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Objective: The aim of this study is to delineate the molecular classification features within Chinese endometrial cancer (EC) patients and to evaluate the concurrence between two widely employed methods for diagnosing EC molecular subtypes., Methods: This retrospective observational cohort study encompassed 479 cases of EC for analysis. Utilizing next-generation sequencing (NGS) panels targeting POLE, TP53, and microsatellite instability (MSI) status, four subtypes [POLE ultramutated (POLE mut), MMR-deficient (MMRd), p53 abnormal (p53abn), and no specific molecular profile (NSMP)] were classified. Immunohistochemistry (IHC) was employed to ascertain the expression of p53 and MMR proteins., Results: Among the 479 patients, the distribution of EC subtypes was as follows: 28 (5.85%) POLE mut, 67 (13.99%) MMRd, 60 (12.53%) p53abn, and 324 (67.64%) NSMP. When compared to published findings on EC subtypes in the Caucasian population, our real-world data on Chinese ECs revealed a notably higher proportion of NSMP/CNL (copy number low). The evaluation of MSI/MMR status through NGS-based and IHC-based methods displayed substantial concordance (Kappa = 0.91). Slight discordance between the two techniques in identifying p53 abnormalities (Kappa = 0.83) might stem from TP53 truncating mutations, cytoplasmic p53 expression, null TP53 mutants, and well-documented challenges in interpreting p53 IHC., Conclusions: Chinese ECs exhibit distinctive molecular attributes. For accurate molecular subtyping of Chinese ECs, additional molecular markers that align with the Chinese population's characteristics should be incorporated into existing classifiers. The study's outcomes underscore a strong agreement between NGS and IHC in TP53/p53 detection and MSI assessment., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Premature ovarian insufficiency (POI) is a clinical syndrome occurring in women before 40 with decreased ovarian function. Up to 25% of POI cases result from genetic factors that remain largely unknown. The Excision repair cross-complementing, group 6 (ERCC6) variant has been found to cause POI, which is hardly ever diagnosed in adolescents., Methods: Whole-exome sequencing was performed on a 19-year-old proband with non-syndromic POI and her parents. Sanger sequencing was used to confirm the identified variant. The effect of the variant on the protein was analyzed in silico and Swiss-MODEL., Results: A novel heterozygous missense variant, c.2444G > A (p. GLy815Asp) of ERCC6 was identified in the proband who inherited the variant from her father. The variant was confirmed in another POI patient from the pedigree and was absent in the proband's mother and sister who presented normally. In silico analysis predicted this variant was deleterious. Swiss-Model revealed that the mutant amino acid formed multiple H-bonds with adjacent residues, which may lead to a dysfunction of ERCC6 protein., Conclusion: We firstly diagnosed an adolescent POI case associated with a novel heterozygous ERCC6 variant. The results expanded the variants spectrum of ERCC6 and provided guidance for POI diagnosis and genetic counselling., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Purpose: To identify the disease-causing genes of Chinese Han women with idiopathic premature ovarian insufficiency (POI)., Methods: Seventy-four Chinese Han women with idiopathic POI were collected to analyze the genetic etiology. Triplet repeat-primed polymerase chain reaction (TP-PCR) was performed to screen the FMR1 (CGG)n premutation, and then 60 POI-related genes were sequenced by targeted next-generation sequencing (NGS) in POI patients with normal FMR1., Results: A total of one patient (1/74) with FMR1 premutation was identified. Targeted NGS revealed that 15.07% (11/73) patients had pathogenic or likely pathogenic variants of Mendelian genes (FOXL2, EIF2B2, CYP17A1, CLPP, MCM9, GDF9, MSH5, ERCC6, POLG). Ten novel variants in six Mendelian genes were identified, such as CLPP c.355A>C (p.I119L) and c.688A>C (p.M230L), MCM9 c.1157C>T (p.T386M) and c.1291A>G (p.M431V), GDF9 c. 238C>T (p.Q80X), MSH5 c.604G>C (p.G202R) and c.2063T>C (p.I688T), ERCC6 c.C1769C>T (p.P590L), POLG c.2832G>C (p.E944D), and c.2821A>G (p.I941V)., Conclusion: This study suggested targeted NGS was an efficient etiologic test for idiopathic POI patients without FMR1 premutation and enriched the variant spectrum of POI-related genes.

