Methods: Defective mismatch repair (dMMR) status was determined by either loss of mismatch repair protein expression on IHC or microsatellite instability (MSI) by PCR in 127 APC biopsies from 124 patients (Royal Marsden [RMH] cohort); MSI by targeted panel next-generation sequencing (MSINGS) was then evaluated in the same cohort and in 254 APC samples from the Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF). Whole exome sequencing (WES) data from this latter cohort were analyzed for pathogenic MMR gene variants, mutational load, and mutational signatures. Transcriptomic data, available for 168 samples, was also performed.
Results: Overall, 8.1% of patients in the RMH cohort had some evidence of dMMR, which associated with decreased overall survival. Higher MSINGS scores associated with dMMR, and these APCs were enriched for higher T cell infiltration and PD-L1 protein expression. Exome MSINGS scores strongly correlated with targeted panel MSINGS scores (r = 0.73, P < 0.0001), and higher MSINGS scores associated with dMMR mutational signatures in APC exomes. dMMRmutational signatures also associated with MMR gene mutations and increased immune cell, immune checkpoint, and T cell-associated transcripts. APC with dMMR mutational signatures overexpressed a variety of immune transcripts, including CD200R1, BTLA, PD-L1, PD-L2, ADORA2A, PIK3CG, and TIGIT.
Conclusion: These data could impact immune target selection, combination therapeutic strategy selection, and selection of predictive biomarkers for immunotherapy in APC.
Funding: We acknowledge funding support from Movember, Prostate Cancer UK, The Prostate Cancer Foundation, SU2C, and Cancer Research UK.
The Journal of clinical investigation. 2018 Nov 01 [Epub]
Nava Rodrigues D1,2, Rescigno P1,2,3, Liu D4,5, Yuan W1, Carreira S1, Lambros MB1, Seed G1, Mateo J1,2, Riisnaes R1, Mullane S4,5, Margolis C4,5, Miao D4,5, Miranda S1, Dolling D1, Clarke M1, Bertan C1, Crespo M1, Boysen G1, Ferreira A1, Sharp A1, Figueiredo I1, Keliher D4,5, Aldubayan S4,5, Burke KP4, Sumanasuriya S1, Fontes MS1,2, Bianchini D1,2, Zafeiriou Z1,2, Teixeira Mendes LS2, Mouw K4, Schweizer MT6,7, Pritchard CC6, Salipante S6, Taplin ME3, Beltran H8, Rubin MA8, Cieslik M9, Robinson D9, Heath E10, Schultz N11, Armenia J11, Abida W11, Scher H11, Lord C1, D'Andrea A4, Sawyers CL11, Chinnaiyan AM9, Alimonti A12, Nelson PS6,7, Drake CG13, Van Allen EM4,5, de Bono JS1,2.
1. The Institute of Cancer Research, London, United Kingdom.
2. Royal Marsden, London, United Kingdom.
3. Department of Clinical Medicine and Surgery, Department of Translational Medical Sciences, Azienda Ospedaliera Universitaria (AOU) Federico II, Naples, Italy.
4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
5. The Broad Institute, Cambridge, Massachusetts, USA.
6. University of Washington, Seattle, Washington, USA.
7. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
8. Weill Medical College of Cornell University, New York, New York, USA.
9. University of Michigan Medical School, Ann Arbor, Michigan, USA.
10. Karmanos Cancer Institute, Detroit, Michigan, USA.
11. Memorial Sloan Kettering Cancer Center, New York, New York, USA.
12. Institute of Oncology Research (IOR), Bellinzona and Faculty of Biomedical Sciences, Università della Svizzera Italiana, Bellinzona, Switzerland.13Columbia University Medical Center, New York, New York, USA.
PubMed J Clin Invest. 2018 Oct 1;128(10):4441-4453. doi: 10.1172/JCI121924. Epub 2018 Sep 4.