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. 2025 Oct 28;22(6):1069–1080. doi: 10.21873/cgp.20556

Genomic Features of Cervical Cancer in Okinawa, Japan: Preliminary Findings From 23 Patients

HITOSHI MAEMOTO 1,2, SHUGO SAKIHAMA 3, KENNOSUKE KARUBE 4, WATARU KUDAKA 5, TOMOKO NAKAMOTO 5, YUSUKE TAIRA 5, YOSHIHISA ARAKAKI 5, YUKO SHIMOJI 5, AKIHIRO NISHIE 2
PMCID: PMC12577608  PMID: 41151859

Abstract

Background/Aim

Regional differences in genomic mutation profiles of uterine cervical cancer have been reported. Japanese people are divided into two genetic background clusters, originating from mainland Japan and Okinawa. Okinawa is an island prefecture surrounded by the sea, located more than 800 km from the southernmost point of mainland Japan. No studies have examined gene mutation profiles of cervical cancer in Okinawa. This study aimed to investigate the mutation profile of cervical cancer in Okinawa.

Patients and Methods

Twenty-three patients with biopsy-proven squamous cell carcinoma and adenocarcinoma of the intact uterine cervix who were treated with definitive radiotherapy were analyzed. Genomic DNA was extracted from fresh frozen tissue samples collected by tumor biopsy prior to treatment. Variants of 224 cancer-related genes were identified using next-generation sequencing.

Results

A total of 29 gene mutations were observed in 16 patients, including nine genes mutated in multiple samples: SCN7A (17%), PIK3CA (13%), FGFR4 (13%), USP6 (13%), SETD2 (9%), KIT (9%), TSC1 (9%), SERPING1 (9%), and NOTCH3 (9%). Compared to a report from mainland Japan, significant differences in mutation frequency were observed in PIK3CA, FBXW7, and ARID1A. Significant mutations in ARID1A, FBXW7, PTEN, TP53, and EP300, reported as relatively common in cervical cancer in other regions were not detected in this study. The rate of 2-year overall survival and progression-free survival was 95.5% and 73.4%, respectively.

Conclusion

Gene mutation profiles of cervical cancer in Okinawa may differ from those in other regions.

Keywords: Cervical cancer, chemoradiotherapy, DNA sequence, genome, radiotherapy

Introduction

Uterine cervical cancer is the fourth most common cancer in women globally, with approximately 660,000 new cases and 350,000 deaths annually (1). Concurrent chemoradiotherapy (CCRT) is the standard of care for patients with advanced disease (2), but the treatment outcomes remain poor. Cervical cancer has a significant impact on society because it disproportionately affects young women. Among children who lose their mothers to cancer, cervical cancer accounts for 20% of maternal deaths (3).

In recent years, genome-based cancer precision medicine with next-generation sequencing (NGS) technologies has been applied across various cancers (4). In the past decade, the genetic landscape of cervical cancer has been described (5,6). Many subsequent reports have documented genetic mutations that affect prognosis, including FGFR (7), KRAS (8-10), PIK3CA (10-13), ERBB2 (10,14), and MLL2 (10), although precision medicine is not yet the standard treatment for cervical cancer.

Comparing reports from different regions indicates regional differences in genomic mutation profiles in cervical cancer (6-8,15). Mutations in PIK3CA, FBXW7, ARID1A, PTEN, and EP300 are relatively common across regions, while the prevalence of mutations in TP53, KMT2C, and RET is reported to be significantly different between patients in China and western countries (15). The prevalence of mutations in the FGFR family of genes is higher in mainland Japan than in other regions (7).

Okinawa is an island prefecture surrounded by the sea with a population of approximately 1.5 million. The island is located more than 800 km from the southernmost point of mainland Japan, making it geographically isolated. Japanese people are divided into two genetic background clusters originating from mainland Japan and Okinawa (16). Therefore, mutation profiling of cervical cancer in Okinawa may differ from the profile reported in mainland Japan. Genetic profiling of cervical cancer has been reported in patients from mainland Japan. No similar studies have been performed in Okinawa.

The purpose of the study was to investigate the mutation profile of cervical cancer in Okinawa through comprehensive somatic gene mutation analysis using NGS. The goal was to contribute to the advancement of personalized treatment for cervical cancer. Additionally, this study aimed to identify genetic mutations that are predictive of prognosis after definitive radiotherapy (RT) for cervical cancer.

