Jumanah Yousef Alshenaifi, MD, MBI (Advisor: E. Scott Kopetz, MD, PhD; Secondary Advisor: Andrew Futreal, PhD)

Elucidating the Multi-omics of Early-Onset Colorectal Cancer

     The incidence and mortality rates of sporadic early-onset colorectal cancer have increased in recent decades, but there is no clear etiological basis for this trend. EOCRC is commonly defined as colon and rectal cancers diagnosed before the age of 50 years. The rising incidence of EOCRC has made it the second most common cancer and the third leading cause of cancer death in this age group. The trend documented internationally in more than 20 countries across different continents.  Clinically, EOCRC has a distinct, more aggressive clinical profile than LOCRC. While approximately 15% of EOCRC cases are hereditary, the remaining ~85% is largely unknown. 

     Exposomes are human environmental risk factors that can be external or internal, such as obesity, lifestyle, antibiotics, or gut microbiota. In epidemiological studies, exposomes have been linked to EOCRC. The impact of the exposome on the biological mechanisms and development of EOCRC remains predominantly unidentified.

     To better understand this alarming trend and identify potential causes, we investigated the multi-omics of the EOCRC. Mutational signatures are the footprints of endogenous or exogenous exposomal exposures.

     In the first study, we focused on early-onset rectal cancer (EORC) where the epidemiologic changes are the most concerning. Using whole-genome and RNA sequencing cohorts, we studied 1,255 microsatellite-stable treatment-naïve rectal cancer tumors across age groups. While the spectrum of mutated genes in early-onset rectal cancer only modestly varies from later onset patients, there are distinctive mutational patterns and signatures, along with transcriptomic profiles, distinguishing early-onset from late-onset. EORC was specifically linked to SBS88 and ID18 (indicating DNA damage caused by colibactin-producing pks+ E. coli) and SBS17b (related to DNA damage caused by reactive oxygen species (ROS)) mutational signatures.  Further metagenomics and transcriptomic analysis validated the mutational signatures and EORC. These signatures suggest a role of exposure to pks⁺ E. coli with EORC tumorigenesis. 

     Aberrant activation of the RAS-ERK pathway plays a significant role in colorectal cancer tumorigenesis and progression. However, its role in EOCRC is not well understood. Therefore, we focused on investigating the role of the MAPK pathway in EOCRC. Hallmark GSEA enrichment analysis revealed that KRAS signaling was consistently downregulated in both cohorts. However, using the novel KRAS-ERK gene signature, which better captures pathway functionality, we found consistent enrichment in both cohorts (p < 0.0001, for both cohorts). 

     This study not only elucidates the unique molecular attributes of EOCRC but also lays the groundwork for exploring KRAS-targeted therapies in this aggressive cancer subtype. Given the escalating incidence of EOCRC, our research carries substantial implications for its early detection, prevention, and the development of precision therapeutic strategies.

Advisory Committee:

• E. Scott Kopetz, MD, PhD, Chair
• Andrew Futreal, PhD, Co-Chair
• John Paul Shen, MD
• Eduardo Vilar-Sanchez, MD, PhD
• Wenyi Wang, PhD

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Meeting ID: 895 3977 5637

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