Shu-Jen Chen

Hepatocellular carcinoma (HCC) is characterized by a notable sex disparity in incidence and tumor aggressiveness. Revealing differences in genetic landscapes between male and female HCCs may expand the understanding of sexual disparities mechanisms and assist the development of precision medicine. Although reports on the sex disparity of HCC are accumulated, studies focusing on sex-related biomarkers among Asian populations remain limited. Here, we conducted a comprehensive genomic profiling analysis to explore differences between male and female patients within a cohort of 195 Taiwanese HCC patients. We did not detect any sex-biased genomic alterations. However, when our investigation extended to the TCGA dataset, we found higher frequencies of gene copy gains in CCNE2 and mutations in CTNNB1 and TP53 among male patients. Besides, we further evaluated the associations between genomic alterations and patients’ prognosis by sex. The results showed that female patients harboring tumors with STAT3 gain and alterations in the JAK–STAT pathway displayed a poor prognosis. These two factors remained independently associated with unfavorable prognosis even after adjusting for the patient’s age and stage characteristics (Hazard ratio = 10.434, 95% CI 3.331–32.677, P < 0.001; Hazard ratio = 2.547, 95% CI 1.195–5.432, P = 0.016, respectively). In summary, this study provides valuable insights into understanding sex disparity in HCC in the East Asian population. Validation through larger cohorts and extensive sequencing efforts is warranted.

Rationale: The diagnosis of anaplastic lymphoma kinase (ALK)-negative inflammatory myofibroblastic tumors (IMT) remains challenging because of their morphological resemblance with spindle cell sarcoma with myofibroblastic characteristics. Patient concerns: A 69-year-old female patient presented with loco-regional recurrent IMT several times within 8 years after primary treatment and neck lymph node metastasis 3.5 years after last recurrence. Diagnosis: The primary, recurrence, and lymph node metastasis lesions were diagnosed as ALK-negative IMTs based on the histopathological features. Interventions: Biopsy samples were obtained during repeated surgeries and evaluated for genomic alterations during first and recurrent presentations. The evaluation was done using pathway-driven massive parallel sequencing, and genomic alterations between primary and recurrent tumors were compared. Outcomes: Copy number gains and overexpression of mouse double minute 2 homolog (MDM2) and cyclin dependent kinase 4 (CDK4) were observed in the primary lesion, and additional gene amplification of Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2), Succinate Dehydrogenase Complex II subunit C (SDHC), and thyroid stimulating hormone receptor (TSHR) Q720H were found in the recurrent tumors. Metastases to the neck lymph node were observed 3.5 years after recurrence. Lessons: Our results indicated genetic evolution in a microscopically benign condition and highlighted the importance of molecular characterization of fibro-inflammatory lesions of uncertain malignant potential.

(1) Background: Bevacizumab-based regimens are a standard treatment for metastatic colorectal cancer (mCRC) patients, however meaningful clinical biomarkers for treatment benefit remain scarce. (2) Methods: Tumor samples from 36 mCRC patients treated with bevacizumab-based chemotherapy underwent comprehensive genomic profiling. Alterations in frequently altered genes and important signaling pathways were correlated with progression-free survival (PFS). (3) Results: Overall genetic alteration analysis of investigated genes and pathways did not identify promising new predictors of PFS. However, when considering mutation subtypes, TP53 DNA binding domain (DBD) missense mutations were associated with prolonged PFS (HR, 0.41; 95% CI, 0.13−0.65; p = 0.005). In contrast, TP53 truncating mutations were associated with short PFS (HR, 2.95; 95% CI, 1.45−27.50; p = 0.017). Importantly, neither TP53 mutation subtype was associated with overall response rate. In multivariate analysis, TP53 DBD missense mutations remained an independent PFS predictor (HR, 0.31; 95% CI, 0.13–0.77; p = 0.011). The other genetic factor independently associated with PFS were PTPRT/PTPRD deleterious alterations, which we previously identified in a screen for biomarkers of bevacizumab response. (4) Conclusions: TP53 DBD missense mutations may predict prolonged PFS in mCRC patients treated with bevacizumab-based therapy. Analyses of TP53 mutations as clinical biomarkers should take the biological impact of different mutation subtypes into consideration to improve patient stratification.

