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. 2023 Mar 1;13(3):570-579.
doi: 10.1158/2159-8290.CD-22-0764.

Racial/Ethnic and Sex Differences in Somatic Cancer Gene Mutations among Patients with Early-Onset Colorectal Cancer

Andreana N Holowatyj  1   2   3 , Wanqing Wen  1 , Timothy Gibbs  4 , Hannah M Seagle  1   3 , Samantha R Keller  1   3 , Digna R Velez Edwards  5 , Mary K Washington  2   6 , Cathy Eng  1   2 , Jose Perea  7   8 , Wei Zheng  1   2 , Xingyi Guo  1   2
Affiliations

Racial/Ethnic and Sex Differences in Somatic Cancer Gene Mutations among Patients with Early-Onset Colorectal Cancer

Andreana N Holowatyj et al. Cancer Discov. .

Abstract

Molecular features underlying colorectal cancer disparities remain uncharacterized. Here, we investigated somatic mutation patterns by race/ethnicity and sex among 5,856 non-Hispanic white (NHW), 535 non-Hispanic Black (NHB), and 512 Asian/Pacific Islander (API) patients with colorectal cancer (2,016 early-onset colorectal cancer patients: sequencing age <50 years). NHB patients with early-onset nonhypermutated colorectal cancer, but not API patients, had higher adjusted tumor mutation rates than NHW patients. There were significant differences for LRP1B, FLT4, FBXW7, RNF43, ATRX, APC, and PIK3CA mutation frequencies in early-onset nonhypermutated colorectal cancers between racial/ethnic groups. Heterogeneities by race/ethnicity were observed for the effect of APC, FLT4, and FAT1 between early-onset and late-onset nonhypermutated colorectal cancer. By sex, heterogeneity was observed for the effect of EP300, BRAF, WRN, KRAS, AXIN2, and SMAD2. Males and females with nonhypermutated colorectal cancer had different trends in EP300 mutations by age group. These findings define genomic patterns of early-onset nonhypermutated colorectal cancer by race/ethnicity and sex, which yields novel biological clues into early-onset colorectal cancer disparities.

Significance: NHBs, but not APIs, with early-onset nonhypermutated colorectal cancer had higher adjusted tumor mutation rates versus NHWs. Differences for FLT4, FBXW7, RNF43, LRP1B, APC, PIK3CA, and ATRX mutation rates between racial/ethnic groups and EP300, KRAS, AXIN2, WRN, BRAF, and LRP1B mutation rates by sex were observed in tumors of young patients. See related commentary by Shen et al., p. 530 . This article is highlighted in the In This Issue feature, p. 517.

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Conflict of interest statement

Conflict of Interest: The authors declare no conflicts of interest with this work.

Figures

Figure 1.
Figure 1.. Genomic landscape of early-onset vs late-onset non-hypermutated colorectal cancer: AACR Project GENIE.
(A) Mutation rates among 6,903 tumor samples from CRC patients. Non-hypermutated tumors were defined using a cutoff (red line) of 17.78+ mutations/Mb. (B) Boxplot of adjusted mutation rates between early-onset and late-onset cases with non-hypermutated CRC. The residual of adjusted mutation rates and P-value were derived from models adjusted for race and ethnicity, sex, tumor site and histology, sequencing assay, and sample type. (C) Forest plot and mutation frequencies of genes differentially expressed between early-onset and late-onset non-hypermutated CRCs in adjusted models that reached statistical significance (P<0.05). Genes with FDR<0.05 are shaded in dark grey.
Figure 2.
Figure 2.. Racial/ethnic patterns of non-silent somatic cancer gene mutations among patients with early-onset non-hypermutated CRC.
API, Asian or Pacific Islander; NHB, non-Hispanic black; NHW, non-Hispanic white. (A-B) Boxplots of adjusted mutation rate residuals (tumor mutational burden, TMB) across racial/ethnic groups for (A) early-onset and (B) late-onset non-hypermutated CRC. The residual of adjusted mutation rates and P-values were derived from models adjusted for sex, tumor site and histology, sequencing assay, and sample type. (C-E) Mutation frequencies between genes differentially expressed between early-onset vs late-onset non-hypermutated CRC cases that reached statistical significance for (C) API, (D) NHB, and (E) NHW patients.
Figure 3.
Figure 3.. Tumor genomic profiles by sex among patients with early-onset non-hypermutated CRC.
(A) Boxplot of adjusted mutation rate residuals (tumor mutational burden, TMB) by sex for early-onset and late-onset non-hypermutated CRC. The residual of adjusted mutation rates and P-values were derived from models adjusted for race and ethnicity, tumor site and histology, sequencing assay, and sample type. (B-C) Mutation frequencies between genes differentially expressed between early-onset vs late-onset non-hypermutated CRC cases that reached statistical significance (P<0.05) for (B) females and (C) males.

(D) Inverse mutation frequencies for EP300 in non-hypermutated CRCs among young patients by sex.
See this image and copyright information in PMC

Comment in

References

    1. Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70(3):145–64. - PubMed
    1. Bailey CE, Hu CY, You YN, Bednarski BK, Rodriguez-Bigas MA, Skibber JM, et al. Increasing disparities in the age-related incidences of colon and rectal cancers in the United States, 1975–2010. JAMA Surg. 2015;150(1):17–22. - PMC - PubMed
    1. Cercek A, Chatila WK, Yaeger R, Walch H, Fernandes GDS, Krishnan A, et al. A Comprehensive Comparison of Early-Onset and Average-Onset Colorectal Cancers. J Natl Cancer Inst. 2021;113(12):1683–92. - PMC - PubMed
    1. Holowatyj AN, Gigic B, Herpel E, Scalbert A, Schneider M, Ulrich CM, et al. Distinct Molecular Phenotype of Sporadic Colorectal Cancers Among Young Patients Based on Multiomics Analysis. Gastroenterology. 2020;158(4):1155–8 e2. - PMC - PubMed
    1. Lieu CH, Golemis EA, Serebriiskii IG, Newberg J, Hemmerich A, Connelly C, et al. Comprehensive Genomic Landscapes in Early and Later Onset Colorectal Cancer. Clin Cancer Res. 2019;25(19):5852–8. - PMC - PubMed

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