Patients and Methods

Study design and eligibility criteria. This single-center, prospective, observational study was approved by the Institutional Review Board of the University of the Ryukyus (approval number: 1649). The study adhered to the principles of the Helsinki Declaration. All patients signed informed consent forms before enrollment and sample collection.

Eligible patients had biopsy-proven squamous cell carcinoma (SCC) or adenocarcinoma (AC) of the intact uterine cervix and were treated with definitive RT alone or CCRT between September 2020 and June 2022 at the University of Ryukyus Hospital. Additional eligibility criteria were 2018 Federation of Gynecology and Obstetrics (FIGO) stage IB2-IVA, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2, ≥20-years-of-age, and no history of RT for the pelvic region.

DNA samples and targeted sequencing. Tumor tissue was obtained from all patients prior to cancer treatment by punch biopsy or a curette when punch biopsy was difficult. The samples were frozen in liquid nitrogen immediately after collection. Hematoxylin and eosin-stained specimens were prepared from all frozen samples. One of the authors, who is a specialized pathologist (K. K.) confirmed that the tumor components were identified in all specimens. Genomic DNA was extracted from fresh frozen tissue samples using a QIAamp DNA Mini Kit (QIAGEN, Hilden, Germany).

Targeted NGS of genomic DNA samples was performed using the SureSelect Customs DNA Target Enrichment Probe (Agilent Technologies, San Diego, CA, USA) and the MiSeq platform (Illumina, San Diego, CA, USA). SureCall software ver.4.2 (Agilent Technologies) was used to identify the variants. The probe was designed for 224 cancer-related genes (Figure 1) that are genetic mutations included in cancer panel tests or mutations that have been potentially associated with cervical cancer (17-22). Variants were filtered out by the following exclusion criteria: [i] synonymous mutations and variants in introns, except for splice sites and a promoter region (TERT), [ii] variants with ≥1% allele frequency in online single nucleotide polymorphism (SNP) databases, and [iii] variants not listed in the Catalogue of Somatic Mutations in Cancer (https://cancer.sanger.ac.uk/cosmic). Additionally, variants considered likely to be benign were excluded based on the Sorting Intolerant From Tolerant score, dbSNP database, or correlation between the tumor proportion in the tissue samples and variant allele frequency.

Figure 1.

Figure 1

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List of targeted 224 genes. The red symbols indicate genes in which significant mutations were detected in this study.

Follow-up evaluations. Follow-up evaluations were typically performed at three-month intervals. The evaluations included gynecological examinations, tumor marker tests, histological or cytological confirmation, and imaging. Oncological event times were measured from the start of RT. Local failure was defined as recurrence or persistent disease in the cervix, uterine corpus, parametria, or vagina. Progression-free survival (PFS) was defined as the absence of disease or death from any cause. Overall survival (OS) was defined as the absence of death due to any cause. Patients without adverse events were censored at the time of their final follow-up evaluation. Late adverse events were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Statistical analyses. Student’s t-test was used to compare the mean values between two groups. Time-to-event analyses were conducted using the Kaplan-Meier method. Fisher’s exact test was used to analyze the difference in the frequency of gene mutations between this study and previous studies. Statistical significance was set at p<0.05. All statistical analyses were performed using EZR ver. 1.41 (Saitama Medical Centre, Jichi Medical University, Saitama, Japan), and a graphical user interface for R (R Foundation for Statistical Computing, Vienna, Austria).

Results

Characteristics of patients, tumors, and treatments. A total of 23 patients were enrolled (Table I). Eighteen cases of SCC (78%) and five cases of AC (22%) were included. Staining for p16 was performed in all five cases of AC and was positive in three cases and negative in two cases. For SCC, p16 staining was performed in only two of 18 cases, and both cases were positive.

Table I. Patient and tumor characteristics (n=23).

graphic file with name cgp-22-1072-i0001.jpg

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SCC, Squamous cell carcinoma; AC, adenocarcinoma; FIGO, International Federation of Gynecology and Obstetrics; PAN, para-aortic node.

The details of the treatments are shown in Table II. CCRT was administered to 21 patients and RT alone to two patients ≥75-years-of-age. RT consisted of external beam radiotherapy (EBRT) and three-dimensional-image-guided brachytherapy (3D-IGBT). EBRT was delivered with a 10 MV photon beam using a linear accelerator (Clinac iX, Varian Medical Systems, Palo Alto, CA, USA). The EBRT fields included the whole pelvis (n=20), small pelvis (n=2), and extended field, including para-aortic node (n=1). Small pelvic irradiation was performed in two elderly patients who were the same as those who were treated without chemotherapy. The upper edge of the extended irradiation field was set to the upper edge of the L1 vertebral body.