Targeted next-generation sequencing reveals recurrence-associated genomic alterations in early-stage non-small cell lung cancer Targeted next-generation sequencing reveals recurrence-associated genomic alterations in early-stage non-small cell lung cancer

Background: Bevacizumab-based regimens are used as standard treatments for colorectal cancer. Unfortunately, there are no established predictive markers for bevacizumab response. Methods: Tumor samples from 36 metastatic colorectal cancer patients treated with bevacizumab plus chemotherapy were analyzed by next-generation sequencing of all coding exons of more than 400 genes. Single gene and signaling pathway analyses were performed to correlate genomic data with response. Results: Among the genes most frequently mutated in our cohort, only mutations in PTPRT, a phosphatase involved in JAK/STAT signaling, were associated with response status, with deleterious mutations being enriched in non-responders. Pathway analysis revealed that deleterious mutations in genes of the JAK/STAT pathway, namely in PTPRT and the related gene PTPRD, correlated with resistance. Mutations in RTK/PI3K/RAS, Wnt and TGFβ pathways did not associate with response. Lack of response was observed in all patients with deleterious mutations or copy number loss of PTPRT/PTPRD (n = 10), compared to only 30.8% (n = 8) of patients without such alterations (relative risk, 3.25; 95% CI, 1.83–5.79, p = 0.0003). Similarly, PTPRT/PTPRD deleterious alterations were associated with shorter progression-free survival, an association that was retained in multivariate analysis (HR, 3.33; 95% CI, 1.47–7.54; p = 0.0038). Conclusion: Deleterious alterations in PTPRT/PTPRD are potential biomarkers for bevacizumab resistance.

3022 Background: Immunologic checkpoint blockade with antibodies that target CTLA-4 or PD-1/PD-L1 have demonstrated promise in a variety of malignancies. However, the treatment response rate of these immunologic checkpoint blockades remains low. Identifying predictive biomarkers to assist patient selection for immunotherapy have become a priority in both clinical and research settings. Methods: Mutations in patients who responded to immunotherapy were identified by Next-Generation Sequencing (NGS). Relationship between mutation of PRKDC, mutation load and known immune biomarkers were analyzed using datasets from The Cancer Genome Atlas (TCGA). Following up, the PRKDC protein expression was evaluated in 439 gastric cancer patients by immunohistochemical staining and their MSI statuses were evaluated by PCR. Results: We first identified PRKDC mutations in two responders to immune checkpoint therapy (1 HCC, 1 gastric cancer). From published literature, we further discovered that 66.7% (2/3) of lung cancer patients and 63.6% (7/11) of melanoma patients whose tumor harbored PRKDC mutation and responded to immunotherapy. Most of these mutations detected in responders were either truncating or located in functional domains. Further analysis showed that PRKDC mutation is significantly associated with high mutation load in cervical cancer, colon adenocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, gastric adenocarcinoma and endometrial cancer ( p= 0.008, p= 0.0108, p= 0.0166, p= 0.0183, p< 0.001 and p< 0.001, respectively). Interestingly, gastric cancer patients harboring PRKDC mutations or with MSI-H demonstrated significantly higher gene expression in PDL1, TIM3, LAG3, IFNG, CXCL9, CXCL10, GZMA and PRF1, compared to MSS patients ( p= 0.0016, p= 0.0142, p= 0.0017, p= 0.0034, p= 0.0118, p< 0.0001, p= 0.0001, p< 0.0102, respectively). Finally, we discovered low expression of PRKDC was a poor prognostic factor and significantly correlated with MSI-H in gastric cancers. Conclusions: PRKDC may be a potential biomarker that can identify responders to immune checkpoint inhibition.

Oncotarget | https://doi.org/10.18632/oncotarget.13456 Angel Chao, Ting-Chang Chang, Nina Lapke, Shih-Ming Jung, Peter Chi, Chien-Hung Chen, Lan-Yan Yang, Cheng-Tao Lin, Huei-Jean Huang, Hung-Hsueh Chou, Jui-Der... Prevalence and Clinical Significance of BRCA1/2 Germline and Somatic Mutations in Taiwanese Patients with Ovarian Cancer

Missense mutations in the TP53 DNA-binding domain predict outcomes in patients with advanced oral cavity squamous cell carcinoma

Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic colorectal cancer patients