, Hispanic ethnicity, and age at diagnosis using Wald tests. Furthermore, we used the stepAIC function in R to conduct stepwise model selection, retaining variables with a p value of less than .05. As stepwise model estimates were very similar to effect estimates obtained from crude and adjusted models, we present crude and adjusted models in the results. We further conducted subgroup analyses by sex, age at diagnosis (children and adolescents [0–19 years] and young adults [20–39 years]), and Hispanic ethnicity (Hispanic and NH White). All analyses were performed using R (Version 4.2.4; R Core Team 2022). All p values were from 2-sided tests and results were deemed sta- tistically significant at p < .05.RESULTSOur study included 1221 cases (age at diagnosis: mean = 29.07 years, standard deviation [SD] = 5.80 years) matched to 61,050 controls based on year of birth (1:50 case to control ratio). Compared to controls, cases were more likely to be male (58.80% vs 51.35%,p < .001), Hispanic (44.88% vs 39.93%, p < .01), and had higher birthweight (mean [SD]: 3412 g [571 g] vs 3376 g [581 g], p = .03) (Table 1). In the fully adjusted model, male sex and Hispanic ethnicity met the Bonferroni corrected threshold (α = 0.003). No significant differences were observed between cases and controls based on gestational age, birth order, mode of delivery, birth plurality, maternal age, maternal education, maternal history of miscarriage or stillbirth, maternal history of complications during pregnancy, maternal history of cesarean section, and paternal education. Inter- action analysis showed statistically significant interaction by sex, Hispanic ethnicity, and age at diagnosis (Supporting Information S1: Table S1). Therefore, we present stratified results based on these three variables.SexIn the overall population, males had 35% higher risk of EOCRC compared to females (OR = 1.35; 95% CI, 1.21–1.52) (Table 2). After adjusting for demographic, birth, and parental characteristics, males had 34% higher risk of EOCRC compared to females (OR = 1.34; 95% CI, 1.20–1.51) (Figure 1). Subgroup analysis based on Hispanic ethnicity showed that Hispanic males had 32% higher risk of EOCRC compared to Hispanic females (OR = 1.32; 95% CI, 1.11–1.57) and NH White males had 35% higher risk of EOCRC compared to NH-White females (OR = 1.35, 95% CI, 1.12–1.57) (Figure 2). Males had higher risk of EOCRC compared to females among the in- dividuals aged 0 to 19 years (OR = 1.36; 95% CI, 0.85–2.17) and 20 to 39 years (OR = 1.34; 95% CI, 1.19–1.51), although the results were statistically significant only among individuals aged 20 to 39 years (Figure 3).Hispanic ethnicityIn the overall study sample, 44.88% identified as Hispanic and 36.45% identified as NH White. After adjusting for demographic, birth, and parental characteristics, Hispanic ethnicity was associated with 43% higher risk of EOCRC, compared to NH White individuals (OR = 1.34; 95% CI, 1.20–1.51) (Figure 1). Although Hispanic ethnicity was not significantly associated with EOCRC risk among the subgroup of in- dividuals aged 0 to 19 years (OR = 1.23; 95% CI, 0.65–2.35), among individuals aged 20 to 39, Hispanic ethnicity was significantly associ- ated with risk of EOCRC (OR = 1.44; 95% CI, 1.23–1.68) (Figure 3). Furthermore, Hispanic females and males had higher risk of EOCRC compared to NH White females and males (OR = 1.39; 95% CI, 1.09–1.76; OR = 1.45; 95% CI, 1.19–1.77, respectively) (Figure 4).BirthweightIn the analysis that only adjusted for year of birth (i.e., the matching variable), every 500 g increase in birthweight was associated with 6% increase in risk of EOCRC (OR = 1.06; 95% CI, 1.00–1.11) (Table 2). After adjusting for the full set of demographic, birth, and parental characteristics, higher birthweight still appeared to be linked to a higher risk of EOCRC, but the