Abstract
Screening reduces incidence of cervical cancer (CC) through identification and treatment of cervical intraepithelial neoplasia (CIN). Triage of CIN must balance between overtreatment versus progression as invasive therapies increase the risk of side effects including obstetric complications. The majority of CIN 1-2 lesions regress and a subset of CIN 3 lesions progress, however, due to inability to differentiate lesions likely to progress, the majority of CIN 2-3 lesions are treated with resection. Improved genomic and molecular identifiers of disease represent an urgent unmet clinical need. Using next generation sequencing of a targeted exome panel of 1109 genes (previously validated), we characterized somatic mutations in 36 CIN (14 CIN 1, 11 CIN 2, 11 CIN 3) and 13 CC samples. Sequencing of CIN samples was performed on exfoliated cervical cells. CIN diagnosis and grade was confirmed on biopsy. Mutation profiles between CIN grades and CC were compared to identify genomic patterns that distinguish these groups. Across the 49 samples sequenced, we identified a total of 5142 somatic mutations, including 2178 missense, 2522 synonymous, 171 nonsense, 62 splice site, 135 inframe indels, and 74 frameshift mutations. The mutation frequency was significantly higher in CC vs CIN1-3 (Table), p<0.01 (Wilcoxon signed-rank test). The difference in mutation frequency and type (Table) was not significant between CIN grades 1, 2 and 3 (p = 0.07, Kruskal-Wallis test). Cancer related pathway signatures were analyzed for the percentage of CC vs CIN samples with at least one altered variant as follows: RTK-RAS (92% vs 31%), PI3K (92% vs 17%), NOTCH (100% vs 39%), WNT (85% vs 14%) and cell cycle (53% vs 3%). Ninety percent of CC samples versus only 30% of CINs had nonsynonymous variants in the RTK-RAS and NOTCH pathways as well as the PI3K pathway which is implicated as a late event in cervical carcinogenesis. We observed recurrent missense variants in ABL1, IGF1R, TSC2 in the CIN2, CIN3 and CC samples, particularly in genes that belong to the RTK-RAS, PI3K, NOTCH pathway signatures. Potential driver mutations in EGFR, PIK3CA, ERBB4, MTOR, CSF1R genes were exclusive to CC samples. Our results show that there is a clear distinction of mutational burden and type between cervical cancer and CIN1-3. However, the pathologic grading of CIN is not consistently associated with dynamic changes in overall mutation burden, type, or specific genes with escalating CIN grade. This data supports the hypothesis that late genetic events in CIN accompany a transition to invasive cervical cancer.
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More From: International Journal of Radiation Oncology*Biology*Physics
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