title: Somatic mutation in PIK3CA is a late event in cervical carcinogenesis.
abstract: Somatic mutations in cervical intraepithelial neoplasia (CIN) are largely unknown. Here, we profiled 35 cervical carcinomas and 23 CIN grade 2/3 (CIN2/3) for mutations in 48 cancer-related genes using a Next Generation Sequencing-based cancer panel. PIK3CA exon 9 was the most frequently mutated locus in cervical carcinoma and the only mutated locus detected in CIN2/3. These PIK3CA exon 9 mutation findings were verified in a large, independent series (n = 647) covering all stages of cervical carcinogenesis using high resolution melting-guided Sanger sequencing. PIK3CA exon 9 mutation frequency was 37.1% (13/35; 95%CI 21.2-54.0%) in cervical carcinoma, and 2.4% (5/209; 95%CI 0.5-4.7%) in CIN3. No PIK3CA exon 9 mutations were detected in CIN2 (0/144), CIN1 (0/154) and normal cervix (0/105). In a third series of 46 CIN2/3 lesions from women with a known 5-year history of preceding high-risk human papillomavirus (hrHPV) infection, detection of PIK3CA exon 9 mutation was confined to 2 (5.4%; 95%CI 0.0-13.2%) CIN3 lesions with preceding hrHPV infection ≥5 years, and was absent in those with a short duration (<5 years) of preceding hrHPV infection. In conclusion, somatic mutation in PIK3CA represents a late event during cervical carcinogenesis, detected in a substantial subset of cervical carcinoma, but only in a minority of CIN3.
authors: Department of Pathology VU University Medical Center Amsterdam The Netherlands.
authors: Wina
authors: W
authors: Verlaat
authors: Department of Pathology VU University Medical Center Amsterdam The Netherlands.
authors: Peter Jf
authors: PJ
authors: Snijders
authors: Department of Pathology VU University Medical Center Amsterdam The Netherlands.
authors: Marinda Ih
authors: MI
authors: van Moorsel
authors: Department of Pathology VU University Medical Center Amsterdam The Netherlands.
authors: Maaike
authors: M
authors: Bleeker
authors: Department of Pathology VU University Medical Center Amsterdam The Netherlands.
authors: Lawrence
authors: L
authors: Rozendaal
authors: Department of Pathology VU University Medical Center Amsterdam The Netherlands.
authors: Daoud
authors: D
authors: Sie
authors: Department of Pathology VU University Medical Center Amsterdam The Netherlands.
authors: Bauke
authors: B
authors: Ylstra
authors: Department of Pathology VU University Medical Center Amsterdam The Netherlands.
authors: Chris Jlm
authors: CJ
authors: Meijer
authors: Department of Pathology VU University Medical Center Amsterdam The Netherlands.
authors: Renske Dm
authors: RD
authors: Steenbergen
authors: Department of Pathology VU University Medical Center Amsterdam The Netherlands.
authors: Daniëlle Am
authors: DA
authors: Heideman
keywords: DNA sequencing; cervix uteri; dysplasia