Comprehensive Genomic Landscapes in Early and Later Onset Colorectal Cancer

Abstract

Purpose: The incidence rates of colorectal cancers are increasing in young adults. The objective of this study was to investigate genomic differences between tumor samples collected from younger and older patients with colorectal cancer.Experimental Design: DNA was extracted from 18,218 clinical specimens, followed by hybridization capture of 3,769 exons from 403 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer. Genomic alterations (GA) were determined, and association with patient age and microsatellite stable/microsatellite instability high (MSS/MSI-H) status established.Results: Overall genomic alteration rates in the younger (<40) and older (!50) cohorts were similar in the majority of the genes analyzed. Gene alteration rates in the microsatellite stable (MSS) younger and older cohorts were largely similar, with several notable differences. In particular, TP53(FDR < 0.01) and CTNNB1 (FDR ¼ 0.01) alterations were more common in younger patients with colorectal cancer, and APC (FDR < 0.01), KRAS (FDR < 0.01), BRAF (FDR < 0.01), and FAM123B (FDR < 0.01) were more commonly altered in older patients with colorectal cancer. In the MSI-H cohort, the majority of genes showed similar rate of alterations in all age groups, but with significant differences seen in APC (FDR < 0.01), BRAF (FDR < 0.01), and KRAS (FDR < 0.01).Conclusions: Tumors from younger and older patients with colorectal cancer demonstrated similar overall rates of genomic alteration. However, differences were noted in several genes relevant to biology and response to therapy. Further study will need to be conducted to determine whether the differences in gene alteration rates can be leveraged to provide personalized therapies for young patients with early-onset sporadic colorectal cancer. Figure 5. Differing rates of specific BRAF and RNF43 mutations by age showing a clear distinction between BRAF V600E mutations versus other BRAF mutations as well as a difference in RNF43 659_660 mutations and RNF43 117 mutations.Genomic Landscape Young-Onset CRC www.aacrjournals.org

Wild-type APC Is Associated with Poor Survival in Metastatic Microsatellite Stable Colorectal Cancer

“…This indicates that additional biological variables associated with APC-WT status may contribute to the poor prognosis of this group. Consistent with prior reports, we showed that APC-WT colorectal cancer occurs more often in younger patients than older patients [10]. A study of 24 first-line clinical trials with metastatic colorectal cancer demonstrated that younger age was associated with worse progression-free survival (PFS) and OS irrespective of type of therapy received and molecular status [25].…”

Genetic Alterations of Metastatic Colorectal Cancer

“…The incidence of CRC increases with the age. In a recent study, Lieu et al on a large panel of CRC samples reported the occurrence of CRCs in 7.8% of patients under the age of 40, 17.6% in the age comprised between 40 and 49 years and 74.6% in patients with an age of 50 or older [ 19 ]. Overall genomic alterations were similar in the majority of genes currently mutated, with some notable differences: in MSS CRC patients, TP53 and CTNNB1 alterations were more common in younger patients with CRC [ 19 ]; in the MSI-H cohort, most of genes displayed a similar frequency of alterations in the two age groups, but significant differences were observed at the level of APC and KRAS alterations more frequent among younger than older patients and BRAF alterations markedly more recurrent among older than younger CRC patients [ 19 ].…”

High incidence of prolonged rectal bleeding and advanced stage cancer in early-onset colorectal cancer patients

“…Similar trends have been noticed across Europe and several other countries, although the rate of increasing incidence in not as dramatic [9,10]. It is also known that when compared with older patients, early-onset patients with CRC tend to have a higher proportion of left-sided tumors [11], microsatellite instability (MSI) [12], underlying hereditary syndromes [13], exhibit specific molecular [14,15] and clinical characteristics associated with a distinct biologic phenotype (e.g., higher grade and mucinous or signet ring histology) [16] and receive more aggressive treatment [17]. Furthermore, younger patients tend to present at a more advanced stage [18,19], although there is conflicting data on survival when compared with stage matched older patients [19][20][21][22][23].…”