Genome-wide Analysis Reveals Molecular Pathway Aberrations in Uterine Serous Cancer

Get Permission

The molecular pathogenesis of uterine serous carcinoma, the most aggressive form of uterine cancer, remains largely undefined. Kuhn and colleagues from Johns Hopkins Medical Institutions recently identified prominent genetic alterations in uterine serous carcinoma using whole-exome sequencing.

Somatic mutations identified by whole-exome sequencing in 10 uterine serous carcinomas and normal blood or tissue sample were verified by Sanger sequencing, with the most frequent alterations being validated in 66 additional uterine serous carcinomas and 9 serous endometrial intraepithelial carcinomas isolated by laser capture microdissection. Gene copy number was also characterized using single-nucleotide polymorphism (SNP) arrays in 23 uterine serous carcinomas, including 10 that were assessed by whole-exome sequencing.

Specific Mutations

Frequent somatic mutations found among the 76 uterine serous carcinomas included those in TP53 (81.6%), PIK3CA (23.7%), FBXW7 (19.7%), and PPP2R1A (18.4%). All nine serous carcinomas with an associated serous endometrial intraepithelial carcinoma had concordant PIK3CA, PPP2R1A, and TP53 mutation status. DNA copy number analysis showed frequent genomic amplification of the CCNE1 locus (which encodes cyclin E, a known substrate of FBXW7) and deletion of the FBXW7 locus. Of 23 uterine serous carcinomas analyzed by SNP array, 7 tumors with FBXW7 mutations (4 with point mutations and 3 with hemizygous deletions) did not have CCNE1 amplification and 13 had either a molecular alteration in FBXW7 or CCNE1 amplification; nearly half of these carcinomas (48%) had PIK3CA mutation or PIK3CA amplification.

As concluded by the investigators, “Molecular genetic aberrations involving the p53, cyclin E–FBXW7, and PI3K pathways represent major mechanisms in the development of uterine serous carcinoma.”

Kuhn E, et al: J Natl Cancer Inst 104:1503-1513, 2012