Background: The increasing molecular characterization of colorectal cancers (CRCs) has spurred the need to look beyond RAS, BRAF, and microsatellite instability (MSI). Genomic alterations, including ERBB2 amplifications and mutations, POLE mutations, MSI, and NTRK1-3 fusions, have emerged as targets for matched therapies. We sought to study a clinically annotated Chinese cohort of CRC subjected to genomic profiling to explore relative target frequencies., Methods: Tumor and matched whole blood were collected from 609 Chinese patients with CRC. Extracted DNA was analyzed for all classes of genomic alterations across 450 cancer-related genes, including single-nucleotide variations (SNVs), short and long insertions and deletions (indels), copy number variations, and gene rearrangements. Next-generation sequencing-based computational algorithms also determined tumor mutational burden and MSI status., Results: Alterations in TP53 (76%), APC (72%), and KRAS (46%) were common in Chinese patients with CRC. For the first time, the prevalence of NTRK gene fusion was observed to be around 7% in the MSI-high CRC cohort. Across the cohort, MSI was found in 9%, ERBB2 amplification in 3%, and POLE pathogenic mutation in 1.5% of patients. Such results mostly parallel frequencies observed in Western patients. However, POLE existed at a higher frequency and was associated with large tumor T-cell infiltration., Conclusion: Comparing to the Western counterparts, POLE mutations were increased in our cohort. The prevalence of NTRK gene fusion was around 7% in the MSI-high CRC cohort. Increased adoption of molecular profiling in Asian patients is essential for the improvement of therapeutic outcomes., Implications for Practice: The increasing use of genomic profiling assays in colorectal cancer (CRC) has allowed for the identification of a higher number of patient subsets benefiting from matched therapies. With an increase in the number of therapies, assays simultaneously evaluating all candidate biomarkers are critical. The results of this study provide an early support for the feasibility and utility of genomic profiling in Chinese patients with CRC., (© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Objective: POLE mutation is a prognostic marker associated with excellent outcome in endometrial carcinoma (EC). However, these EC tumors frequently have aggressive histology. The aim of this study was to determine how to integrate the implications of POLE mutations into existing risk assessment strategies and further stratify patients., Methods: We detected POLE mutations in a cohort of 426 ECs from Chinese women and observed their prognostic significance in terms of survival and recurrence outcomes in combination with histological and other molecular characteristics, including microcystic, elongated and fragmented (MELF) pattern invasion, histologic subtype, tumor grade, myometrial invasion and p53 protein and mismatch repair protein expression status., Results: POLE mutations were identified in 38 of 426 ECs (8.9%). The most common mutations were P286R (31.6%), V411L (15.8%) and Q453R (15.8%). We confirmed that POLE mutation was associated with improved overall survival (P = .047), although it did not show a statistically significant relationship with progression-free survival (P = .45). Interestingly, further analyses indicated that in POLE-mutant tumors, MELF pattern invasion was associated with a 15.1-fold increase in tumor recurrence or progression risk (HR = 15.1, 95%CI = 1.57-145.3, P = .018), whereas this phenomenon was not present in the POLE-wild-type subgroup (HR = 0.90, 95%CI = 0.39-2.08, P = .80). Furthermore, higher staging and deeper myometrial invasion also showed much higher risk in patients harboring POLE mutations compared with those without POLE mutations., Conclusions: Although POLE mutation was associated with favorable overall survival, the combined consideration of POLE mutation status and established clinicopathologic factors in the risk assessment of endometrial cancer is more accurate than the consideration of clinicopathologic factors alone and might lead to precise and individualized therapeutic strategies., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To confirm diagnosis and explore the genetic aetiology in a Chinese patient suspected to have Cockayne syndrome (CS)., Methods: The patient was clinically examined, and the patient and her biological parents underwent genetic analysis using whole exome sequencing (WES) and Sanger sequencing. The foetus of the patient's mother underwent prenatal diagnostic Sanger sequencing using amniotic fluid obtained at 19 weeks' gestation., Results: Clinical examination of the patient showed developmental delay, progressive neurologic dysfunction and premature aging. Two compound, heterozygous ERCC excision repair 6, chromatin remodelling factor ( ERCC6 ) gene mutations were detected in the proband by WES and confirmed by Sanger sequencing, comprising a known paternal nonsense mutation (c.643G > T, p.E215X) and a novel maternal short insertion and deletion mutation (c.1614_c.1616delGACinsAAACGTCTT, p.K538_T539delinsKNVF). The patient was consequently diagnosed with CS type I. The foetus of the patient's mother was found to carry only the maternally-derived c.1614_c.1616delGACinsAAACGTCTT variant., Conclusion: This study emphasized the value of WES in clinical diagnosis, and enriched the known spectrum of ERCC6 gene mutations.

