RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer

Abstract

Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAFV600E colorectal cancer (mCRCBRAF-V600E). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRCBRAF-V600E treated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors. Analysis of an independent validation cohort confirmed the relevance of RNF43 mutations to predicting clinical benefit (72.7% versus 30.8%; P = 0.03), as well as longer progression-free survival (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.12–0.75; P = 0.01) and overall survival (HR, 0.26; 95% CI, 0.10–0.71; P = 0.008), in patients with MSS-RNF43mutated versus MSS-RNF43wild-type tumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS-mCRCBRAF-V600E tumors not exposed to anti-BRAF targeted therapies. Overall, our findings suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumor activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimize the clinical management of these patients.

Multidimensional Molecular Characteristics of Early-Onset Endometrioid Endometrial Carcinoma, And Potential Predictors Of Response To Fertility Sparing Therapy

“…Interestingly, progestin-insensitive EEECs showed higher fractional genome alteration (FGA), especially loss (Fig 7A and Fig 7D), indicating that chromosomal instability promoted endocrine resistance which was consistent with previous findings in breast 75 , and prostate cancer 76 Inspired by previous reports that mutation hotspots are associated with functional selective pressure 77 conferring fitness advantage on tumor progression 78 and therapy-resistance 79 , we reasoned that SIGLEC10 Q144K might promote tumorigenesis and progestin resistance in EEECs.…”

Recurrent mutations in tumor suppressor FBXW7 bypass Wnt/β-catenin addiction in cancer

“…As the role of the recurrent RNF43 G659 microsatelliterelated frameshift mutations remains controversial (22)(23)(24)(25), we analyzed those separately from the non-G659-related truncations. For missense mutations of RNF43, we annotated them on the basis of previous characterization studies (24,26) and classified them as driver mutations (loss of function, partial loss of function, or dominantnegative) or mutations of unknown significance. Cancer cases with known benign missense mutations in RNF43 were excluded.…”

Scalable and efficient DNA sequencing analysis on different compute infrastructures aiding variant discovery

“…The pipeline has been used within the field of cancer research [22][23][24][25][26][27] and beyond, such as the identification of rare variants in tinnitus patients [28], finding SNPs in driver genes related to stress-response in cowpeas [29], the genomic profiling of wild and commercial bumble bee populations [30], or the Personal Genome Project-UK [31].…”