Current molecular testing of HGOC uses panel testing of fixed tumour tissue. Matched tumour-germline WGS is now in the NHS National Genomic Test Directory for fresh frozen (FF) samples. WGS offers significant advantages over panel tests, particularly for accurate measures of mutational processes (homologous recombination deficiency [HRD], tumour mutational burden [TMB]). We report the experience of integrating WGS into routine NHS pathways for women with HGOC between April and November 2022.
WGS of somatic (×80) and germline (×30) was performed by the NHS Genomics Medicine Sequencing Centre using Illumina chemistries. Processing of the sequence data and variant triage was performed by Genomics England WGS analysis pipeline. All patients (pts) gave written informed consent for germline and tumour testing.
WGS was performed in 19 pts (table). After an initial 3 month run-in period using banked FF samples, prospective testing was integrated into routine care from July 22. The median time from consent to clinical reporting was 48 days (IQR 44-68).
WGS results changed the diagnosis in 3 patients: 2 with image-guided biopsies were changed from HGOC to low grade subtype and 1 recurrent poorly differentiated gynaecological carcinoma had unusually high TMB and APOBEC signatures that was inconsistent with HGOC enabling compassionate use of pembrolizumab.
Estimating HRD from WGS using the CHORD algorithm showed strong concordance with Myriad MyChoice (9/11; 82%). One clinically platinum-refractory case was proficient by CHORD and had a genomic instability score [GIS] of 42. The second pt had a germline deleterious BRIP1 variant with GIS 36 and was deficient by CHORD. CCNE1 amplification was only present in platinum resistant cases.
| Median age at diagnosis (range) years | 60 (36-79) |
| Carcinosarcoma, N | 1 |
| Clear cell, N | 1 |
| High grade serous, N | 16 |
| Poorly differentiated, N | 1 |
| Surgery | |
| Diagnosis, N | 2 |
| Primary, N | 6 |
| Recurrence, N | 2 |
| Radiology | |
| Diagnosis, N | 6 |
| Recurrence, N | 1 |
Biopsy pathways for FF and WGS are feasible for diagnostic pathways in the NHS. WGS offers clinically relevant measures of mutational processes in HGOC with diagnostic and predictive value.