Comprehensive genomic variation profiling of cervical intraepithelial neoplasia and cervical cancer identifies potential targets for cervical cancer early warning

Abstract

BackgroundTo better understand the pathogenesis of cervical cancer (CC), we systematically analysed the genomic variation and human papillomavirus (HPV) integration profiles of cervical intraepithelial neoplasia (CIN) and CC.MethodsWe performed whole-genome sequencing or whole-exome sequencing of 102 tumour-normal pairs and human papillomavirus probe capture sequencing of 45 CCs, 44 CIN samples and 25 normal cervical samples, and constructed strict integrated workflow of genomic analysis.ResultsMutational analysis identified eight significantly mutated genes in CC including four genes (FAT1, MLL3, MLL2 and FADD), which have not previously been reported in CC. Targetable alterations were identified in 55.9% of patients. In addition, HPV integration breakpoints occurred in 97.8% of the CC samples, 70.5% of the CIN samples and 42.8% of the normal cervical samples with HPV infection. Integrations of high-risk HPV strains in CCs, including HPV16, 18, 33 and 58, also occurred in the CIN samples. Moreover, gene mutations were detected in 52% of the CIN specimens, and 54.8% of these mutations occurred in genes that also mutated in CCs.ConclusionOur results lay the foundation for a deep understanding of the molecular mechanisms and finding new diagnostic and therapeutic targets of CC.

Human Papilloma Virus-Associated Cervical Cancer and Health Disparities

“…Recent studies have identified several oncogenic factors involved in promoting CC progression, including HMGA1, BAP31, KLF5, Fibulin 3, mirRNA-196a, miR-146b-3p, and various long non-coding RNAs (Figure 3) [22,23,24,25,26,27,28]. On the other hand, the CC suppressor role of miR-27a, miR-424, mir140-5p, and mir-328 were also demonstrated [29,30,31,32]. In parallel, high throughput genome sequencing of progressive CC specimens from 120 women identified novel somatic mutations in FAT1 , MLL3 , MLL2 , and FADD (Figure 3) [32].…”

“…On the other hand, the CC suppressor role of miR-27a, miR-424, mir140-5p, and mir-328 were also demonstrated [29,30,31,32]. In parallel, high throughput genome sequencing of progressive CC specimens from 120 women identified novel somatic mutations in FAT1 , MLL3 , MLL2 , and FADD (Figure 3) [32]. In addition, this study identified HPV integration breakpoints in 97.8% of CCs, 70.5% of cervical intraepithelial neoplasias (CINs), and 42.8% of HPV + normal cervical epithelium [32].…”

Squamous cell carcinoma of the common bile duct: A case report with genomic profiling

“…In 99 EBD adenocarcinomas, CREBBP rearrangement was found in one case (1%) and MLL2 alterations in four cases (4%), while to our knowledge alterations in the remaining four genes, NOTCH1, FAT1, CTCF, and MAGI2 have not been reported in EBD adenocarcinomas. In contrast, aberrations in FBXW7, NOTCH1, FAT1, CREBBP, and/or MLL2 have been reported in SCC of the esophagus, lung, uterine cervix and head and neck . In primary esophageal SCC and in metastatic SCC of the anal canal, MLL2 was among the most frequently mutated genes, while in a series of 20 primary anal SCCs, FBXW7 (15%), FAT1 (15%), and NOTCH1 (10%) were found most often mutated.…”

“…In SCC of the uterine cervix, FBXW7 represented the second most frequently altered gene, and it was suggested that this might represent one of the driver mutations in this neoplasm . The same study found also alterations in FAT1, MLL2, NOTCH1, and CREBBP in SCC of the cervix, but neither these genes nor FBXW7 were mutated in their CIN specimens . Taken together, these studies indicate that some molecular features of EBD‐SCC, but far from all, are shared with SCC from other organs.…”

“…Hypermethylation of MAGI2 was found in cervical intraepithelial neoplasia (CIN) and SCC of the uterine cervix . In SCC of the uterine cervix, FBXW7 represented the second most frequently altered gene, and it was suggested that this might represent one of the driver mutations in this neoplasm . The same study found also alterations in FAT1, MLL2, NOTCH1, and CREBBP in SCC of the cervix, but neither these genes nor FBXW7 were mutated in their CIN specimens .…”