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Poster Display session 3

4634 - Comparative molecular analyses between microsatellite stable BRAFV600E mutant colorectal cancers and BRAFV600E mutant melanomas.

Date

30 Sep 2019

Session

Poster Display session 3

Topics

Translational Research

Tumour Site

Melanoma

Presenters

Mohamed Salem

Citation

Annals of Oncology (2019) 30 (suppl_5): v760-v796. 10.1093/annonc/mdz268

Authors

M.E. Salem1, J. Xiu2, A. Puccini3, A. Grothey4, R.M. Goldberg5, J.J. Hwang1, Z. Gatalica6, R. Feldman2, M. Saul2, W..M. Korn2, M.J. Hall7, W. El-Deiry8, A.F. Shields9, J.L. Marshall10, H.J. Lenz11, A.M. VanderWalde12

Author affiliations

  • 1 Oncology, Levine Cancer Institute, 28204 - Charlotte/US
  • 2 Medical Affairs, Caris Life Sciences, 85040 - Phoenix/US
  • 3 Medical Oncology 1, IRCCS AOU San Martino - IST-Istituto Nazionale per la Ricerca sul Cancro, 16132 - Genova/IT
  • 4 Oncology, West Cancer Center, 38138 - Germantown/US
  • 5 Oncology, West Virginia University Cancer Institute, 26506 - Morgantown/US
  • 6 Pathology, Caris Life Sciences, New York/US
  • 7 Department Of Clinical Genetics, Fox Chase Cancer Center, 19111 - Philadelphia/US
  • 8 Department Of Pathology And Laboratory Medicine, Warren Alpert Medical School, Brown University, 02912 - Providence/US
  • 9 Oncology, Karmanos Cancer Institute, Wayne State University, 48201 - Detroit/US
  • 10 Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 20057 - Washington/US
  • 11 Medical Oncology, USC - Norris Comprehensive Cancer Center, 90033 - Los Angeles/US
  • 12 Hematology/oncology Department, West Cancer Center, 38138 - Germantown/US

Resources

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Abstract 4634

Background

Several studies in BRAFV600E colorectal cancers (CRC) have failed to replicate the efficacy of BRAF inhibitors in treatment of BRAFV600E melanomas (Mel), suggesting the existence of different resistance mechanisms as well as molecular and biological differences between the 2 tumor types. Herein, we examine these differences.

Methods

Tumor samples submitted to Caris Life Sciences for NGS DNA sequencing (592 gene panel) and RNA sequencing (54 gene panel) between the years 2015 and 2019 were retrospectively studied. Only microsatellite stable (MSS) tumors with either BRAFV600E mutation or wild type (WT) BRAF status were included in this initial analysis. Chi-square tests determined differences.

Results

A total of 8409 tumor samples were analyzed: CRC (N = 7453: BRAFV600E=373; WT = 7080) and Mel samples (N = 956: BRAFV600E=274; WT = 682). The most frequently mutated genes in BRAFV600E CRC were TP53 (81%), APC (26%), and SMAD4 (22.4%), compared to CDKN2A (22%), PTEN (13%), and TP53 (13%) in BRAFV600E Mel. Molecular alterations that are significantly more frequent in BRAFV600E CRC vs BRAFV600E Mel but not significantly different between BRAF WT CRC vs BRAF WT Mel included RSPO3 fusions (CRC=22.6% vs Mel=0%, P = 0.027); RNF43 deletions (2.0% vs 0%, p = 0.019); and mutations in RNF43 (18.8% vs 0%, P < 0.001), AKT1 (3.5% vs 0.4%, p = 0.008), and MTOR (2.4% vs 0.4%, p = 0.037). RSPO3 fusions and RNF43 mutations/deletions are mutually exclusive. Significantly more frequent alterations in BRAFV600E Mel compared to BRAFV600E CRC (but not in either WT) included deletions in PTEN (7% vs 3%, p = 0.005) and mutations in PTEN (12.9% vs 5.4%), MITF (1.9% vs 0%), STK11 (1.5% vs 0%), ERCC2 (1.1% vs 0%), FANCC (1.2% vs 0%), and CDK4 (1.5% vs 0%) (p < 0.05 for all).

Conclusions

BRAFV600E CRC carry molecular alterations that are distinct from BRAFV600E Mel. RSPO3 fusions and RNF43 alterations are prevalent in BRAFV600E CRC tumors in a mutually exclusive manner, suggesting that Wnt pathway activation via genetic alterations in upstream Wnt pathway regulators may play an important role in BRAFV600E CRC tumorigenesis and resistance to BRAF inhibitors. Drug combinations that target both the MAPK and Wnt pathways may warrant further investigation.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

M.E. Salem: Travel / Accommodation / Expenses: Caris Life Sciences. J. Xiu: Full / Part-time employment: Caris Life Sciences. A. Grothey: Travel / Accommodation / Expenses: Caris Life Sciences. R.M. Goldberg: Research grant / Funding (self), Travel / Accommodation / Expenses: Caris Life Sciences. Z. Gatalica: Full / Part-time employment: Caris Life Sciences. R. Feldman: Full / Part-time employment: Caris Life Sciences. M. Saul: Full / Part-time employment: Caris Life Sciences. W..M. Korn: Full / Part-time employment: Caris Life Sciences. A.F. Shields: Research grant / Funding (institution), Travel / Accommodation / Expenses: Caris Life Sciences. J.L. Marshall: Advisory / Consultancy: Caris Life Sciences. H.J. Lenz: Travel / Accommodation / Expenses: Caris Life Sciences. All other authors have declared no conflicts of interest.

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