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Background De novo variations are a primary cause of Rett syndrome and Tubulinopathy, accounting for over 90% of cases. Some studies have identified and documented parental inheritance by mosaicism in these two disorders, albeit with limited data. Methods Clinical characteristics and diagnosis, including genetic tests of members of two families, were obtained from medical reports. Results The first family with Rett syndrome (RTT) presented with two offspring carrying FOXG1 c.460dup. Both affected RTT pregnancies did not show anomalies within the first trimester, preventing prenatal recognition at an early stage. The second family had two of three offspring confirmed with TUBA1A c.172G>A related to Tubulinopathy. Both young couples from the two families harbored none of the variants correlating to their children's conditions. Diagnosis of parental mosaics with higher rates of recurrence was reasonably determined, and genetic counseling played a major role in guiding and managing their subsequent pregnancies. Conclusion In genetic disorders with a high penetration of de novo variants, the risk of having a recurrent baby is an important topic to discuss with affected families. By examining variants that siblings share, clinical diagnosis can offer valuable information about the presence of mosaic inheritance. To effectively manage in the long term, adequate genetic counseling and strategic planning for future pregnancies should be emphasized to mitigate the risk of recurrent offspring.

The identification and quantification of actionable mutations are of critical importance for effective genotype-directed therapies, prognosis and drug response monitoring in patients with non-small-cell lung cancer (NSCLC). Although tumor tissue biopsy remains the gold standard for diagnosis of NSCLC, the analysis of circulating tumor DNA (ctDNA) in plasma, known as liquid biopsy, has recently emerged as an alternative and noninvasive approach for exploring tumor genetic constitution. In this study, we developed a protocol for liquid biopsy using ultra-deep massively parallel sequencing (MPS) with unique molecular identifier tagging and evaluated its performance for the identification and quantification of tumor-derived mutations from plasma of patients with advanced NSCLC. Paired plasma and tumor tissue samples were used to evaluate mutation profiles detected by ultra-deep MPS, which showed 87.5% concordance. Cross-platform comparison with droplet digital PCR demonstrated comparable detection performance (91.4% concordance, Cohen's kappa coefficient of 0.85 with 95% CI = 0.72-0.97) and great reliability in quantification of mutation allele frequency (Intraclass correlation coefficient of 0.96 with 95% CI = 0.90-0.98). Our results highlight the potential application of liquid biopsy using ultra-deep MPS as a routine assay in clinical practice for both detection and quantification of actionable mutation landscape in NSCLC patients.

Background Non-invasive multi-cancer early detection (MCED) tests have shown promise in enhancing early cancer detection. However, their clinical utility across diverse populations remains underexplored, limiting their routine implementation. This study aims to validate the clinical utility of a multimodal non-invasive circulating tumor DNA (ctDNA)-based MCED test, SPOT-MAS (Screening for the Presence Of Tumor by DNA Methylation And Size). Methods We conducted a multicenter prospective study, K-DETEK (ClinicalTrials.gov identifier: NCT05227261), involving 9057 asymptomatic individuals aged 40 years or older across 75 major hospitals and one research institute in Vietnam. Participants were followed for 12 months. Results Of the 9024 eligible participants, 43 (0.48%) tested positive for ctDNA. Among these, 17 were confirmed with malignant lesions in various primary organs through standard-of-care (SOC) imaging and biopsy, with 9 cases matching our tissue of origin (TOO) predictions. This resulted in a positive predictive value of 39.53% (95%CI 26.37–54.42) and a TOO accuracy of 52.94% (95%CI 30.96–73.83). Among the 8981 participants (99.52%) who tested negative, 8974 were confirmed cancer-free during a 12-month period after testing, yielding a negative predictive value of 99.92% (95% CI 99.84–99.96). The test demonstrated an overall sensitivity of 70.83% (95%CI 50.83–85.09) and a specificity of 99.71% (95% CI 99.58–99.80) for detecting various cancer types, including those without SOC screening options. Conclusions This study presents a prospective validation of a multi-cancer early detection (MCED) test conducted in a lower middle-income country, demonstrating the potential of SPOT-MAS for early cancer detection. Our findings indicate that MCED tests could be valuable additions to national cancer screening programs, particularly in regions where such initiatives are currently limited. Trial registration ClinicalTrials.gov ID: NCT05227261. Date of registration: 07/02/2022.

