Abstract
It has been well established that ovarian low-grade and high-grade serous carcinomas are fundamentally different types of tumours. While the molecular genetic features of ovarian high-grade serous carcinomas are now well known, the pathogenesis of low-grade serous carcinomas, apart from the recognition of frequent somatic mutations involving KRAS and BRAF, is largely unknown. In order to comprehensively analyse somatic mutations in low-grade serous carcinomas, we applied exome sequencing to the DNA of eight samples of affinity-purified, low-grade, serous carcinomas. A remarkably small number of mutations were identified in seven of these tumours: a total of 70 somatic mutations in 64 genes. The eighth case displayed mixed serous and endometrioid features and a mutator phenotype with 783 somatic mutations, including a nonsense mutation in the mismatch repair gene, MSH2. We validated representative mutations in an additional nine low-grade serous carcinomas and 10 serous borderline tumours, the precursors of ovarian low-grade, serous carcinomas. Overall, the genes showing the most frequent mutations were BRAF and KRAS, occurring in 10 (38%) and 5 (19%) of 27 low-grade tumours, respectively. Except for a single case with a PIK3CA mutation, other mutations identified in the discovery set were not detected in the validation set of specimens. Our mutational analysis demonstrates that point mutations are much less common in low-grade serous tumours of the ovary than in other adult tumours, a finding with interesting scientific and clinical implications.