Molecular Analyses of Left- and Right-Sided Tumors in Adolescents and Young Adults with Colorectal Cancer

Abstract

Background. The incidence of colorectal cancer (CRC), particularly left-sided tumors (LT), in adolescents and young adults (AYA) is rising. Epigenetic events appear to play an important role in tumorigenesis and cancer progression, especially in younger patients. We compared molecular features of LT to right-sided tumors (RT) in AYA. Materials and Methods. A total of 246 LT and 56 RT were identified in a cohort of 612 AYA with primary CRC. Tumors were examined by next-generation sequencing (NGS), protein expression, and gene amplification. Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined based on NGS data. Results. RT showed higher mutation rates compared with LT in several genes including BRAF (10.3% vs. 2.8%), KRAS (64.1% vs. 45.5%), PIK3CA (27% vs. 11.2%), and RNF43 (24.2% vs. 2.9%). Notably, additional mutations in distinct genes involved in histone modification and chromatin remodeling, as well as genes associated with DNA repair and cancer-predisposing syndromes, were characteristic of RT; most frequently KMT2D (27.8% vs. 3.4%), ARID1A (53.3% vs. 21.4%), MSH6 (11.1% vs. 2.3%), MLH1 (10.5% vs. 2.3%), MSH2 (10.5% vs. 1.2%), POLE (5.9% vs. 0.6%), PTEN (10.8% vs. 2.3%), and BRCA1 (5.4% vs. 0.6%). MSI was seen in 20.8% of RT versus 4.8% of LT. RT had a higher frequency of TMB-high regardless of MSI status. Conclusion. Molecular profiling of AYA CRC revealed different molecular characteristics in RT versus LT. Epigenetic mechanisms and alteration in DNA repair genes warrant further investigation and may be a promising treatment target for CRC in AYA. The Oncologist 2020;25:404-413 Implications for Practice: Colorectal cancer (CRC) in adolescents and young adults (AYA) comprises a distinct entity with different clinicopathologic features and prognosis compared with older patients. Molecular profiling of right-and left-sided tumors in AYA is needed to gain novel insight into CRC biology and to tailor targeted treatment in this age group. This study found that right-and leftsided CRC show distinct molecular features in AYA, overall and in subgroups based on microsatellite instability status. Alterations in DNA double-strand break repair and homologous recombination repair, as well as epigenetic mechanisms, appear to play a critical role. The present molecular profiling data may support the development of personalized treatment strategies in the AYA population.

Sexual Dimorphism in Colon Cancer

“…As previously mentioned, right-sided (proximal) tumors occur predominantly in women and older patients, and are less common than left-sided distal tumors ( 23 , 24 ). Proximal tumors have higher microsatellite instability, hypermethylation and mutation burden, whereas more distal tumors are characterized by chromosomal instability ( 221 , 222 ). The burden of genetic mutations also varies between male and female CRC patients.…”

Post‐translational Wnt receptor regulation: Is the fog slowly clearing?

“…It has been observed that CRCs found in the right side of the colon show the MSI‐high phenotype, concentrated BRAF‐RNF43 mutations, and poor prognosis due to a lack of response to standard chemotherapy and the metastatic nature of the cancer cells, whereas CRCs in the left side have a better prognosis associated with the MSS phenotype and frequent APC‐KRAS mutations. [ 91–93 ] It is known that the right side of the colon (from the duodenum to two‐third of the transverse colon) originates from the midgut during embryogenesis, whereas the left side of the colon (from one‐third of the transverse colon to the anal canal) originates from the hindgut (Figure 3). [ 94 ] These facts suggest that the difference of gene mutation subsets between BRAF‐RNF43 and APC‐KRAS may be related to the different embryonic origins of the cells in these two regions.…”

Surgical management of sarcoma in adolescent and young adult patients

“…The 5-year survival rate in AYA sarcoma patients is approximately 70% [10,16], although prognoses in AYA patients may vary depending on age [16]. Our previous study showed that the 5-year survival rate of elderly sarcoma patients was 86% [17].…”