association did not reach statistical significance (OR for every 500 g increase in birthweight = 1.03; 95% CI, 0.98–1.09) (Figure 1). Among females, every 500 g increase in birthweight was associated with 10% increase in EOCRC risk (OR = 1.10; 95% CI, 1.01–1.21); however, among males, birthweight SIDDIQUE ET AL. - 3 of 12 ### Page 4 T A B L E 1 Characteristics of the study population, California Linkage Study of Early-Onset Cancers.Birth Characteristics Cases ControlspN % N %Total 1221 1.96 61,050 98.04 Age at diagnosis (years) 0–14 16 1.31 15–19 60 4.91 20–39 1145 93.78 Sex Female 503 41.2 29,701 48.65 <.001a Male 718 58.8 31,349 51.35 Race and ethnicity NH Asian/Pacific Islander 106 8.68 5786 9.48 <.01a NH Black 103 8.44 5327 8.73 Hispanic 548 44.88 24,378 39.93 NH White 445 36.45 24,832 40.67 Other/unknown 19 2.55 727 1.19 Birth weight (g, continuous) 3412 (571) 3376 (581) .03a Birth weight (g, categorical)<2500 65 5.32 3538 5.80 .20 2500–2999 162 13.27 9303 15.24 3000–3499 444 36.36 22,482 36.83 3500–3999 398 32.60 18,560 30.40≥4000 152 12.45 7167 11.74 Gestational age (weeks)≤36 97 7.94 ,489 8.99 .09 37–41 988 80.92 48,719 79.8≥42 43 3.52 2807 4.6 Unknown 93 7.62 4035 6.61 Birth order First 475 38.9 24,719 40.49 .15 Second 374 30.63 19,256 31.54 Third or higher+ 372 30.47 17,075 27.97 Mode of delivery Vaginal 965 79.03 47,894 78.45 .65 Cesarean 256 20.97 13,156 21.55 Birth plurality Singleton 1,197 98.03 59,777 2.09 .85 Multiple 24 1.97 1273 97.91 Maternal age (years)<20 123 10.07 6975 11.43 .55 20–24 341 27.93 17,273 28.29 25–29 375 30.71 18,619 30.54 of 12 - RISK FACTORS OF EOCRC ### Page 5 was not significantly associated with risk of EOCRC (OR = 0.99; 95% CI, 0.92–1.06) (Figure 4). Among Hispanic and NH White individuals, the association between every 500 g increase in birthweight and risk of EOCRC was not statistically significant (OR = 1.02; 95% CI, 0.94–1.11; OR = 1.06; 95% CI, 0.96–1.16, respectively) (Figure 2). Among individuals aged 0 to 19 years, birthweight was not signifi- cantly associated with EOCRC risk (OR = 0.90; 95% CI, 0.76–1.12); however, among individuals aged 20 to 39, every 500 g increase in birthweight was associated with 5% increase in risk of EOCRC (OR = 1.05; 95% CI, 1.00–1.11) (Figure 3). Analysis of birthweight as a categorical variable showed that birthweight above the 3000 to 3499 g reference range was associated with higher risk of EOCRC; however, the association was not statistically significant (Supporting Information S1: Table S2). For example, having birthweight ≥4000 g was associated with 7% higher odds of EOCRC (OR = 1.07; 95% CI, 0.89–1.29).T A B L E 1 (Continued)Birth Characteristics Cases ControlspN % N %30–34 258 21.13 12,461 20.41 35+ 124 10.16 5722 9.37 Maternal education High school or below 234 19.16 11,914 19.52 .91 At least some college 136 11.14 6611 10.83 Unknown 851 69.7 42,525 69.66 Maternal history of miscarriage/stillbirth Yes 209 17.12 10,405 17.04 .98 No 1012 82.88 50,645 82.96 Maternal birthplace United States 788 64.54 39,292 64.36 .92 Foreign 433 35.46 21,758 35.64 Maternal history of complications during pregnancy Yes 235 19.67 12,668 21.27 .40 No 959 80.25 46,835 78.65 Unknown 1 2.04 48 0.08 Maternal history of Cesarean delivery Yes 77 6.31 4068 6.66 .85 No 1143 93.61 56,945 93.28 Unknown 1 2.63 37 0.06 Paternal age (years)<20 49 4.01 2747 4.05 .24 20–24 225 18.43 12,395 20.3 25–29 362 29.65 17,598 28.83 30–34 276 22.6 14,402 23.59 35+ 261 21.38 11,585 18.98 Unknown 48 3.93 2596 4.25 Paternal education High school or below 217 17.78 11,047 18.95 .91 At least some college 134 10.97 6498 10.64 Unknown 870 71.25 43,505 71.26 Abbreviation: NH, non-Hispanic. aIndicates statistical significance at p < .05. SIDDIQUE ET AL. - 5 of 12 ### Page 6 T A B L E 2 Odds ratios and 95% CIs from unconditional logistic regression models that only adjusted