Background: Nonsmall cell lung cancer (NSCLC) mainly contains adenocarcinoma (AC) and squamous cell carcinoma (SqCC). This study investigated single nucleotide polymorphism (SNP) of topoisomerase II alpha (TOP2A) and dual-specificity phosphatase 6 (DUSP6) in a hospital-based case and control cohort of individuals for association with risk of different histological subtypes of NSCLC., Materials and Methods: A total of 454 (237 SqCC and 217 AC) NSCLC patients, and 454 healthy controls were recruited for analysis of TOP2A rs471692 and DUSP6 rs2279574 genotypes using the TaqMan polymerase chain reaction technique., Results: TOP2A rs471692 and DUSP6 rs2279574 SNPs were in complete linkage disequilibrium; however, frequency of DUSP6 rs2279574 genotype was significantly different between the case and control, that is, DUSP6 rs2279574a/A and A/C genotypes might contribute to an increased risk of lung squamous carcinoma compared with the C/C genotype. Moreover, DUSP6 rs2279574 AA genotype was also significantly associated with advanced stages of lung cancer. In contrast, frequency of the TOP2A rs471692 genotype had no association between cases and controls (P = 0.906). Genotype frequency of DUSP6 rs2279574 was 11.9% for C/C, 43.6% for C/A, and 44.5% for A/A in the case versus 16.7% C/C, 43.4% C/A, and 39.9% A/A in the control population (χ 2 = 3.136, P= 0.077 by Hardy-Weinberg equilibrium test [HWE]). The genotype frequency of TOP2A rs471692 was 50.0% for C/C, 41.6% for C/T, and 8.4% for T/T in the case versus 50.2% C/C, 43.0% C/T, and 6.8% T/T in the control populations (χ 2 = 0.023, P= 0.879 by HWE test)., Conclusion: Individuals are carrying DUSP6 rs2279574 AA and AC genotypes associated with an increased risk in developing lung squamous carcinoma in Han Chinese and with advanced NSCLC stages., Competing Interests: There are no conflicts of interest

Cockayne syndrome (CS) is a rare autosomal recessive disorder characterized principally by progressive growth failure, neurologic abnormality and premature aging. Mutations of excision repair cross‑complementation group 6 (ERCC6) and ERCC8 are predominantly responsible for CS, of which mutation of ERCC6 accounts for approximately two thirds of cases. The current report describes two siblings with severe neurologic abnormality and premature aging. Whole exome sequencing identified two novel mutations in ERCC6 that had not been previously reported. One was a nonsense mutation at codon 612 in exon 9 (c.1834C>T, p.Arg612Ter), and the other a missense mutation at codon 975 in exon 16 (c.2923C>T, p.Arg975Trp). Cosegregation analysis revealed c.1834C>T was paternal and c.2923C>T was maternal. A healthy baby with no mutated alleles was delivered based on prenatal diagnosis performed by genetic testing of amniocytes for the causative mutation. The present study will enrich the clinical and genetic spectrum of CS in China and world wide, and provides more evidence for future genotype‑phenotype studies.