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Turner syndrome (TS) with 45,X/46,XY mosaic karyotype is a rare sex chromosome disorder with an occurrence of 0.15‰ at birth. We report the generation of an induced pluripotent stem cell (iPSC) line from peripheral blood mononuclear cells of a Chinese adult male with 45,X/46,XY mosaicism. The iPSC line retains the original 45,X/46,XY mosaic karyotype, expresses pluripotency markers and undergoes trilineage differentiation. Therefore, it offers an unprecedented cellular model to investigate the profound symptoms like infertility of TS in the male, and serve as a useful tool to develop therapies for the disease.

Landscape of pathogenic or likely pathogenic (P/LP) germline mutations in cancer predisposition genes have been well-studied among patients or survivors of childhood cancer in the US. However, little is known for cancer predisposing germline mutations in Chinese survivors of childhood cancer including acute lymphoblastic leukemia (ALL). To characterize the spectrum and prevalence of cancer predisposing germline mutations, and to assess the relationship between the mutation status and cancer family history, whole-exome sequencing (>80-fold) was performed on blood DNA for 91 childhood ALL survivors who were ≥5 years from initial cancer diagnosis. All patients enrolled and consented for the study were previously diagnosed and treated either at Nanjing Children’s Hospital of Nanjing Medical University (n=28) or Guangzhou Women and Children’s Medical Center (n=63). Germline mutations in 156 cancer predisposition genes were analyzed and classified for their pathogenicity based on the American College of Medical Genetics and Genomics (ACMG) guideline. Clinical information was extracted from medical records and family history were collected based on questionnaire and phone interview. Of 91 survivors of childhood ALL (median age [range], 11 [6-22] years; 58 [63.7%] male), P/LP mutations were identified in 7 (6.4%) survivors. The mutations occurred in well-established ALL predisposition genes such as ATM, BLM, and SBDS, and other cancer-associated genes such as PALB2, for which two P/LP mutations were identified. Notably, PALB2 was also included in “Add-On” gene panel provided by Invitae, a genetic testing company, for leukemia predisposition testing. Most of these mutated genes (ATM, BLM, LIG4 and PALB2) are involved in DNA repair pathways. Using East Asian (EAS) population from Genome Aggregation Consortium (genomAD) database as controls, the cancer predisposing germline mutations were significantly enriched (Odds Ratio [95% CI], 6.3 [2.9-13.7]) among survivors of childhood ALL. Among survivors with cancer family information (n=82), the prevalence of mutation carriers is 18.8% (3/16) for survivors with positive cancer family history, compared to 4.5% (3/66) for survivors with negative family history, but the association between mutation status and cancer family history is not statistically significant (Fisher’s exact test P = 0.09). To our knowledge, we’re the first to assess cancer predisposing mutations in Chinese survivors of childhood ALL. Our findings showed slightly higher level of prevalence of cancer predisposing mutation than US survivors, suggesting disparity across different populations. The results highlight the importance of genetic counselling and testing which could inform personalized screening strategy for second cancer for survivors and for cancer risk stratification and early prevention for other family members. Note: This abstract was not presented at the meeting. Citation Format: Ru Zhang, Yao Xue, Liwen Zhu, Meiyun Kang, Xiangye Xu, Jie Huang, Liucheng Rong, Juncheng Dai, Zhibin Hu, Yongjun Fang, Zhaoming Wang. Germline mutations in cancer predisposition genes are prevalent among survivors of childhood acute lymphoblastic leukemia in a Chinese population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1685.

The human induced pluripotent stem cell (iPSC) technique promises to provide an unlimited, reliable source of genetically matched pluripotent cells for personalized therapy and disease modeling. Recently, it is observed that cells with ring chromosomes 13 or 17 autonomously correct the defects via compensatory uniparental disomy during cellular reprogramming to iPSCs. This breakthrough finding suggests a potential therapeutic approach to repair large-scale chromosomal aberrations. However, due to the scarceness of ring chromosome samples, the reproducibility of this approach in different individuals is not carefully evaluated yet. Moreover, the underlying mechanism and the applicability to other types of chromosomal aberrations remain unknown. Here we generated iPSCs from four 45,X chorionic villous fibroblast lines and found that only one reprogrammed line acquired 46,XX karyotype via uniparental disomy of the entire X chromosome. The karyotype correction was reproducible in the same cell line by either retroviral or episomal reprogramming. The karyotype-corrected iPSCs were subject to X chromosome inactivation and obtained better colony morphology and higher proliferation rate than other uncorrected ones. Further transcriptomic comparison among the fibroblast lines identified a distinct expression pattern of cell cycle regulators in the uncorrectable ones. These findings demonstrate that the iPSC technique holds the potential to correct X monosomy, but the correction rate is very low, probably due to differential regulation of cell cycle genes between individuals. Our data strongly suggest that more systematic investigations are needed before defining the iPSC technique as a novel means of chromosome therapy.