Background Late detection of hepatocellular carcinoma (HCC) results in an overall 5-year survival rate of less than 16%. Liquid biopsy (LB) assays based on detecting circulating tumor DNA (ctDNA) might provide an opportunity to detect HCC early noninvasively. Increasing evidence indicates that ctDNA detection using mutation-based assays is significantly challenged by the abundance of white blood cell-derived mutations, non-tumor tissue-derived somatic mutations in plasma, and the mutational tumor heterogeneity. Methods Here, we employed concurrent analysis of cancer-related mutations, and their fragment length profiles to differentiate mutations from different sources. To distinguish persons with HCC (PwHCC) from healthy participants, we built a classification model using three fragmentomic features of ctDNA through deep sequencing of thirteen genes associated with HCC. Results Our model achieved an area under the curve (AUC) of 0.88, a sensitivity of 89%, and a specificity of 82% in the discovery cohort consisting of 55 PwHCC and 55 healthy participants. In an independent validation cohort of 54 PwHCC and 53 healthy participants, the established model achieved comparable classification performance with an AUC of 0.86 and yielded a sensitivity and specificity of 81%. Conclusions Our study provides a rationale for subsequent clinical evaluation of our assay performance in a large-scale prospective study.

Targeted therapy with tyrosine kinase inhibitors (TKI) provides survival benefits to a majority of patients with non-small cell lung cancer (NSCLC). However, resistance to TKI almost always develops after treatment. Although genetic and epigenetic alterations have each been shown to drive resistance to TKI in cell line models, clinical evidence for their contribution in the acquisition of resistance remains limited. Here, we employed liquid biopsy for simultaneous analysis of genetic and epigenetic changes in 122 Vietnamese NSCLC patients undergoing TKI therapy and displaying acquired resistance. We detected multiple profiles of resistance mutations in 51 patients (41.8%). Of those, genetic alterations in EGFR , particularly EGFR amplification (n = 6), showed pronounced genome instability and genome-wide hypomethylation. Interestingly, the level of hypomethylation was associated with the duration of response to TKI treatment. We also detected hypermethylation in regulatory regions of Homeobox genes which are known to be involved in tumor differentiation. In contrast, such changes were not observed in cases with MET (n = 4) and HER2 (n = 4) amplification. Thus, our study showed that liquid biopsy could provide important insights into the heterogeneity of TKI resistance mechanisms in NSCLC patients, providing essential information for prediction of resistance and selection of subsequent treatment.

In Vietnam, colorectal cancer is one of the top diagnosed cancers, with 5–10% originating from inherited mutations. This study aims to define the mutation spectrum associated with hereditary colorectal cancer syndromes (HCCS) in Vietnam, evaluate the influence of genetic testing on carriers’ awareness, and also investigate the barriers in familial testing. Genetic test reports were collected to identify HCCS cases, then cases underwent a survey investigating self-risk and familial-risk awareness, proactive cancer screening, and familial testing barriers. Participant characteristics, mutation prevalence, and results from the survey were descriptively analyzed and reported. Of all genetic test results, 3% (49/1632) were identified with mutations related to HCCS. Over 77% of them belonged to Lynch syndrome. PMS2 appeared to be the gene with the highest mutation frequency, while MLH1 was the lowest. 44% of cases further undertook cancer screening tests, and 48% of cases' families had uptake genetic testing. The biggest barrier of familial members for not taking genetic test was psychological reasons (fear, not being interested, or not feeling necessary). This study provided new evidence for HCCS mutation spectrum in Vietnamese population and the success in promoting cascade test in high-risk family members through financial and technical support. Also, study has suggested the needs of an innovative genetic testing process focusing on the quality of pre-and post-test consultancy, an increase in follow-ups, and the change in policy for permission of contacting relatives directly to improve the rate of cascade testing and proactive cancer screening.

