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WRN mutated Colorectal Cancer (CRC) is characterized by a distinct molecular and immunological profile

Date

29 Sep 2019

Session

Poster Display session 2

Presenters

Andreas Seeber

Citation

Annals of Oncology (2019) 30 (suppl_5): v198-v252. 10.1093/annonc/mdz246

Authors

A. Seeber1, A. Puccini2, J. Xiu3, Y. Baca3, G. Spizzo4, K. Zimmer4, H.J. Lenz5, F. Battaglin6, R.M. Goldberg7, A. Grothey8, A.F. Shields9, M.E. Salem10, J.L. Marshall11, W..M. Korn3, D. Wolf4, F. Kocher4

Author affiliations

  • 1 Hematology And Oncology, Medical University of Innsbruck, 6020 - Innsbruck/AT
  • 2 Oncologia Medica 1, Ospedale Policlinico San Martino – IRCCS, Genova/IT
  • 3 Medical Affairs, Caris Life Sciences, 85040 - Phoenix/US
  • 4 Hematology And Oncology, Medical University of Innsbruck, Innsbruck/AT
  • 5 Medical Oncology, USC - Norris Comprehensive Cancer Center, 90033 - Los Angeles/US
  • 6 Clinical And Experimental Oncology Department, University of Southern California Norris Comprehensive Cancer Center, 90033 - Los Angeles/US
  • 7 Director Of Cancer Signature Program, West Virginia University Cancer Institute, Morgantown/US
  • 8 Oncology, West Cancer Center, 38138 - Germantown/US
  • 9 Oncology, Karmanos Cancer Institute, Wayne State University, 48201 - Detroit/US
  • 10 Oncology, Levine Cancer Institute, 28204 - Charlotte/US
  • 11 Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 20057 - Washington/US
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Resources

Abstract 5515

Background

Werner syndrome gene (WRN) encodes a DNA helicase with an exonuclease activity that contributes to DNA repair. In cancer, WRN mutations lead to genomic instability. It is known that WRN is necessary to sustain in-vivo growth of cancers cells with microsatellite instability (MSI), including CRC. WRN is a very promising new target especially in cancers with MSI. There is still a lack of knowledge about the frequency of WRN alterations and their association with immunological and molecular phenotypes.

Methods

Tumour samples from 6854 CRC patients were analyzed using NGS (NextSEQ on 592 genes), in-situ hybridization and immunohistochemistry (Caris Life Sciences, Phoenix, AZ, USA). Tumour mutational burden (TMB) was calculated based on somatic non-synonymous missense mutations, and MSI was evaluated by NGS of known MSI loci.

Results

WRN mutations (WRN-mut) were observed in 80 of 6854 samples (1.2%). A higher prevalence of WRN-mut was detected in right- compared to left-sided CRC (2.4% vs 0.7%, p<.0001). In WRN-mut (MT) CRC, TMB (43 vs. 8.6 mutations/megabase [mut/MB], p<.0001) and PD-L1 expression (13% vs 4%, p<.0001) were higher compared to WRN wild-type (WT). A higher frequency of MSI-H was seen in cancers harboring WRN-mut (56% vs 7%, p<.0001). Also, WRN-mut was associated with a higher TMB in both MSI-H subgroup of tumors (54 vs 40 mut/MB, p=.03) and MSS subgroup (43 vs 8.6 mut/MB, p<.0001). Several differences between WRN-mut and WRN-WT CRC was observed, including TP53 (47% vs 73%), KRAS (34% vs 49%), APC (56% vs 73%), BRAF (26% vs 9%), ASXL1 (25% vs 4%), ERBB2 (9% vs 2%), BRCA1 (8% vs 1%), BRCA2 (15% vs 2%), CDK12 (10% vs 1%), (p<.01 for all). Copy number alterations (CNA) of CDX2 were seen only in WRN-WT tumours (6.4% vs 1%, p=.026) and CNAs seen more frequently in WRN-mut tumours included CD274, CALR, CRTC1, ELL, JAK3, KEAP1, LYL1, MEF2B (p<.01).

Conclusions

This is the largest profiling study to investigate the molecular and immunological landscape of WRN-mut CRCs. We show the high prevalence of MSI in WRN-mut tumours and their association with higher TMB and PD-L1 expression. Furthermore, it revealed that WRN-mut CRC is characterized by a distinct genetic profile. Our data might serve to tailor treatment in WRN-mut CRC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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