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

Abstract

Background. The prognostic implication of wild type APC (APC-WT) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) is not well defined. Methods. APC prognostic value was evaluated retrospectively in two independent cohorts of patient with MSS mCRC with a confirmatory analysis from a public data set from Memorial Sloan Kettering Cancer Center (MSKCC). Results. In comparison to the APC-mutant (APC-MT) population (n=255), APC-WT patients (n = 86) tended to be younger (59% of age <40 vs 26% of age > 50), right-sided (41.7% vs. 27%), BRAF-V600E mutated (23.3% vs. 0.8%), and KRAS WT (65.1% vs. 49.8%). Alternative WNT pathway alterations, RNF43 and CTNNB1 were over-represented in the APC-WT vs APC-MT population (7% vs 0.4% and 4.7% vs 0.4%, respectively). APC-WT patients had a worse overall survival (OS) than APC-MT patients (22.6 vs 45.6 months, p<0.0001). Using a multivariate model correcting for primary tumor location, RAS and BRAF status, APC-WT was predictive of poor survival (APC-MT vs APC-WT, HR=0.62, 95%CI 0.44-0.86, P=0.0037). The prognostic implication of APC-WT on OS was confirmed further in a similar multivariate model of 934 stage IV patients from MSKCC public database (APC-MT vs APC-WT, HR=0.63, 95%CI 0.49-0.81, p<0.0001). Conclusion. APC-WT is associated with poor OS in MSS mCRC regardless of RAS and BRAF status. Compared with APC-MT mCRC tumors, APC-WT tumors were associated with other Wnt activating alterations, including RNF43 and CTNBB1. Our data suggest alternative therapy needs to be investigated in APC-WT patients. The Oncologist 2020;9999:• • Implications for Practice: MSS mCRC patients with APC-WT had a worse OS than patients with APC-MT regardless of RAS/ RAF status. APC status should be considered as a stratification factor in prospective trials and novel therapeutic strategies need to be developed for this subgroup of patients.

Evaluation of Somatic Mutations in Solid Metastatic Pan-Cancer Patients

“…Colorectal (322, 33.6%) and thoracic (229, 23.9%) accounted for 57.5% of all cancer diagnosis in our cohort, and TP53, APC, KRAS, and LRP1B mutation rates are higher in colorectal cancers and non-small cell lung cancers (NSCLC) [ 26 , 27 , 28 , 29 ]. APC gene mutations are known to be associated with chromosomal instability, however, similar to our findings several studies have identified that mutated APC was associated with improved survival as compared to wild-type APC in colorectal cancer [ 30 , 31 , 32 , 33 , 34 ].…”

The Added Value of Baseline Circulating Tumor DNA Profiling in Patients with Molecularly Hyperselected, Left-sided Metastatic Colorectal Cancer

“…On top of that, the low number of patients in the RAS/PIK3CA mutated subgroups did not allow us to properly assess the interaction with the two treatment arms. Finally, in light of the poor prognostic role of APC wild-type status in mCRC, 26,27 we acknowledge that the low frequency of APC mutations in our dataset is clearly related to the relatively low coverage of the gene sequence by the hotspots included in this custom panel.…”

Mutational profile of KRAS-positive colorectal cancer

“…Однако при возникновении мутации он теряет способность связывать и разрушать β-катенин, в результате чего последний проникает в ядро и активирует транскрипцию ряда онкогенов, в том числе c-myc, циклин D1, которые являются промоторами клеточной пролиферации. Мутации в гене APC при спорадическом КРР встречаются довольно часто и могут составлять до 75 % случаев, мутации, как правило, возникают уже на ранней стадии развития опухоли [20,21]. Ген TP53, изменения в котором наряду с геном APC чаще всего встретились в обследованной группе, является наиболее известным опухолевым супрессором, отвечающим за стабильное состояние генома.…”