Whole exome sequencing reveals diverse genomic relatedness between paired concurrent endometrial and ovarian carcinomas

Introduction
Concurrent non-serous endometrial and ovarian tumours are often managed clinically as two separate primary tumours, but almost all exhibit evidence of a genomic
relationship.

Methodology
This study investigates the extent of relatedness using whole exome sequencing,
which was performed on paired non-serous endometrial and ovarian carcinomas from
27 patients with concurrent tumours in a cohort with detailed clinicopathological
annotation. Four whole exome sequencing-derived parameters (mutation, mutational
burden, mutational signatures and mutant allele tumour heterogeneity scores) were
used to develop a novel unsupervised model for the assessment of genomic similarity
to infer genomic relatedness of paired tumours.

Results
This novel model demonstrated genomic relatedness across all four parameters in all
tumour pairs. Mutations in PTEN, ARID1A, CTNNB1, KMT2D and PIK3CA occurred
most frequently and 24 of 27 (89%) tumour pairs shared identical mutations in at least
one of these genes, with all pairs sharing mutations in a number of other genes.
Ovarian endometriosis, CTNNB1 exon 3 mutation, and progression and death from
disease were present across the similarity ranking. Mismatch repair deficiency was
associated with less genomically similar pairs.

Discussion
Although there was diversity across the cohort, the presence of genomic similarity in all
paired tumours supports the hypothesis that concurrent non-serous endometrial and
ovarian carcinomas are genomically related and may have arisen from a common
origin.