Molecular analyses of left- and right-sided tumors in adolescents and young adults (AYA) with colorectal cancer (CRC)
Megan H. Jagosky, Richard M. Goldberg, Derek Raghavan, Alberto Puccini, Anthony F. Shields, David Arguello, W. Michael Korn, Andreas Seeber, Jimmy J. Hwang, Philip A. Philip, John L. Marshall, Francesca Battaglin, Edward Kim, Heinz-‐Josef Lenz and Mohamed E. Salem
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in the USA. 
The incidence and mortality of CRC has been decreasing among adults aged ≥ 50 years, counterbalanced by an increased incidence among adolescents and young adults ≤ 40 years (AYA), driven by tumors in the descending colon and rectum. 
The reasons behind this rise of CRC rates in the younger population, which are expected to further increase over the coming decade, remains unclear.
Epigenetic events appear to play an important role in tumorigenesis and cancer progression, especially in AYA. 
Additionally, tumor sidedness has emerged as an important prognostic and predictive factor in the treatment of colorectal cancer. [4, 5]
Whole-exome sequencing studies previously have shown differences in AYA and adult colon cancer mutations. 
Herein, we compared molecular features of left-sided colorectal tumors (LT) in AYA to right-sided tumors (RT) in AYA and to LT in older patients.
PATIENTS AND METHODS
AYA with colon cancer had primary tumors annotated by site of origin- left-sided (LT) and right-sided (RT) tumors.
Tumors were examined by next generation sequencing (NGS) (592 genes) for mutations and copy number variance (CNV) while protein expression was evaluated using immunohistochemistry (IHC).
Tumor mutation burden (TMB) was calculated by enumerating somatic missense mutations.
Chi-square testing was used for comparisons (SPSSv24).
SUMMARY AND CONCLUSIONS
Molecular portraits of right- and left-sided AYA colon cancer revealed significant differences in protein expression, gene amplification and mutation.
Significantly higher molecular alteration rates of BRAF, ERBB2, KRAS, PIK3CA, and PTEN were found in right-sided AYA colon cancer. Left-sided AYA colon cancers were found to have higher rates of APC and TP53. Different treatment strategies may be warranted based on tumor sidedness.
Right-sided AYA colon cancer had statistically significant higher rates of TMB, POLE mutations, and MMRd (MLH1 and PMS2 loss), implying RT cancers may derive more benefit from immune checkpoint blockade therapy. 
Targeting alterations in histone modification may be more beneficial in AYA populations relative to older (>=65 year old) groups.
Given the increasing rates of colon cancer in younger populations, further studies are urgently needed.