for year of birth.bCharacteristic Overall Sex Hispanic ethnicity Age (years) OR (95% CI) Female Male Hispanic NH White 0–19 20–39Sex Female Ref Ref Ref Ref Ref Male 1.35 (1.21–1.52)a 1.33 (1.12–1.58)a 1.37 (1.13–1.66)a 1.31 (0.83–2.09) 1.36 (1.21–1.53)a Race and ethnicity NH Asian/Pacific Islander 1.02 (0.82–1.26) 0.90 (0.63–1.26) 1.12 (0.85–1.46) 2.10 (1.04–4.12) 0.95 (0.75–1.19) NH Black 1.08 (0.87–1.33) 1.28 (0.93–1.74) 0.94 (0.69–1.26) 0.59 (0.14–1.71) 1.12 (0.88–1.37) Hispanic 1.26 (1.11–1.43)a 1.26 (1.04–1.54)a 1.26 (1.07–1.49)a 1.20 (0.70–2.09)a 1.26 (1.11–1.44)a NH White Ref Ref Ref Ref Ref Other/unknown 1.46 (0.88–2.25) 0.76 (0.23–1.79) 1.94 (1.10–3.19)a 1.63 (0.90–8.11) 1.45 (0.87–2.27) Birth weight (each 500-g increase.) 1.06 (1.00–1.11)a 1.10 (1.01–1.19)a 0.99 (0.97–1.01) 1.02 (0.94–1.11) 1.07 (0.99–1.17) 0.90 (0.75–1.10) 1.07 (1.01–1.12)a Maternal birthplace United States Ref Ref Ref Ref Ref Ref Ref Foreign 0.99 (0.88–1.12) 1.02 (0.85–1.22) 0.97 (0.83–1.14) 0.87 (0.73–1.04) 0.80 (0.53–1.15) 0.96 (0.60–1.52) 0.99 (0.88–1.12) Paternal age (years)<20 1.09 (0.79–1.48) 1.23 (0.75–1.94) 1.01 (0.65–1.50) 1.06 (0.69–1.59) 1.62 (0.82–2.94) 0.92 (0.26–2.50) 1.10 (0.79–1.51) 20–24 Ref Ref Ref Ref Ref Ref Ref 25–29 1.13 (0.96–1.34) 1.25 (0.96–1.63) 1.06 (0.85–1.31) 1.07 (0.83–1.38) 1.41 (0.104–1.94) 0.57 (0.29–1.12) 1.19 (0.99–1.41) 30–34 1.06 (0.88–1.26) 1.08 (0.81–1.43) 1.04 (0.83–1.31) 1.14 (0.84–1.54) 1.26 (00.92–1.74) 0.56 (0.28–1.10) 1.10 (0.92–1.33) 35+ 1.24 (1.04–1.49)a 1.37 (1.04–1.82)a 1.16 (0.92–1.47) 1.32 (0.93–1.85) 1.45 (1.05–2.02)a 0.87 (0.45–1.65) 1.27 (1.05–1.54)a Unknown 1.01 (0.74–1.38) 1.27 (0.78–1.99) 0.86 (0.54–1.29) 0.98 (0.90–1.54) 1.10 (0.57–1.95) 0.32 (0.51–1.12) 1.10 (0.79–1.51) Abbreviations: EOCRC, early-onset colorectal cancer; NH, non-Hispanic; OR, odds ratio. aIndicates p < .05. bORs and 95% CIs were derived from unconditional logistic regression models that adjusted for year of birth (i.e., the matching variable). Each model included EOCRC case/control status as the dependent variable and two independent variables: each characteristic presented in the table and year of birth.6 of 12 - RISK FACTORS OF EOCRC ### Page 7 Maternal birthplaceIn our study, the majority of cases had US-born mothers (64.54%). Of those with foreign-born mothers, the majority were born in Mexico (60.97%). After adjusting for demographic, birth, and parental characteristics, having a foreign-born mother was significantly asso- ciated with lower risk of EOCRC (OR = 0.85; 95% CI, 0.73–0.97) (Figure 1). Though not significantly associated with EOCRC risk among females (OR = 1.02; 95% CI, 0.99–1.03), among males, having a foreign-born mother was significantly associated with lower risk of EOCRC (OR = 0.79; 95% CI, 0.65–0.95) (Figure 4). Among Hispanic and NH White individuals, having a foreign-born mother was associated with lower (though not statistically significant) risk of EOCRC (OR = 0.87; 95% CI, 0.73–1.04; OR = 0.77; 95% CI, 0.51–1.12, respectively) (Figure 2). Furthermore, among individuals aged 0 to 19 and 20 to 39 years, having a foreign-born mother was associated with lower, though not statistically significant, risk of EOCRC (OR = 0.68; 95% CI, 0.38–1.19; OR = 0.86; 95% CI, 0.74–1.00, respectively) (Figure 3).Paternal ageIn our study sample, a majority of participants had fathers aged 25 to 29 years (29.65%), followed by ages 30 to 34 (22.60%) and ≥35 years (21.38%) (Table 1). Among females, after adjusting for demographic, birth, and parental characteristics, having a father aged 35 years or older was associated with higher risk of EOCRC (OR = 1.56; 95% CI, 1.08–2.25) (Figure 4). Among males, having a father aged 35 years or older was associated with higher risk of EOCRC, though this associa- tion was not statistically significant (OR = 1.07; 95% CI, 0.79–1.45).DISCUSSIONIn this