Table II. Treatment details.

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CCRT, Concurrent chemotherapy and radiotherapy; RT, radiotherapy; WP, whole pelvis; SP, small pelvis; EF, extended field including para-aortic node; EBRT, external beam radiotherapy; EQD2, equivalent dose in two Gy fractions; HR-CTV, high-risk clinical target volume.

The prescribed EBRT dose was 50 Gy in 25 fractions with central shielding after 40 Gy. An initial dose of 40 Gy in 20 fractions was delivered using a four-field technique, and a subsequent dose of 10 Gy in five fractions was delivered using an anterior-posterior field with a 4 cm-wide central shield. Additional radiation of 6 Gy in three fractions was administered to the parametrial tissue in T3b cases and/or lymph node metastases. All patients were treated with three-dimensional conformal radiation therapy, and no intensity-modulated radiation therapy was administered.

3D-IGBT was delivered using a high-dose-rate 192Ir remote afterloading system (MicroSelectron, Elekta, Stockholm, Sweden). IGBT was planned based on computed tomography (CT) images with a 1.25 mm slice thickness, with applicators inserted. Three brachytherapy sessions were performed. All patients received intracavitary irradiation alone without interstitial irradiation. The dose regimen was optimized considering the dose to the tumor and surrounding organs at risk. The high-risk clinical target volume (HR-CTV) was contoured according to Japanese Radiation Oncology Study Group (JROSG). The cumulative doses from EBRT and 3D-IGBT were calculated by a simple summation in the biological equivalent dose 2 Gy per fraction (EQD2) using the linear-quadratic model with an α/β of 10 Gy for tumors and 3 Gy for organs at risk. The median cumulative dose for HR-CTV D90 was 71.5 Gy (range=60.7-82.1 Gy), bladder D2cm3 was 65.0 Gy (58.0-79.2 Gy), rectum D2cm3 was 59.2 Gy (44.8-73.4 Gy), and small bowel D2cm3 was 51.8 Gy (43.9-63.6 Gy).

Weekly cisplatin (40 mg/m2) was the standard chemotherapy regimen, which could be skipped due to the patient’s condition. A median of five courses (range=3-6 courses) was administered. A triweekly paclitaxel and cisplatin regimen (paclitaxel, 50 mg/m2, days 1, 8, and 15; cisplatin, 50 mg/m2, day 1) was administered to six patients: five with adenocarcinoma histology and one with SCC with para-aortic node positivity.

Somatic mutations in 224 cancer-related genes in Okinawa cervical cancer cases. No genetic mutations remained after filtering in seven cases. One or more genetic mutations were observed in the remaining 16 cases (Figure 2). The details of filtering are described in the Materials and Methods section. The following mutations were manually omitted after systematic filtering: M784V (BRCA2), G520R (PARN), D215H (UQURC), I1698F (NOTCH2), D235N (RET), F238L (HLA-DQA), and R1279H (NOTCH1).

Figure 2.

Figure 2

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Summary of mutated genes across 23 cervical cancer biopsy specimens in Okinawa. Data of histology, status of disease-progression after treatment, Federation of Gynecology and Obstetrics (FIGO) stage (2018), age, type of mutations, and significantly mutated genes are presented.

A total of 29 gene mutations were observed in 16 patients (Figure 2). The following genes were mutated in multiple cases: SCN7A (17%), PIK3CA (13%), FGFR4 (13%), USP6 (13%), SETD2 (9%), KIT (9%), TSC1 (9%), SERPING1 (9%), and NOTCH3 (9%). The most commonly mutated gene was SCN7A, with mutations L1357F (n=3) and I605M (n=1).

Comparison of genetic mutation profiles between patients in Okinawa, mainland Japan, China, and Western countries. Genes with mutations reported at a frequency ≥10% in the current study or reports from other regions (6,7,15,23,24) were compared (Table III). The most commonly mutated gene in the current study was SCN7A (17%), although no other reports mentioned the frequency of SCN7A mutations in cervical cancer. PIK3CA mutations, which have been reported frequently in other regions (17-40%), were detected in 13% of the patients in the current study.

Table III. Comparison of gene mutation frequencies in patients with cervical cancer.

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Genes with a mutation frequency ≥10% in any of the above reports. TCGA, The Cancer Genome Atlas Research.

