A large California study suggests that characteristics present at birth and parental factors may help shape the risk of developing colorectal cancer before age 40, offering new clues into why rates are rising in younger adults.
Study: Demographic, birth, parental characteristics, and the risk of early-onset colorectal cancer: A population-based nested case-control study in California. Image credit: Tama2u/Shutterstock.com
A new study published in the journal Cancer reveals that male sex, Hispanic ethnicity, higher birth weight among females, and older paternal age are potential risk factors for early-onset colorectal cancer.
Rising colorectal cancer cases prompt search for early-life risk factors
Colorectal cancer (CRC) is the second most common cancer and the third leading cause of cancer-related deaths in the United States. Although the prevalence of CRC among older adults aged 50 years or above (late-onset CRC) has decreased since the mid-1980s, diagnoses among individuals aged less than 50 years (early-onset CRC) have increased steadily in the past two decades.
Early-onset CRC is typically found in the rectum and distal colon, and cancers in these regions are associated with excessive alcohol drinking and high intake of Western diets, including red meat and processed foods.
Existing studies have identified several risk factors that may increase CRC risk, including demographic, birth-related, and parental characteristics. However, it remains largely unknown whether these risk factors are associated with early-onset CRC risk.
To fill this gap in the literature, researchers at Yale School of Public Health, USA, conducted a large population-based nested case-control study to investigate the association between a range of demographic, birth, and parental characteristics and risk of early-onset CRC among individuals born in the state of California who were diagnosed before age 40.
Male sex and Hispanic ethnicity stand out
The study included 1221 cases of early-onset CRC diagnosed between the ages of 0 and 39 years, with an average age at diagnosis of 29 years. These cases were matched by year of birth to 61,050 cancer-free controls. The researchers identified statistically significant interactions by sex, Hispanic ethnicity, and age at diagnosis, prompting further subgroup analyses.
After accounting for demographic, birth, and parental characteristics, males had a 34% higher risk of early-onset CRC than females, while Hispanic individuals had a 34% higher risk than non-Hispanic White individuals. The overall analysis also showed that having a foreign-born mother was associated with a lower risk of early-onset CRC.
Birth and parental factors show sex-specific patterns
In contrast, associations with birth weight and paternal age were evident only in specific subgroups. In an analysis adjusted only for birth year, every 500-gram increase in birth weight was associated with a 6% increase in early-onset CRC risk, but this association was no longer statistically significant after adjustment for all demographic, birth, and parental characteristics. However, when the data were analyzed separately by sex, every 500-gram increase in birth weight was associated with a 10% higher risk among females, whereas no significant association was observed among males.
A similar pattern was observed for paternal age. Females whose fathers were aged 35 years or older had a significantly higher risk of early-onset CRC, whereas no significant association was found among males. The protective association with maternal birthplace also differed by sex: having a foreign-born mother was associated with a lower risk among males, but no statistically significant association was observed among females.
Study identifies several early-life risk factors
By analyzing a large set of demographic, birth, and parental characteristics, the study reveals that male sex, Hispanic ethnicity, higher birth weight among females, and older paternal age among females were associated with higher early-onset CRC risk only in specific subgroup analyses, whereas having a foreign-born mother was associated with a lower risk, particularly among males.
Evidence has linked higher blood levels of free testosterone to an increased CRC risk, which may help explain why males have a higher risk of developing early-onset CRC than females. Furthermore, clinical evidence has highlighted an inverse association between estrogens and CRC risk, reflecting a protective effect of female reproductive hormones.
Why might these factors influence cancer risk?
Recent evidence suggests that Hispanic individuals are more likely to develop CRC at a younger age. The current study findings also support this evidence by showing that Hispanic females and males had 39% and 45% higher risks, respectively, of early-onset CRC compared to their non-Hispanic White counterparts. Certain structural barriers may explain this inequality, including limited access to cancer screening and care, language and cultural competency, lower income, and lack of health insurance.
One notable finding of this study is that offspring of foreign-born mothers were associated with a lower risk of developing early-onset CRC, particularly among male children. Although the mechanism driving this protective effect remains largely unknown, a healthier dietary pattern and a lower prevalence of obesity during pregnancy in first-generation foreign-born Hispanic women compared with their US-born counterparts may partly explain the observed benefit among offspring.
The study reports that females having a father aged 35 years or older are significantly more likely to develop early-onset CRC. One possible explanation for this finding may be the increased rate of de novo mutations among children born to older fathers. In this context, one genome-wide mutation study has reported that the diversity in mutation rates of single-nucleotide polymorphisms is strongly dependent on the father's age at the time of the child's conception.
Study has important limitations
The authors also noted several limitations. The study included only individuals diagnosed before age 39 years, so the findings may not generalize to all early-onset CRC cases diagnosed between ages 40 and 49 years.
The subgroup analysis of individuals aged 0–19 years included relatively few cases, parental education data were missing for approximately 70% of participants, and unmeasured factors such as maternal obesity may have influenced the results. Because numerous factors were examined, some associations may also reflect false-positive findings due to multiple comparisons.
Early-life factors may help explain rising CRC
Overall, this large population-based nested case-control study identifies a set of novel demographic, birth, and parental factors that may contribute to the risk of early-onset CRC. Future studies are needed to further validate and evaluate potential mechanisms.
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