Rectal and left-sided colon cancers are not clearly delineated by location but rather are characterized by a range of distinct molecular variations, a phenomenon that has implications for developing tailored treatments in the future, according to data presented at the Gastrointestinal Cancers Symposium.
“Colorectal cancers (CRCs) carry a continuum of molecular alterations from the right to the left side, rather than displaying sharp, clear-cut differences according to location,” Mohamed E. Salem, MD, GI oncologist, assistant professor of clinical medicine, and Associate Fellowship Program Director in the division of hematology and oncology at Lombardi Comprehensive Cancer Center, Georgetown University, told Healio Gastroenterology.
Mohamed E. Salem
To better define the molecular differences between left sided colon tumors and rectal tumors, Salem and colleagues used NextGen sequencing, protein expression, and gene amplification to evaluate these differences in 1,457 tumors originating in the splenic flexure to the descending colon, the sigmoid colon, or the rectum. They also used microsatellite instability fragment analysis to measure microsatellite instability, and used somatic nonsynonymous missense mutations to calculate tumor mutational load (TML).
Compared with tumors originating in the splenic flexure to the descending colon, rectal tumors had a higher frequency of TP53 and APC, and a lower frequency of PIK3CA, BRAF, GNAS, HNF1A, and CTNNB1.
“Interestingly the incidence of microsatellite instability significantly decreased when moving from the descending colon (7%) to the sigmoid (4%) and on to the rectum (1%; P = 0.015),” Salem said. “On the other hand, although HER2 overexpression and amplification did not vary significantly across left-sided tumor locations, HER2 amplification was more common in rectal compared with right-sided colon tumors (5.4% vs. 1.3%; P = 0.0328).”
In addition, rectal tumors had a higher expression of TOPO1, ERCC1, and MGMT compared with tumors originating in the splenic flexure to the descending colon. Furthermore, compared with sigmoid colon tumors, rectal tumors showed higher expression of TLE3, TOPO1, TUBB3, and MGMT.
Conversely, the frequency of PD-L1 expression on tumor cells and tumor-infiltrating lymphocytes, as well as HER-2 expression and amplification were comparable across tumor types. PD-1 and tumor mutational load correlated in rectal tumors but not in colon cancers from either left or right locations. Tumor mutational load was highly concordant with microsatellite instability across all tumor types.
“It is possible that moving forward, comprehensive molecular testing will help us to better understand disease biology and mechanisms of resistance to treatment, as well as allowing us to better stratify patients; thus enabling a transition from one-size-fits-all treatment to individually tailored therapy,” Salem said. – by Adam Leitenberger
Marshall J, et al. Abstract 522. Presented at: Gastrointestinal Cancers Symposium; Jan. 19-21, 2017; San Francisco.
Disclosures: Salem reports no relevant financial disclosures. Please see the study abstract for a list of all other researchers’ relevant financial disclosures.