Breast cancer is the leading cause of cancer death in Vietnamese women, but its mutational landscape and actionable alterations for targeted therapies remain unknown. After treatment, a sensitive biomarker to complement conventional imaging to monitor patients is also lacking. In this prospective multi‐center study, 134 early‐stage breast cancer patients eligible for curative‐intent surgery were recruited. Genomic DNA from tumor tissues and paired white blood cells were sequenced to profile all tumor‐derived mutations in 95 cancer‐associated genes. Our bioinformatic algorithm was then utilized to identify top mutations for individual patients. Serial plasma samples were collected before surgery and at scheduled visits after surgery. Personalized assay tracking the selected mutations were performed to detect circulating tumor DNA (ctDNA) in the plasma. We found that the mutational landscape of the Vietnamese was largely similar to other Asian cohorts, showing higher TP53 mutation frequency than in Caucasians. Alterations in PIK3CA and PI3K signaling were dominant, particularly in our triple‐negative subgroup. Using top‐ranked mutations, we detected ctDNA in pre‐operative plasma in 24.6–43.5% of the hormone‐receptor‐positive groups and 76.9–80.8% of the hormone‐receptor‐negative groups. The detection rate was associated with breast cancer subtypes and clinicopathological features that increased the risk of relapse. Interim analysis after a 15‐month follow‐up revealed post‐operative detection of ctDNA in all three patients that had recurrence, with a lead time of 7–13 months ahead of clinical diagnosis. Our personalized assay is streamlined and affordable with promising clinical utility in residual cancer surveillance. We also generated the first somatic variant dataset for Vietnamese breast cancer women that could lay the foundation for precision cancer medicine in Vietnam. The authors determine, for the first time, the somatic variant landscape of Vietnamese women with breast cancer, and establish a personalized tumor‐informed assay (K‐Track®) to detect ctDNA in liquid biopsy. This assay is streamlined and affordable, with promising clinical utilities in both residual cancer surveillance and actionable mutation profiling for breast cancer patients.

The under-representation of several ethnic groups in existing genetic databases and studies have undermined our understanding of the genetic variations and associated traits or diseases in many populations. Cost and technology limitations remain the challenges in performing large-scale genome sequencing projects in many developing countries, including Vietnam. As one of the most rapidly adopted genetic tests, non-invasive prenatal testing (NIPT) data offers an alternative untapped resource for genetic studies. Here we performed a large-scale genomic analysis of 2683 pregnant Vietnamese women using their NIPT data and identified a comprehensive set of 8,054,515 single-nucleotide polymorphisms, among which 8.2% were new to the Vietnamese population. Our study also revealed 24,487 disease-associated genetic variants and their allele frequency distribution, especially 5 pathogenic variants for prevalent genetic disorders in Vietnam. We also observed major discrepancies in the allele frequency distribution of disease-associated genetic variants between the Vietnamese and other populations, thus highlighting a need for genome-wide association studies dedicated to the Vietnamese population. The resulted database of Vietnamese genetic variants, their allele frequency distribution, and their associated diseases presents a valuable resource for future genetic studies.

The clinical utilization of circulating tumor DNA (ctDNA) in breast cancer (BC) management is not well-defined. In this prospective study, 168 patients with early-stage BC were recruited, serial blood samples were collected before and after surgery. Tumor-informed ctDNA testing was performed, which sequenced tumors for 95 genes followed by bespoke mPCR to track 1–9 mutations in the plasma. ctDNA was detected before surgery in 14.6%, 40.0%, 83.8%, and 80.0% of HR+ low-risk, HR+ high-risk, HR-HER2+ and HR-HER2- patients, respectively. Pre-operative ctDNA positivity was significantly associated with decreased disease-free survival (DFS) (adjusted HR = 3.09, 95% CI 2.65–80.0, p  = 0.001). After a median 26.6-month follow-up, 11 patients relapsed, and ctDNA at landmark time point 2–4 weeks after surgery was detected in 50.0% (5/10) of cases. Landmark ctDNA clearance was associated with significantly longer DFS ( p  = 0.0009) and positive ctDNA persistence after adjuvant therapy occurred in 36.4% (4/11) of stage-III patients. During surveillance, ctDNA detection had 90.9% sensitivity and 98.8% specificity to predict recurrence, and median lead time of 9.7 months. Patients with detected ctDNA had shorter DFS than those with undetectable ctDNA (adjusted HR = 207.05, 95% CI 41.38- > 1000, p  = 0.001). Therefore, ctDNA status both before and after surgery could help stratify recurrence risk for BC patients.