title: Somatic mutation profiles in primary colorectal cancers and matching ovarian metastases: Identification of driver and passenger mutations.
abstract: The mutational profiles of primary colorectal cancers (CRCs) and corresponding ovarian metastases were compared. Using a custom-made next generation sequencing panel, 115 cancer-driving genes were analyzed in a cohort of 26 primary CRCs and 30 matching ovarian metastases (four with bilateral metastases). To obtain a complete overview of the mutational profile, low thresholds were used in bioinformatics analysis to prevent low frequency passenger mutations from being filtered out. A subset of variants was validated using Sanger and/or hydrolysis probe assays. The mutational landscape of CRC that metastasized to the ovary was not strikingly different from CRC in consecutive series. When comparing primary CRCs and their matching ovarian metastases, there was considerable overlap in the mutations of early affected genes. A subset of mutations demonstrated less overlap, presumably being passenger mutations. In particular, primary CRCs showed a substantially high number of passenger mutations. We also compared the primary CRCs and matching metastases for stratifying variants of six genes (KRAS, NRAS, BRAF, FBXW7, PTEN and PIK3CA) that select for established (EGFR directed) or future targeted therapies. In a total of 31 variants 12 were not found in either of the two locations. Tumours thus differed in the number of discordant variants between the primary tumours and matching metastases. Half of these discordant variants were definitive class 4/5 pathogenic variants. However, in terms of temporal heterogeneity, no clear relationship was observed between the number of discordant variants and the time interval between primary CRCs and the detection of ovarian metastases. This suggests that dormant metastases may be present from the early days of the primary tumours.
authors: Department of Pathology Leiden University Medical Center Leiden the Netherlands.
authors: Stijn
authors: S
authors: Crobach
authors: Department of Pathology Leiden University Medical Center Leiden the Netherlands.
authors: Dina
authors: D
authors: Ruano
authors: Department of Pathology Leiden University Medical Center Leiden the Netherlands.
authors: Ronald
authors: R
authors: van Eijk
authors: Department of Pathology Leiden University Medical Center Leiden the Netherlands.
authors: Melanie
authors: M
authors: Schrumpf
authors: Department of Pathology Leiden University Medical Center Leiden the Netherlands.
authors: Gertjan
authors: G
authors: Fleuren
authors: Department of Pathology Leiden University Medical Center Leiden the Netherlands.
authors: Tom
authors: T
authors: van Wezel
authors: Department of Pathology Leiden University Medical Center Leiden the Netherlands.
authors: Hans
authors: H
authors: Morreau
keywords: cancer; colon cancer; gene panel; high‐throughput sequencing; metastases; molecular diagnostics