large, population-based nested case-control study, we found that male sex and Hispanic ethnicity were associated with higher risk and having a foreign-born mother was associated with lower risk ofF I G U R E 1 Adjusted odds ratios (ORs)a and 95% CIs evaluating the association between demographic, birth, and parental characteristics and risk of early-onset colorectal cancer in the California Linkage Study of Early-Onset Cancers. aThe ORs and 95% CIs were derived from a single multivariable unconditional logistic regression model that simultaneously adjusted for all variables presented in the figure as well as gestational age, birth order, mode of delivery, birth plurality, maternal age, maternal education, maternal history of miscarriage or stillbirth, maternal history of complications during pregnancy, maternal history of cesarean section, and paternal education. Birthweight is modeled as a continuous variable, and the OR shown is for each 500-g increase in birthweight.F I G U R E 2 Adjusted odds ratios (OR)a and 95% CIs evaluating the association between demographic, birth, and parental characteristics and risk of early-onset colorectal cancer in the California Linkage Study of Early-Onset Cancers, stratified by Hispanic ethnicity. aThe ORs and 95% CIs were derived from a single multivariable unconditional logistic regression model that simultaneously adjusted for all variables presented in the figure as well as gestational age, birth order, mode of delivery, birth plurality, maternal age, maternal education, maternal history of miscarriage or stillbirth, maternal history of complications during pregnancy, maternal history of cesarean section, and paternal education. Birthweight is modeled as a continuous variable, and the OR shown is for each 500-g increase in birthweight. SIDDIQUE ET AL. - 7 of 12 ### Page 8 EOCRC. Furthermore, among females, higher birthweight and older paternal age were associated with higher risk of EOCRC. We did not observe a statistically significant association between other de- mographic, birth, and parental characteristics (i.e., gestational age, birth order, mode of delivery, birth plurality, maternal age, maternal education, maternal history of miscarriage or stillbirth, maternal history of complications during pregnancy, maternal history of ce- sarean section, and paternal education) and risk of EOCRC.Sex-based differences in EOCRC risk and its implicationsPreviously, sexual dimorphism has been reported in CRC etiology and prognosis broadly, with males experiencing distinct genetic patterns, worse overall survival, and higher incidence rates than females.32–35 Findings from our study similarly indicate that male sex is a risk factor for EOCRC. These differences may be attributable toF I G U R E 4 Adjusted odds ratios (OR)a and 95% CIs evaluating the association between demographic, birth, and parental characteristics and risk of early-onset colorectal cancer in the California Linkage Study of Early-Onset Cancers, stratified by sex. aThe ORs and 95% CIs were derived from a single multivariable unconditional logistic regression model that simultaneously adjusted for all variables presented in the figure as well as gestational age, birth order, mode of delivery, birth plurality, maternal age, maternal education, maternal history of miscarriage or stillbirth, maternal history of complications during pregnancy, maternal history of cesarean section, and paternal education. Birthweight is modeled as a continuous variable, and the OR shown is for each 500-g increase in birthweight.F I G U R E 3 Adjusted odds ratios (OR)a and 95% CIs evaluating the association between demographic, birth, and parental characteristics and risk of early-onset colorectal cancer in the California Linkage Study of Early-Onset Cancers, stratified by age of diagnosis for cases and corresponding age for