Kohei Nakamura

Clinical Sequence Revealed the Prevalence and Biological Significance of Somatic Pathogenic Variants in Thoracic Cancer: Implications for Germline Status

Transcriptome Concordance Between Borderline Tumors and Endometrioid Carcinoma: An Integrative Genomic Analysis

ABSTRACTBackgroundBorderline ovarian tumors (BOTs) differ from ovarian carcinomas in their clinical presentation and behavior, yet their molecular characteristics remain poorly understood. This study aims to address this gap by integrating whole‐exome sequencing (WES) and RNA sequencing (RNA‐seq) to compare BOTs with high‐grade serous carcinoma (HGSC), endometrioid carcinoma (EC), and clear‐cell carcinoma (CCC).ObjectiveTo elucidate the molecular features of BOTs and evaluate their similarities and differences in comparison to HGSC, EC, and CCC.MethodsThe study analyzed 44 ovarian tumor samples, employing WES to identify genomic alterations and RNA‐seq to examine transcriptomic profiles. Comparative analyses were conducted to investigate the molecular relationships among the tumor types.ResultsThe genomic analysis revealed that BOTs share significant similarities with EC. Furthermore, the transcriptomic data highlighted a novel and substantial similarity between BOTs and EC, suggesting deeper biological linkages, including potentially shared oncogenic pathways or tumor microenvironmental factors. These findings challenge traditional classifications and suggest a closer molecular alignment of BOTs with EC than previously understood.ConclusionsThis study provides new insights into the molecular characteristics of BOTs, demonstrating their significant resemblance to EC at both the genomic and transcriptomic levels. These results underscore the potential need to reconsider the molecular classification of ovarian tumors and open new avenues for research into the pathogenesis and treatment strategies for BOTs.

Coexistence of complete intestinal tract, prostatic tissue, prostatic urethra and bladder structure in ovarian mature cystic teratoma: a case report

Mature cystic teratomas (MCTs) of the ovary comprise tissues from all three germ layers. The coexistence of the complete intestinal tract, prostatic tissue, and bladder component within the same ovarian MCT is unprecedented. Here, we report the diagnosis and management of such a rare case. A 26-year-old woman presented with a right ovarian mass, which was later confirmed as an MCT by histopathological examination. The patient underwent a successful laparoscopic cystectomy with no evidence of malignancy or postoperative complications. Histological examination revealed that this MCT contained the complete organ structures including a lower intestinal tract and male genital tract with prostate, urethra, and bladder components, which is unusual. This case underscores the importance of understanding the pathogenesis of extensive organogenesis in MCTs and raises questions about the differentiation processes leading to such unique presentations.

Genetic Profiling of Sebaceous Carcinoma Arising from an Ovarian Mature Teratoma: A Case Report

Ovarian mature teratomas (OMTs) originate from post-meiotic germ cells. Malignant transformation occurs in approximately 1–2% of OMTs; however, sebaceous carcinoma arising from OMTs is rare. This is the first report of a detailed genomic analysis of sebaceous carcinoma arising from an OMT. A 36-year-old woman underwent evaluation for abdominal tumors and subsequent hysterectomy and salpingo-oophorectomy. Pathologically, a diagnosis of stage IA sebaceous carcinoma arising from an OMT was established. Eight months post-surgery, the patient was alive without recurrence. Immunohistochemically, the tumor was negative for mismatch repair proteins. A nonsense mutation in TP53 (p.R306*) and a deletion in PIK3R1 were identified. Single nucleotide polymorphisms across all chromosomes displayed a high degree of homozygosity, suggestive of uniparental disomy. Herein, the OMT resulting from the endoreduplication of oocytes underwent a malignant transformation to sebaceous carcinoma via TP53 as an early event and PIK3R1 as a late event.

BRCA1/2 reversion mutations in a pan‐cancer cohort

AbstractTumor sensitivity to platinum (Pt)‐based chemotherapy and poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors is increased by homologous recombination deficiency‐causing mutations; in particular, reversion mutations cause drug resistance by restoring protein function. Treatment response is predicted by breast cancer susceptibility gene 1/2 (BRCA1/2) mutations; however, BRCA1/2 reversion mutations have not been comprehensively studied in pan‐cancer cohorts. We aimed to characterize BRCA1/2 reversion mutations in a large pan‐cancer cohort of Japanese patients by retrospectively analyzing sequencing data for BRCA1/2 pathogenic/likely pathogenic mutations in 3738 patients with 32 cancer types. We identified somatic mutations in tumors or circulating cell‐free DNA that could restore the ORF of adverse alleles, including reversion mutations. We identified 12 (0.32%) patients with somatic BRCA1 (n = 3) and BRCA2 (n = 9) reversion mutations in breast (n = 4), ovarian/fallopian tube/peritoneal (n = 4), pancreatic (n = 2), prostate (n = 1), and gallbladder (n = 1) cancers. We identified 21 reversion events—BRCA1 (n = 3), BRCA2 (n = 18)—including eight pure deletions, one single‐nucleotide variant, six multinucleotide variants, and six deletion–insertions. Seven (33.3%) reversion deletions showed a microhomology length greater than 1 bp, suggesting microhomology‐mediated end‐join repair. Disease course data were obtained for all patients with reversion events: four patients acquired mutations after PARP‐inhibitor treatment failure, two showed somatic reversion mutations after disease progression, following Pt‐based treatment, five showed mutations after both treatments, one patient with pancreatic cancer and BRCA1 reversion mutations had no history of either treatment. Although reversion mutations commonly occur in BRCA‐associated cancers, our findings suggest that reversion mutations due to Pt‐chemotherapy might be correlated with BRCA1/2‐mediated tumorigenesis even in non‐BRCA‐associated histologies.

