Comprehensive profiling of actionable mutations in non-small cell lung cancer (NSCLC) is vital to guide targeted therapy, thereby improving the survival rate of patients. Despite the high incidence and mortality rate of NSCLC in Vietnam, the actionable mutation profiles of Vietnamese patients have not been thoroughly examined. Here, we employed massively parallel sequencing to identify alterations in major driver genes (EGFR, KRAS, NRAS, BRAF, ALK and ROS1) in 350 Vietnamese NSCLC patients. We showed that the Vietnamese NSCLC patients exhibited mutations most frequently in EGFR (35.4%) and KRAS (22.6%), followed by ALK (6.6%), ROS1 (3.1%), BRAF (2.3%) and NRAS (0.6%). Interestingly, the cohort of Vietnamese patients with advanced adenocarcinoma had higher prevalence of EGFR mutations than the Caucasian MSK-IMPACT cohort. Compared to the East Asian cohort, it had lower EGFR but higher KRAS mutation prevalence. We found that KRAS mutations were more commonly detected in male patients while EGFR mutations was more frequently found in female. Moreover, younger patients (<61 years) had higher genetic rearrangements in ALK or ROS1. In conclusions, our study revealed mutation profiles of 6 driver genes in the largest cohort of NSCLC patients in Vietnam to date, highlighting significant differences in mutation prevalence to other cohorts. Lung cancer is the most common malignancy and the leading cause of cancer related deaths worldwide (18.4% of total cancer deaths), with non-small cell lung cancer (NSCLC) being the most common subtype, accounting for approximately 85% of all diagnosed cases 1,2. The majority of NSCLC patients display advanced disease when diagnosed and thus have poor prognosis 2,3. It is well established that acquired genetic alterations in certain driver genes result in tumour growth and invasiveness, and that patients harboring certain mutations may benefit from targeted therapies 4,5. Indeed, a randomized clinical trial reported that advanced NSCLC patients harboring activating mutations in EGFR, one of the major driver genes of NSCLC, exhibited longer progression-free period when treated with a tyrosine kinase inhibitor (TKI), gefitinib, compared to those treated with standard platinum based chemotherapy 6. However, those who were treated with TKI drugs can acquire secondary resistant mutations, in which case a new treatment regimen is needed to maintain therapeutic effect 7,8. In addition to EGFR, NSCLC patients carrying ALK or ROS1 rearrangement were shown to respond well to a different TKI drug,

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.

24The under-representation of several ethnic groups in existing genetic databases and studies 25 have undermined our understanding of the genetic variations and associated traits or diseases 26 in many populations. Cost and technology limitations remain the challenges in performing large-27 scale genome sequencing projects in many developing countries, including Vietnam. As one of 28 the most rapidly adopted genetic tests, non-invasive prenatal testing (NIPT) data offers an 29 alternative untapped resource for genetic studies. Here we performed a large-scale genomic 30 analysis of 2,683 pregnant Vietnamese women using their NIPT data and identified a 31 comprehensive set of 8,054,515 single-nucleotide polymorphisms, among which 8.2% were 32 new to the Vietnamese population. Our study also revealed 24,487 disease-associated genetic 33 variants and their allele frequency distribution, especially 5 pathogenic variants for prevalent 34 genetic disorders in Vietnam. We also observed major discrepancies in the allele frequency 35 distribution of disease-associated genetic variants between the Vietnamese and other 36 populations, thus highlighting a need for genome-wide association studies dedicated to the 37 Vietnamese population. The resulted database of Vietnamese genetic variants, their allele 38 frequency distribution, and their associated diseases presents a valuable resource for future 39 genetic studies. 40

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.

Purpose: Accurate profiling of population-specific recessive diseases is essential for the design of cost-effective carrier screening programs. However, minority populations and ethnic groups, including Vietnamese, are still under-represented in existing genetic studies. Here we reported the first comprehensive study of recessive diseases in the Vietnamese population. Methods: Clinical exome sequencing (CES) data of 4,503 disease-associated genes obtained from a cohort of 985 Vietnamese individuals was analyzed to identify pathogenic variants, associated diseases and their carrier frequencies in the population. Results: Eighty-five recessive diseases were identified in the Vietnamese population, among which seventeen diseases had carrier frequencies of at least 1% (1 in 100 individuals). Three diseases were especially prevalent in the Vietnamese population with carrier frequencies of 2-12 times higher than in other East Asia or the world populations, including Beta-thalassemia (1 in 25), citrin deficiency (1 in 33) and phenylketonuria (1 in 40). Seven novel pathogenic and three likely pathogenic variants associated with nine recessive diseases were also discovered. Conclusions: The comprehensive profile of recessive diseases identified in this study shall enable the design of cost-effective carrier screening programs specific to the Vietnamese population. The newly discovered pathogenic variants may also exist in other populations at extremely low frequencies, thus representing a valuable resource for future research. Our study has demonstrated the advantage of population-specific genetic studies to advance the knowledge and practice of medical genetics. Keywords: carrier frequency; carrier screening; recessive diseases.

Accurate profiling of population‐specific recessive diseases is essential for the design of cost‐effective carrier screening programs. However, minority populations and ethnic groups, including Vietnamese, are still underrepresented in existing genetic studies. Here, we reported the first comprehensive study of recessive diseases in the Vietnamese population. Clinical exome sequencing data of 4503 disease‐associated genes obtained from a cohort of 985 Vietnamese individuals was analyzed to identify pathogenic variants, associated diseases and their carrier frequencies in the population. A total of 118 recessive diseases associated with 164 pathogenic or likely pathogenic variants were identified, among which 28 diseases had carrier frequencies of at least 1% (1 in 100 individuals). Three diseases were prevalent in the Vietnamese population with carrier frequencies of 2–12 times higher than in the world populations, including beta‐thalassemia (1 in 23), citrin deficiency (1 in 31), and phenylketonuria (1 in 40). Seven novel pathogenic and two likely pathogenic variants associated with nine recessive diseases were discovered. The comprehensive profile of recessive diseases identified in this study enables the design of cost‐effective carrier screening programs specific to the Vietnamese population.

Background: The under-representation of Vietnamese ethnic groups in existing genetic databases and studies have undermined our understanding of the genetic variations and associated traits or diseases in the population. Cost and technology limitations remain the challenges in performing large-scale genome sequencing projects in Vietnam and many developing countries. Non-invasive prenatal testing (NIPT) data offers an alternative untapped resource to study genetic variations in the Vietnamese population. Results: We analyzed the low-coverage genomes of 2,683 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 five 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. Conclusions: We have demonstrated a successful analysis of NIPT data to reconstruct the Vietnamese genetic profiles. This application provides a powerful yet cost-effective approach for large-scale population genetic studies.

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