Comparing this study with a report from mainland Japan (7), significant differences in mutation frequency were observed in PIK3CA (p=0.045), FBXW7 (p=0.022), and ARID1A (p=0.004). The frequency of FGFR4 mutations was similar (13% in Okinawa and 11% in mainland Japan). FGFR3 and NOTCH1 mutations were relatively frequent in mainland Japan (21% and 19%, respectively) but only 4% each in Okinawa, although the differences were not statistically significant.

In several reports from other regions, FBXW7 (11-19%), ARID1A (7-26%), PTEN (4-10%), TP53 (7-16%), and EP300 (6-12%) mutations were found at relatively high frequencies in cervical cancer but were not detected in the current study.

Clinical outcomes. Except for one patient who was lost to follow-up at 14 months, all patients were followed-up for at least 24 months from the start of treatment. The median follow-up period was 32 months (range=14-40 months). Two deaths and six recurrences (local only, n=2; distant only, n=2; local and distant, n=2) were observed during the follow-up period. The pathology of the two deceased patients was AC, and none of the 18 patients with SCC died during the observation period. Recurrence was observed in three of five patients with AC and in three of 18 patients with SCC.

The 2-year OS for all 23 patients was 95.5%, 2-year PFS was 73.4% (Figure 3), and 2-year local control (LC) was 82.0%. Analyses of the association between pathology or gene mutations and survival were performed. However, the interpretability of the results was limited by the small sample size. Appropriately, these results were not included in the paper.

Figure 3.

Figure 3

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Overall survival (OS) and progression-free survival (PFS) of all 23 cases calculated by Kaplan-Meier methods. The 2-year OS was 95.5% and the 2-year PFS was 73.4%.

Late adverse events of CTCAE Grade ≥2 were gastro-intestinal (9%), urinary (4%), and pelvic bone fracture (4%).

Discussion

This study investigated the genetic profile of cervical cancer in Okinawa. The findings suggest that the profile may differ from the profiles in other regions, including mainland Japan. Some genetic mutations reported to be relatively common in cervical cancer in other regions were not detected in the present study.

Previous reports have suggested that the frequencies of gene mutations that can be targeted by small-molecule drugs are low in cervical cancer. As a small-molecule targeted drug for recurrent or metastatic cervical cancer, selpercatinib is considered useful for RET fusion-positive tumors, and larotrectinib/entrectinib is considered useful for NTRK fusion-positive tumors (25). However, it is obvious from previous reports that these gene mutations are rare. Consistent with previous reports, the present study did not identify any mutations that could be targets of small-molecule drugs.

PIK3CA, ARID1A, FBXW7, PTEN, and TP53 mutations have been reported relatively frequently in cervical cancer from other regions and are considered attractive targets for novel molecular-targeted drugs (26-30), which are expected to lead to improved treatment outcomes. However, the current study suggests that mutations in genes other than PIK3CA are rare in Okinawa. Therefore, establishing unique treatment strategies for cervical cancer is essential in this region.

Besides the studies compared in the present analysis, another report has identified PIK3CA as the most frequently mutated gene among all genomic alterations in cervical cancer (31). Based on the available evidence, PIK3CA mutations appear to be common in cervical cancer regardless of geographic region. It is noteworthy that while some genetic mutations show regional variations in frequency, others do not. Elucidating the underlying reasons for these differences may be an important focus of future research.

SCN7A was the most frequently mutated gene. SCN7A belongs to the SCN family, which plays a vital role in several pathophysiological processes of tumors by manipulating, cell proliferation, migration, and invasion (32). SCN7A is one of the key genes associated with colorectal cancer, and mutations in SCN7A worsen the prognosis of colorectal cancer (33). In recent years, SCN7A has attracted attention as a new biomarker of cancers, including gastric cancer (34), esophageal cancer (35), lung cancer (36), and hepatocellular carcinoma (32). However, no studies have reported the frequent detection of SCN7A mutations in cervical cancer, and the association between SCN7A mutations and prognosis has not been addressed. In the current study, the impact of SCN7A mutation on the prognosis of cervical cancer after definitive RT was not clarified. Furthermore, SCN7A mutations were detected in both SCC and AC. However, the differences in SCN7A mutations according to histopathological type remain unclear owing to the modest cohort size. Experiments with SiHa and HeLa cells have reported that overexpression of GPER1 has tumor-promoting effects in cervical SCC and tumor-suppressing effects in cervical AC, respectively, suggesting that identical alterations may have different effects depending on the histological subtype of cervical cancer (37). In the future, to clarify the role of SCN7A in cervical cancer, it will be necessary to evaluate its impact in both SCC and AC.