CXCL9 and CXCL13 shape endometrial cancer immune‐activated microenvironment via tertiary lymphoid structure formation

AbstractImmune checkpoint inhibitor (ICI) therapy has been successfully applied to various cancers; however, not all patients respond to ICI therapy. Tumors with an immune‐activated environment are highly responsive to ICIs. To identify the cells and molecules essential to the formation of an immune‐activated cancer microenvironment, we focused on the tertiary lymphoid structure (TLS) and performed histological and genomic analyses using endometrial cancer material. In the high immunogenic group, numerous TLSs were observed, and CXCL9 and CXCL13 expression was markedly increased. CXCL9‐positive antigen‐presenting and CXCL13‐positive follicular dendritic cells were distributed in the T‐ and B‐cell zones of TLSs, respectively. A group of molecules whose expression was upregulated along with CXCL9 and CXCL13 expression was strongly associated with cellular immunity. These results suggest that CXCL9‐expressing antigen‐presenting cells and CXCL13‐expressing follicular dendritic cells coordinately shape the immune‐activated microenvironment through TLS formation. The current findings will contribute to a better understanding of the mechanisms underlying the activated cancer immune microenvironment, thereby advancing the field of precision cancer medicine.

Prognostic Biomarker of Fertility‐Preserving Hormonal Therapy Based on Multigene Panel Testing for Endometrial Cancer

ABSTRACT In this study, we identified prognostic biomarkers that predict treatment outcome in patients receiving fertility‐preserving high‐dose medroxyprogesterone acetate (MPA) therapy through comprehensive multigene panel testing. A total of 38 patients (20 atypical endometrial hyperplasia and 18 stage IA G1 without myometrial invasion) who received first‐line MPA therapy were enrolled. Genomic DNA was extracted from formalin‐fixed paraffin‐embedded samples, and PleSSision‐Rapid multigene panel testing was performed. Of the 38 patients, 31 (82%) achieved complete response (CR), 2 (5%) had stable disease (SD), and 5 (13%) had progressive disease (PD) following initial treatment. The median duration to achieve tumor disappearance was 7 months (range: 4–14 months). Following initial treatment, 25 of 32 patients (78%) experienced recurrence, with a median recurrence‐free survival (RFS) of 21 months (range: 2–84 months). The most frequently observed actionable gene mutations were PTEN (68.4%), CTNNB1 (55.2%), and PIK3CA (33.3%). Patients harboring PTEN mutations in EMG1 required a significantly longer duration to achieve tumor disappearance ( p  = 0.011). In addition, the presence of PIK3CA mutations in AEH was significantly associated with shorter RFS ( p  = 0.048). Molecular classification identified 34 patients (89%) with no specific molecular profile (NSMP), 1 patient (3%) with POLE mutation, and 3 patients (8%) with deficient mismatch repair (d‐MMR). Most patients undergoing MPA therapy were classified as having NSMP. Genetic alterations, specifically mutations in PTEN and PIK3CA , were significantly associated with treatment outcomes, highlighting their potential as prognostic biomarkers.

Clinical availability and characteristics of multigene panel testing for recurrent/advanced gynecologic cancer

Japan's health insurance covers multigene panel testing. This study aimed to determine the potential availability and utility of gene panel testing clinically in gynecologic oncology. We analyzed the characteristics of patients with gynecologic cancer who underwent gene panel testing using FoundationOne Out of 102 patients analyzed, 32, 18, 43, 8, and 1 had cervical, endometrial, ovarian cancers, sarcoma, and vaginal cancer, respectively. Druggable gene alteration was found in 70 patients (68.6%; 21 with cervical cancer, 15 with endometrial cancer, 28 with ovarian cancer, 5 with sarcoma, and 1 with other). The most common druggable gene alteration was PIK3CA mutation (n = 21), followed by PTEN mutation (n = 12) and high tumor mutation burden (TMB-H) (n = 11). TMB-H was detected in 5 patients with cervical cancer, 5 with endometrial cancer, and 1 with endometrial stromal sarcoma. Eleven patients (10.8%) received molecularly targeted therapy according to their gene aberrations. Gene panel testing was mostly performed when the second-line treatment was ineffective. Of all 102 patients, 60 did not have recommended treatment, and 15 died or had worsened conditions before obtaining the test results. Through multigene panel testing, although many patients had druggable gene alterations, 10.8% of them received the recommended treatment. TMB-H was mainly observed in cervical/endometrial cancer, suggesting its potential as a therapeutic biomarker of immune checkpoint inhibitors. Furthermore, patients' prognosis and performance status should be considered before performing the test.