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The incidence of early\u2010onset CRC (EOCRC) has been rising in the past few decades. Given the multifaceted nature of EOCRC, the genetic and environmental factors contributing to this malignancy have remained elusive. Systems genetics is a multi\u2010omics tool that analyzes multiple genes as a collective network. Transcriptional correlation, protein\u2013protein interaction network, functional annotation, and drug\u2010gene interaction analyzes enable investigators to explore the functional roles of target genes and aid with discovery of novel diagnostic biomarkers and potential therapeutics. To clarify the objective of this work, this manuscript serves three purposes: a narrative review of recent systems genetics applications in EOCRC research, a step\u2010by\u2010step protocol for conducting these analyses, and a discussion of current advances in systems genetics to address limitations in generalizability and context dependence. Through this manuscript, we envision a future in which emerging oncology researchers adopt these tools into their investigations of EOCRC and other malignancies.<\/jats:p>","DOI":"10.1111\/cbdd.70379","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T15:38:36Z","timestamp":1786462716000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Application of Systems Genetics to Investigate Molecular Pathology of Early\u2010Onset Colorectal Cancer"],"prefix":"10.1111","volume":"108","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3445-0619","authenticated-orcid":false,"given":"Minjae J.","family":"Kim","sequence":"first","affiliation":[{"name":"University of Tennessee Health Science Center College of Medicine  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney L.","family":"Carr","sequence":"additional","affiliation":[{"name":"University of Tennessee Health Science Center College of Medicine  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3555-4401","authenticated-orcid":false,"given":"Vishnutheertha","family":"Kulkarni","sequence":"additional","affiliation":[{"name":"University of Queensland Medical School  Brisbane Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary\u2010Louise","family":"Manchadi","sequence":"additional","affiliation":[{"name":"University of Queensland Medical School  Brisbane Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.31557\/APJCP.2025.26.7.2511"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25179371"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-024-08739-5"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-25-0445"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.5395\/rde.2024.49.e21"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae1128"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad1040"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2024.115172"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-026-69152-2"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-93791-5_2"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-024-05766-x"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.12659\/MSM.923707"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1010348"},{"key":"e_1_2_11_15_1","first-page":"768","article-title":"A Localized GTEx Database and Its Potential Applications in Biomedical Research","volume":"59","author":"Churakov G. 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