controls. aThe ORs and 95% CIs were derived from a single multivariable unconditional logistic regression model that simultaneously adjusted for all variables presented in the figure as well as gestational age, birth order, mode of delivery, birth plurality, maternal age, maternal education, maternal history of miscarriage or stillbirth, maternal history of complications during pregnancy, maternal history of cesarean section, and paternal education. Birthweight is modeled as a continuous variable, and the OR shown is for each 500-g increase in birthweight.8 of 12 - RISK FACTORS OF EOCRC ### Page 9 variations in sex steroid hormones and the gut microbiome. Clinical studies have indicated that compared to premenopausal CRC pa- tients, postmenopausal CRC patients have significantly lower levels of free estradiol, total estradiol, and estrone levels, indicating an in- verse association between estrogens and CRC risk.23,36 Furthermore, higher levels of free testosterone have been linked to an increased risk of CRC.37 Notable differences in gut microbiome environment between the sexes have also been correlated with sex differences in CRC risk.32 These differences, along with less favorable prognosis and survival among males with EOCRC, underscore the need to improve screening initiatives among young individuals, particularly among males that appear to have higher risk of CRC compared to females.33,38Rise in CRC incidence among young Hispanic individualsThough CRC incidence broadly is lower among Hispanic individuals compared to NH White, NH American Indians/Alaska Natives, and NH Black individuals, recent studies have noted that Hispanic in- dividuals are more likely to develop CRC at a younger age.29,39 Notably, the proportion of Hispanic individuals aged 20 to 29 years experiencing distant-stage CRC increased from 28% to 41% between 2000 and 2016.39 Findings from our study indicate that Hispanic females and males had between 39% and 45% higher risk of EOCRC compared to their NH White counterparts. Furthermore, Hispanic individuals continue to experience structural barriers to accessing screening and care, including language and cultural competency, in- come and a lack of health insurance.40,41 Per recent recommenda- tions by the US Preventive Services Task Force to initiate CRC screening among average-risk individuals aged 45 years or older, it is important to note that people younger than age 45 years are not eligible for routine screening. Yet, our finding of Hispanic ethnicity being a risk factor for CRC is particularly relevant to this group of young individuals who are experiencing a high incidence of CRC.39Foreign-born mothers with favorable health outcomes among offspringTo our knowledge, no prior studies have evaluated the relationship between maternal country of birth and risk of EOCRC. Our findings indicate that having a foreign-born mother is significantly associated with lower risk of EOCRC, particularly among males. The mechanism of this protective effect remains obscure. Prior studies have showed that foreign-born Hispanic mothers, the largest subgroup of foreign-born mothers in our study, experience favorable pregnancy outcomes compared to their US-born counterparts.42 First-generation foreign-born Hispanic women tend to have healthier diet and lower preva- lence of obesity during pregnancy compared to their US-born coun- terparts.43–45 Maternal obesity is associated with higher risk of CRC in the offspring because of its impact on the structure and function of adipose tissue, appetite regulation, insulin sensitivity, and metabo- lism.46–48 The potentially improved dietary and behavioral practices and lower likelihood of experiencing obesity during pregnancy among foreign-born mothers may have contributed to the observed lower EOCRC risk among the offspring in our study.Paternal age is correlated