The frequency of USP6 mutations in cervical cancer has not been reported in studies performed in other regions. USP6 mutations were found in 13% of cases in the current study. USP6 encodes a deubiquitinating enzyme that plays critical roles in diverse cellular processes. Recent studies have demonstrated that USP6 promotes tumorigenesis through multiple pathways, including the Wnt, JAK1-STAT3, and c-Jun pathways (38,39). USP6 activity has been reported to be associated with the development of Ewing sarcoma (40), but the clinical impact of USP6 mutations on cervical cancer remains unknown.

In terms of treatment outcome, the 2-year LC of 82%, which was 10% lower than the 5-year LC of 92% reported in a global large-scale prospective observational study (41). The reason for the lower LC rate may be the difference in cumulative target dose, which was a median of 90 Gy (EQD2, α/β=10 Gy) in the prior study and 71.5 Gy in the current study. The reason for the lower target dose in the current study than in the prior study may be that the interstitial brachytherapy was not performed, and CT was used instead of magnetic resonance imaging as the imaging modality. Additionally, as shown in Table I, there may have been more slim patients in this study than the global standard. The small intestine tends to be located close to the uterus in slim patients (42). Thus, the prescribed radiation dose must be reduced to avoid high-dose exposure to the small intestine.

The small sample size (n=23) is the main limitation of this study. Therefore, the power of statistical analysis is limited, and the results should be interpreted with caution. In addition, this study was performed at a single institution, although this is uncontrollable given that our institution is the only one in Okinawa that offers definitive RT for cervical cancer. Nevertheless, the results of this study provide preliminary insight into the genomic profile of cervical cancer in Okinawa, which has not been reported previously. Although we acknowledge that the data from this study alone are not sufficient to draw definitive conclusions, the hypotheses generated by this study provide a basis for future studies with large cohorts.

As for other limitations, it was unclear whether all patients had their genetic origins in Okinawa, and patients who lived in Okinawa but were not genetically of Okinawan origin might have been included. However, Okinawa is an island located 800 km away from mainland Japan. Therefore, this geographical isolation makes it likely that the patient’s genetic origin was restricted to Okinawa. Only cases planned for definitive RT were included in the study; patients with FIGO stages IA and IV were excluded. Only gene mutations in tumor tissues were analyzed, and the comparison with normal tissues was absent. Therefore, it was not possible to be certain that the mutations were definitely somatic. Nevertheless, we believe that our decision on whether a mutation is significant was reasonable, because the decision was made referring to online databases and/or by comparing the tumor proportion in collected tissues with variant allele frequencies as in past similar studies; however, the results may have not been completely accurate.

In conclusion, NGS revealed that the genetic profile of cervical cancer may be unique in Okinawa. Further studies with larger sample sizes are warranted.

Conflicts of Interest

Kennosuke Karube received research grants from Eisai Co. Ltd. and Takeda Pharmaceuticals. Akihiro Nishie received a research grant from Canon Medical Systems Corporation. Both grants did not involve the submitted work. The Authors declare no competing interest.

Authors’ Contributions

Conceptualization, H.M., S.S. and K.K.; methodology, H.M., S.S. and K.K.; validation, H.M., S.S. and K.K.; formal analysis, H.M. and S.S.; investigation, H.M., S.S. and K.K.; resources, H.M., S.S., K.K., W.K., T.N., Y.T., Y.A., Y.S., N.A.; data curation, H.M. and S.S.; writing - original draft preparation, H.M.; writing - review and editing, S.S., K.K., W.K., T.N., Y.T., Y.A., Y.S., and A.N.; visualization, H.M.; supervision, K.K. and A.N.; project administration, H.M.; funding acquisition, H.M. All Authors have read and agreed to the published version of the manuscript.

Acknowledgements

The Authors thank Prof. Takuya Fukushima for kindly providing the research laboratory space and equipment.

Funding

This study was supported by the Japan Society for the Promotion of Science (JSJP) KAKENHI (grant number: JP20K16731).

Artificial Intelligence (AI) Disclosure

During the preparation of this manuscript, a large language model (ChatGPT, OpenAI) was used solely for language editing and stylistic improvements in select paragraphs. No sections involving the generation, analysis, or interpretation of research data were produced by generative AI. All scientific content was created and verified by the authors. Furthermore, no figures or visual data were generated or modified using generative AI or machine learning-based image enhancement tools.

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