Serrated Pathway Colorectal Carcinoma without Microsatellite Instability Demonstrates Aggressive Features and Is Associated with Poor Overall Survival
Christophe Rosty, Joanne P Young, Michael D Walsh, Rhiannon Walters, Mark A Jenkins, Aung Ko Win, Melissa C Southey, Susan Parry, John L Hopper, Graham G Giles, Dallas R English, Daniel D Buchanan. Queensland Institute of Medical Research, Brisbane, Australia; University of Queensland, Brisbane, Australia; Envoi Pathology, Brisbane, Australia; Sullivan Nicolaides Pathology, Brisbane, Australia; University of Melbourne, Melbourne, Australia; Middlemore Hospital, Auckland, Australia; Cancer Council Victoria, Melbourne, Australia
Background: The serrated pathway of colorectal carcinoma (CRC) is primarily defined by BRAF mutation. Within the BRAF-mutated subset of CRC, the microsatellite instability (MSI) phenotype divides the tumours into MSI-H CRC and microsatellite stable (MSS) CRC. MSS BRAF-mutated CRC are reported to be associated with poor prognosis.
Design: We analyzed the available data regarding clinical, pathologic and molecular features of BRAF-mutated CRCs from the Melbourne Collaborative Cohort Study. The features of BRAF-mutated MSS CRCs were compared with BRAF-mutated MSI-H CRCs using two-sided chi-square tests or t-test. Survival curves were plotted using the Kaplan-Meier method and a multivariate Cox regression analysis was performed to determine hazard ratio (HR).
Results: There were 127/765 CRCs with BRAF mutation (17% of all CRCs). Of those, 74 (56%) were MSS. Compared to MSI-H BRAF-mutated CRC, MSS BRAF-mutated CRC were significantly different for the following features:
|BRAF-mutated MSS CRC n = 74||BRAF-mutated MSI-H CRC n = 53||P value|
|Mean age at diagnosis (years)||68.0||72.7||0.001|
|Distal colonic location||39/72 (54%)||5/50 (10%)||<0.001|
|Mucinous differentiation||4/67 (6%)||14/37 (30%)||<0.001|
|Tumor budding||30/57 (53%)||8/45 (18%)||<0.001|
|Venous invasion||17/67 (25%)||3/49 (6%)||0.007|
|Metastatic lymph nodes||45/66 (68%)||16/51 (31%)||<0.001|
|P53 overexpression||41/69 (59%)||9/45 (20%)||<0.001|
|CIMP phenotype||25/68 (37%)||37/48 (77%)||<0.001|