02 - chinese university of hong kong · landmark achievements have been made. first, the team...

Technical Report on Research Progamm

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PI:

Dennis Lo (Li Ka Shing Professor of Medicine, Department of Chemical Pathology),

Rossa Chiu (Department of Chemical Pathology)

Team:

Allen Chan, Hao Sun, Nancy Tsui, Rebecca Chan, Lisa Chan, Macy Heung, Peiyong Jiang, Gabriel Lam, Shara Lee, Fiona Lun, Yu Kwan Tong, Yama Zheng, Kam Wing Chan, Kiwi Chan, Anita Cheng, Katherine Chow, Yoyo Jin, Coral Lee, Xiaoxi Su, Sze Wan Yeung

The non-invasive test for Down syndrome detection based on maternal plasma DNA sequencing developed by the team was launched as a clinical test in the United States (US) in October 2011. The service became available in Hong Kong in December 2011. To date, the service is available in many countries, including Germany, Austria, Switzerland, Czech Republic, Slovakia, Israel, Singapore, Malaysia, Japan, and Australia. The American College of Obstetricians and Gynecologists published a recommendation in November 2012 supporting the use of the maternal plasma DNA based non-invasive test for Down syndrome screening among high risk pregnancies. In addition, The Scientist Magazine named 2012 as The Year of the Fetus (http://www.the-scientist.com/?articles.view/articleNo/33735/title/Year-of-the-Fetus/) due to the rapid adoption of non-invasive detection of Down syndrome in the US.

In the current reporting period, Professor Dennis Lo and his team pushed the envelope further in terms of non-invasive prenatal diagnostics. Several landmark achievements have been made. First, the team developed a method to bring the non-invasive prenatal diagnosis of single gene disorders, such as beta-thalassaemia, closer to reality. A targeted sequencing methodology was developed which enabled the assessment of the fetal inheritance of paternal and maternal mutations to be made

RESEARCH PROGRESS SUMMARY:

Research into Circulating Fetal Nucleic Acids02

Research into Circulating Fetal Nucleic Acids

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at a lower cost than the whole fetal genome approach previously developed by the team. This new approach also provided a means to perform the test on families with highly similar genetic structures.

Another landmark that the team achieved was the development of a bioinformatics algorithm, named FetalQuant, which can deduce the genotypes of the fetus and the mother at polymorphic sites in the genome directly from the maternal plasma DNA sequencing data. The fractional fetal DNA concentration of the maternal plasma sample could also be estimated directly from the massively parallel sequencing data. This algorithm facilitates the expansion of the potential applications of maternal plasma DNA sequencing.

Besides maternal plasma, the team was also the first to study the presence of fetal DNA in maternal urine using massively parallel sequencing. The study resolved a longstanding controversy in the field and confirmed the presence of cell-free fetal DNA in maternal urine. Fetal DNA was detected in five of the seven maternal urine samples, with the fractional fetal DNA concentrations ranged from 1.92% to 4.73%. Fetal DNA became

undetectable in maternal urine after delivery. The total urinary cell-free DNA molecules were less intact comparing with plasma DNA with very short urinary fetal DNA fragments between 29 bp to 45 bp in length. The presence of transrenal fetal DNA in maternal urine was unambiguously confirmed.

The research team previously reported the size difference between maternal- and fetal-derived DNA in maternal plasma. The team further investigated if the original observation could be extended to haematopoietically and nonhaematopoietically derived plasma DNA in general. Using massively parallel sequencing, the biological characteristics of plasma DNA molecules of haematopoietic stem cell transplantation were invest igated. The data indeed showed that the nonhaemotopoietically derived plasma DNA molecules were shorter than the haematopoietically derived ones.

These data have important implications and paved the way for clinical application of next generation sequencing in molecular diagnostics. The team published in a total of 15 peer-reviewed articles and 43 conference papers.


