Increased incidence of FBXW7 and POLE proofreading domain mutations in young adult colorectal cancers

Abstract

Background The incidence and outcomes for patients with colorectal cancer (CRC) varies by age. Younger patients tend to have sporadic cancers not detected by screening and worse survival. To understand if genetic differences exist between age cohorts we sought to characterize unique genetic alterations in patients with CRC. Methods We identified 283 patients with sporadic CRC between 1998 and 2010 and divided them by age into two cohorts: ≤45 years old (younger) or ≥65 years old (older) and performed targeted exome sequencing. Fisher’s Exact test was used to detect differences in mutation frequencies between the two groups. Whole exome sequencing was performed on 21 additional younger patient samples for validation. Findings were confirmed in The Cancer Genome Atlas CRC dataset. Results 246 samples were included for final analysis (195 older, 51 younger). Mutations in FBXW7 were more common in the younger cohort (27.5% vs. 9.7%, p=0.0022) as were mutations in the proofreading domain of POLE (9.8% vs. 1.0%, p= 0.0048). There were similar mutation rates between cohorts with regards to TP53 (64.7% vs. 61.5%), KRAS (43.1% vs. 46.2%), and APC (60.8% vs 73.8%). BRAF mutations were numerically more common in the older cohort, though not statistically significant (2.0% vs 9.7%, p=0.082). Conclusions In this retrospective study, we identified a unique genetic profile for younger CRC patients as compared to patients diagnosed at an older age. These findings should be validated in a larger study and could have an impact on future screening and treatment modalities for younger CRC patients.

Impact of Patient Age on Molecular Alterations of Left-Sided Colorectal Tumors

“…Our study confirms previous observations suggesting a higher rate of POLE mutations in younger patients, although in our cohort, only 1.6% of patients aged ≤45 years harbored POLE mutations, whereas 9.8% were detected in a prior study . Recently, in 4,500 stage II/III CRCs, Domingo et al showed that POLE mutations are mutually exclusive with dMMR.…”

A mutational comparison of adult and adolescent and young adult (AYA) colon cancer

“…In 2016 a study published by Kothari et al, a targeted panel of 1321 genes was used to perform exome sequencing on colorectal cancer tumors from 195 older patients (aged ≥ 65 years) and 30 younger patients (aged ≤ 45 years). In that study, 2 genes, FBXW7 and POLE , had significantly greater mutation rates in younger patients . However, only 17 of the 43 genes identified in our current study as having a greater mutation frequency in AYA patients were on that panel of 1321 genes.…”

“…Thus, we have included it in Supporting Table 3 (see online supporting information), which describes the nature of the mutations in the genes of interest. Two POLE mutations identified in our AYA samples—P286R (a proline to arginine mutation at position 286) and P697A (a proline to alanine mutation at position 697) (for details, see Supporting Table 3 in the online supporting information)—overlap with the POLE mutations identified in young patients from the study by Kothari et al…”

“…In that study, 2 genes, FBXW7 and POLE, had significantly greater mutation rates in younger patients. 43 However, only 17 of the 43 genes identified in our current study as having a greater mutation frequency in AYA patients were on that panel of 1321 genes. Within the aforementioned study's validation set of 21 younger patients, none of the other 26 genes in our panel were identified as more frequently mutated in younger patients.…”

Association of Obesity With Risk of Early-Onset Colorectal Cancer Among Women

“…With the emerging evidence that sporadic, young-onset CRC may have distinct molecular features compared to cancers that arise in older individuals (e.g. chromosomal instability, higher prevalence of mucinous or poorly differentiated tumors), 22–26 and the fact that these patients are often detected at a more advanced stage 9 with dramatically greater years of life lost, 27 there is an urgent and unmet public health and clinical need to identify risk factors of young-onset CRC to develop targeted preventive and detection strategies for younger adults with higher risk. 8,28 …”