Abstract
Radiotherapy is a definitive treatment for early-stage cervical cancer; however, a subset of this disease recurs locally, necessitating establishment of predictive biomarkers and treatment strategies. To address this issue, we performed gene panel-based sequencing of 18 stage IB cervical cancers treated with definitive radiotherapy, including two cases of local recurrence, followed by in vitro and in silico analyses. Simultaneous mutations in KRAS and SMAD4 (KRASmt/SMAD4mt) were detected only in a local recurrence case, indicating potential association of this mutation signature with radioresistance. In isogenic cell-based experiments, a combination of activating KRAS mutation and SMAD4 deficiency led to X-ray resistance, whereas either of these factors alone did not. Analysis of genomic data from 55,308 cancers showed a significant trend toward co-occurrence of mutations in KRAS and SMAD4. Gene Set Enrichment Analysis of the Cancer Cell Line Encyclopedia dataset suggested upregulation of the pathways involved in epithelial mesenchymal transition and inflammatory responses in KRASmt/SMAD4mt cancer cells. Notably, irradiation with therapeutic carbon ions led to robust killing of X-ray-resistant KRASmt/SMAD4mt cancer cells. These data indicate that the KRASmt/SMAD4mt signature is a potential predictor of radioresistance, and that carbon ion radiotherapy is a potential option to treat early-stage cervical cancers with the KRASmt/SMAD4mt signature.
Highlights
Cervical cancer occurs in approximately 0.5 million women worldwide annually, and mortality from this type of tumor ranks fourth among all cancers [1]
We identified simultaneous mutations in KRAS and SMAD4 in a pre-treatment tumor obtained from a case of stage IB cervical cancer with local recurrence
To the best of our knowledge, this is the first report of a mutation profile associated with radioresistance in patients with early-stage cervical cancer who received definitive radiotherapy
Summary
Cervical cancer occurs in approximately 0.5 million women worldwide annually, and mortality from this type of tumor ranks fourth among all cancers [1]. The radiosensitivity index (RSI), an algorithm composed of mRNA expression levels of ten genes, predicts the tumor responsiveness to radiotherapy; the clinical utility of RSI was validated by multiple cohorts [5] Both tests are of relatively low convenience in the clinic as the former and the latter requires a polarographic oxygen electrode and a fresh-frozen tumor specimen, respectively. Somatic mutation profiles identified by this approach are used to guide prediction of tumor response to molecular-targeted drugs [6], indicating the potential applicability of gene panel testing to radiotherapy personalization; mutation profiles associated with intrinsic radioresistance of early-stage cervical cancer have not been fully elucidated. We performed in vitro and in silico analyses to assess the contribution of candidate mutation profiles to radioresistance and to estimate the underlying mechanisms, respectively
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