30 CHAPTER 2 Table 2. Tumour and biomarker details per patient of the MSI cohort Histologic tumour type, biomarker characteristics and classification of clinical benefit per patient in the MSI cohort. CB, clinical benefit; PFS, progression-free survival (given in weeks, at data cut-off; > denotes benefit ongoing at cut-off); CRC, colorectal cancer; EC, endometrial cancer; GBM, glioblastoma multiforme; Lynch, Lynch syndrome; ML, mutational load; MSIseq, microsatellite instability score; MSS, microsatellite stable; mut, mutation; NA, not applicable; NE, not evaluable; no., case number; PD, progressive disease; PR, partial response; SD, stable disease; somatic, different from germline DNA; UCC, urothelial cell carcinoma. aThe use of − denotes that no baseline WGS data are available. bCopy number gain of CD274. cUse of + denotes >20% prevalence of ‘Catalogue of Somatic Mutations in Cancer’ (COSMIC) mutational signature. Signatures are only mentioned in case of >10% prevalence (https://cancer.sanger.ac.uk/cosmic/signatures). No. Tumour type Pre-enrolment Baseline WGS CB PFS Somatic or Lynch MSI profile MSI seqa ML JAK1 and/ or JAK2 mutations CD274b COSMIC signaturec 1 CRC Somatic MLH1/PMS2 loss − NE NA 2 CRC Somatic MLH1/PMS2 loss, MLH1 methylation 76.9 1,589 3× 6+, 9, 15, 12, 17 PR >105 3 UCC Lynch MSH2 mut, MSH2 loss, MSI 35.2 973 3× 1+, 6+ PR >92 4 CRC Somatic MLH1/PMS2 loss − PD 8 5 Cervix Lynch MSH2 mut, MSH2/MSH6 loss 23.1 776 2× 6+, 1+, 14, 12 PR >88 6 CRC Somatic MLH1/PMS2 loss, MLH1 methylation 66.7 1,301 2× 12+, 6+, 9, 20 PR >83 7 CRC Somatic MLH1/PMS2 loss, MLH1 methylation 17.1 638 2× PR >90 8 CRC Somatic MLH1/PMS2 loss − NE NA 9 CRC Somatic MLH1/PMS2 loss, MSI, MLH1 methylation − SD 23 10 Breast Somatic MLH1/PMS2 loss, MLH1 not methylated 20.9 287 JAK2 p.Tyr20Asn 8× 6+, 12, 9, 1 PR 23 11 CRC Somatic MLH1/PMS2 loss,MLH1 methylation 65.9 1,036 JAK1 p.Ala639Val 2× 12+, 6+, 9 SD 24 12 CRC Somatic MLH1/PMS2 loss 10.6 346 2× 6+, 12 SD >68 13 CRC Somatic MLH1/PMS2 loss, MLH1 methylation 58.6 912 JAK1 p.Lys860fs 2× 6+, 12, 21, 9 PR >69 14 Breast Somatic MLH1/PMS2 loss, MLH1 not methylated − PR >72 15 CRC Somatic MLH1/PMS2 loss, MSI, BRAFV600E, MLH1 methylation 0.5 73 2× 1+, 8, 17, 18, 11 NE NA
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