with de novo mutation rate in childWe observed, among females, having a father aged 35 years or older was associated with statistically significant higher risk of EOCRC. In the literature, the association between paternal age and risk of CRC has not been fully elucidated. One prior study evaluating the rela- tionship between paternal age and risk of digestive diseases reported null associations.49 Older paternal age is associated with adverse birth outcomes, such as stillbirths, as well as musculoskeletal syn- dromes, cleft palate, acute lymphoblastic leukemia, and retinoblas- toma.50 The mechanism underlying the observed association between older paternal age and an increased risk of EOCRC may be related to increases in rate of de novo mutations among children born to older fathers. One genome-wide mutation study has reported that the diversity in mutation rate of single nucleotide poly- morphisms is dominated by the age of the father at conception of the child.51 Our finding, although novel and intriguing, needs to be confirmed in future studies.Strengths and limitationsOur study has multiple strengths. First, to our knowledge, this is the largest study evaluating the relationship between a comprehensive set of demographic, birth, parental characteristics and risk of EOCRC. With an unparalleled sample size, we evaluated CRC etiology among a diverse group of individuals. Second, given the large percentage of Hispanic cases in our study, we were able to evaluate EOCRC risk factors in both NH White and Hispanic subgroups, with the latter experiencing a higher incidence of EOCRC but underrepresented in prior studies. Third, since the California Linkage Study of Early-Onset Cancers is a record linkage-based study, we were able to obtain preexisting, nonidentifiable data from all eligible subjects. This aspect of our study minimized potential selection and information bias. Nonetheless, we note the following limitations of our study. Because EOCRC risk increases with age, our subgroup analysis of individuals aged 0 to 19 years only included 76 cases. Therefore, the subgroup analysis of this age group may be underpowered because of the smaller sample size. Furthermore, in our evaluation of maternal and paternal education as possible risk factors for EOCRC, approximately 70% of the cases and controls had missing information. Nonetheless, our evaluation of EOCRC risk among those with complete parental education data did not suggest an association between parental ed- ucation and EOCRC risk. Next, because a large number of novel birth, demographic, and parental characteristics were evaluated in our SIDDIQUE ET AL. - 9 of 12 ### Page 10 study, there is potential for false positives due to multiple compari- sons. Our efforts to conduct stepwise model selection reduced the number of exposures being evaluated and showed similar effect es- timates as those from our crude and fully adjusted models. However, there may be residual confounding because of unmeasured factors such as maternal obesity that has been shown to be associated with CRC risk in the offspring.46 Next, since our analytic sample included cases born between 1982 and 2021, the oldest age group included in our analysis was 39 years. Previously, age groups up to 39 years have been classified by the National Cancer Institute as adolescents and young adults.52,53 Therefore, our findings may not be applicable to a broader cohort of EOCRC patients (i.e., individuals diagnosed be- tween the ages 40 and 49 years). Finally, because our study popu- lation includes cases and controls ≤39 years, they do not meet the eligibility criteria to receive routine CRC screening for individuals with average risk of CRC according to the US Preventive Services Task Force.54 Nonetheless, evaluating screening practices among parents and/or their offspring as well as factors