Genomic analysis of low‐grade serous ovarian carcinoma to identify key drivers and therapeutic vulnerabilities

Abstract

Low-grade serous ovarian carcinoma (LGSOC) is associated with a poor response to existing chemotherapy, highlighting the need to perform comprehensive genomic analysis and identify new therapeutic vulnerabilities. The data presented here represent the largest genetic study of LGSOCs to date (n = 71), analysing 127 candidate genes derived from whole exome sequencing cohorts to generate mutation and copy-number variation data. Additionally, immunohistochemistry was performed on our LGSOC cohort assessing oestrogen receptor, progesterone receptor, TP53, and CDKN2A status. Targeted sequencing identified 47% of cases with mutations in key RAS/RAF pathway genes (KRAS, BRAF, and NRAS), as well as mutations in putative novel driver genes including USP9X (27%), MACF1 (11%), ARID1A (9%), NF2 (4%), DOT1L (6%), and ASH1L (4%). Immunohistochemistry evaluation revealed frequent oestrogen/progesterone receptor positivity (85%), along with CDKN2A protein loss (10%) and CDKN2A protein overexpression (6%), which were linked to shorter disease outcomes. Indeed, 90% of LGSOC samples harboured at least one potentially actionable alteration, which in 19/71 (27%) cases were predictive of clinical benefit from a standard treatment, either in another cancer's indication or in LGSOC specifically. In addition, we validated ubiquitin-specific protease 9X (USP9X), which is a chromosome X-linked substrate-specific deubiquitinase and tumour suppressor, as a relevant therapeutic target for LGSOC. Our comprehensive genomic study highlighted that there is an addiction to a limited number of unique 'driver' aberrations that could be translated into improved therapeutic paths.

Distinct transcriptional programs stratify ovarian cancer cell lines into the five major histological subtypes

“…In line with a HGSOC, OCMs 64-1, OCM.64-3 Ep− and OCM.64-3 Ep+ all have an identical TP53 mutation [ 27 ]. However, panel-based next-generation sequencing (NGS) on the primary tumour block and exome sequencing of the OCM [ 27 ] demonstrated a mutation in KRAS , consistent with the high frequency of this mutation in LGSOC [ 16 , 17 , 79 – 82 ]. Indeed, while the local (primary) pathology diagnosis reported HGSOC for this tumour [ 27 ], a review by an expert gynaecological pathologist (S.D.)…”

“…LGSOC arise from serous cystadenoma or adenofibroma, which progresses through serous borderline tumour to invasive carcinoma in a slow stepwise manner [ 3 ]. LGSOC often harbour activating mutations of genes involved in the MAPK signalling pathway, including KRAS (~20–35%), BRAF (~10–40%), ERBB2 (~5%) and NRAS (~10%) [ 16 , 17 , 79 – 82 ]. Mutations in key MAPK pathway genes are mutually exclusive, meaning one of these genes is mutated in around half to two-thirds of LGSOC [ 17 , 79 , 80 ].…”

“…In keeping with the frequency of MAPK pathway mutations in LGSOC, cell lines in this cluster harbour the highest frequency of KRAS mutations (4 of 8) and additionally show BRAF (2 of 8), NRAS (1 of 8) and ERBB2 (1 of 8) mutations; in fact, 7 of 8 cell lines have a mutation in at least one of these genes. However, none of these cell lines harboured mutations in USP9X , which has recently been found at a high frequency in LGSOC cases [ 17 ]. Also, OV-56 more likely represents CCOC, as described above, based on alternative datasets [ 50 , 51 ].…”

“…LGSOC often harbour activating mutations of genes involved in the MAPK signalling pathway, including KRAS (~20-35%), BRAF (~10-40%), ERBB2 (~5%) and NRAS (~10%) [16,17,[79][80][81][82]. Mutations in key MAPK pathway genes are mutually exclusive, meaning one of these genes is mutated in around half to twothirds of LGSOC [17,79,80].…”

“…Expansion of next-generation sequencing has revealed the distinct molecular characteristics of each subtype; for example, HGSOC is characterised by nearubiquitous TP53 mutation, germline and/or somatic mutations in genes involved in homologous recombination (HR) repair and genome-wide copy-number variation (CNV) [8][9][10]. Unlike HGSOC, the other subtypes are characterised by mutations in the MAPK and PI3K/ AKT pathway, and while~60% of MOC also have TP53 mutations [11,12], TP53 is altered in only around 15-20% of ENOC and CCOC [13][14][15] and less than 10% of LGSOC [16][17][18].…”