such as family history or genetic predisposition to CRC would improve case ascertainment in future studies.CONCLUSIONSIn this large case-control study nested within the California birth cohort, male sex and Hispanic ethnicity were associated with higher risk of EOCRC, whereas having a foreign-born mother was associated with lower risk of EOCRC among males, in particular. Furthermore, among females, high birthweight and older paternal age were asso- ciated with higher risk of EOCRC. These findings require further research for validation and evaluation of possible mechanisms.AUTHOR CONTRIBUTIONS Sunny Siddique: Conceptualization; investigation; funding acquisi- tion; writing—original draft; methodology; visualization; writing— review and editing; software; formal analysis; data curation. Rong Wang: Conceptualization; investigation; writing—review and editing; software; project administration; data curation; resources. Domenica Berardi: Writing—review and editing. Caroline H. Johnson:Writing—review and editing. Joseph L. Wiemels: Writing—review and editing. Catherine Metayer: Resources; writing—review and editing; project administration. Xiaomei Ma: Conceptualization; investigation; funding acquisition; writing—review and editing; methodology; project administration; supervision.ACKNOWLEDGMENTSThis work was supported by the National Cancer Institute under the Ruth L. Kirschstein National Research Service Award Individual Pre- doctoral Fellowship to S.S. (award number 1F31CA281335-01). S.S. was also supported by the Yale Cancer Prevention and Control Training Program through a T32 award from the National Cancer Institute (award number 2T32CA250803-06). The authors thank the Center for Health Statistics and Informatics within the California Department of Public Health for the data used in this analysis. The collection of cancer incidence data used in this study was sup- ported by the California Department of Public Health pursuant to California Health and Safety Code Section 103885; Centers for Dis- ease Control and Prevention’s National Program of Cancer Registries, under cooperative agreement 1NU58DP007156; the National Cancer Institute’s Surveillance, Epidemiology and End Results Program under contract HHSN261201800032I awarded to the University of Cali- fornia, San Francisco, contract HHSN261201800015I awarded to the University of Southern California, and contract HHSN261201800009I awarded to the Public Health Institute. The ideas and opinions expressed herein are those of the author(s) and do not necessarily reflect the opinions of the State of California, Department of Public Health, the National Cancer Institute, and the Centers for Disease Control and Prevention or their Contractors and Subcontractors.CONFLICT OF INTEREST STATEMENTR.W. reported receiving grants from Flatiron Health outside the submitted work. X.M. reported receiving consultation fees from Bristol Myers Squibb outside the submitted work.DATA AVAILABILITY STATEMENTThe data that support the findings of this study are available from California Department of Public Health. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from the author(s) with the permission of California Department of Public Health.ROLE OF FUNDER/SPONSOR STATEMENTThe funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official view of the NIH.ORCIDSunny Siddique https://orcid.org/0000-0002-5746-1161Rong Wang https://orcid.org/0000-0002-2169-4174Catherine Metayer https://orcid.org/0000-0003-3467-4145REFERENCES1. Patel SG, Ahnen DJ. Colorectal cancer in the young. Curr Gastro- enterol Rep. 2018;20(4):15. doi:10.1007/s11894-018-0618-9 2. Siegel RL, Fedewa SA, Anderson WF, et al. Colorectal cancer inci- dence patterns in the United States, 1974-2013. J Natl Cancer Inst. 2017;109(8). doi:10.1093/jnci/djw322 3. 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