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RECOGNITIONS:

AWARDS AND FELLOWSHIPS

Member’s Name Details

Dennis Lo• AACC - NACB Award for Outstanding Contributions to Clinical Chemistry in a Selected

Area of Research for year 2012, National Academy of Clinical Biochemistry, USA

• 2012 Ernesto Illy Trieste Science Prize in Human Health, The World Academy of Sciences (TWAS)

Rossa Chiu• 2012 APEC Science Prize for Innovation, Research and Education (ASPIRE Prize)

• 中國青年女科學家獎 2012


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GRANTS AND CONSULTANCYGrants

Details Member’s Name Amount (HK$)

Focused Investments Scheme (1/7/2006 - 30/6/2012)Title: Centre for Research into Circulating Fetal Nucleic Acids.

Dennis Lo 13,000,000

Innovation and Technology Fund (1/9/2011 - 31/8/2016)Title: State Key Laboratories CPY.

Dennis Lo 666,666

Areas of Excellence Scheme (The University Grants Committee) (1/1/2012 - 31/12/2015)Title: Centre for Research into Circulating Fetal Nucleic Acids.


Areas of Excellence Scheme (CUHK Matching Fund) (1/1/2012 - 31/12/2015)Title: Centre for Research into Circulating Fetal Nucleic Acids.


CUHK Research Committee Funding (1/3/2012 - 28/2/2013)Title: Non-invasive Prenatal Diagnostics by Massively Parallel

Sequencing.Rossa Chiu 100,000

Focused Investment Scheme (1/7/2012 - 30/6/2016)Title: State Key Laboratory (SKL) Oncology.

Dennis Lo 1,425,285

Focused Investment Scheme (1/7/2012 - 30/6/2016)Title: AoE Circulating Nucleic Acids.

Dennis Lo 7,350,000

CUHK Internal Review Scheme (1/9/2012 - 30/8/2013)Title: Sequencing analysis of plasma DNA.

Rossa Chiu 15,000


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Professor Dennis Lo received the 2012 Ernesto Illy Trieste Science Prize from China’s President Hu Jintao.

Copyright © 2012 The World Academy of Sciences

PUBLICATIONS:

1. Jiang, P., Chan, K. C., Liao, G. J., Zheng, Y. W., Leung, T. Y., Chiu, R. W., Lo, Y. M., & Sun, H. (2012). FetalQuant: deducing fractional fetal DNA concentration from massively parallel sequencing of DNA in maternal plasma. Bioinformatics, 28(22), 2883-2890.

2. Tsui, N. B., & Lo, Y. M. (2012). Recent advances in the analysis of fetal nucleic acids in maternal plasma. Current Opinion in Hematology, 19(6), 462-468.

3. Tsui, N. B., Jiang, P., Chow, K. C., Su, X., Leung, T. Y., Sun, H., Chan, K. C., Chiu, R. W., & Lo, Y. M. (2012). High resolution size analysis of fetal DNA in the urine of pregnant women by paired-end massively parallel sequencing. PLoS One, 7(10), e48319.

4. Lam, K. W., Jiang, P., Liao, G. J., Chan, K. C., Leung, T. Y., Chiu, R. W., & Lo, Y. M. (2012). Noninvasive prenatal diagnosis of monogenic diseases by targeted massively parallel sequencing of maternal plasma: application to β-thalassemia. Clinical Chemistry, 58(10), 1467-1475.

5. Tong, Y. K., Chiu, R. W., Chan, K. C., Leung, T. Y., & Lo, Y. M. (2012). Technical concerns about immunoprecipitation of methylated fetal DNA for noninvasive trisomy 21 diagnosis. Nature Medicine, 18(9), 1327-1328.

6. Poon, T. C., Pang, R. T., Chan, K. C., Lee, N. L., Chiu, R. W., Tong, Y. K., Chim, S. S., Ngai, S. M., Sung, J. J.,& Lo, Y. M. (2012). Proteomic analysis reveals platelet factor 4 and beta-thromboglobulin as prognostic markers in severe acute respiratory syndrome. Electrophoresis, 33(12), 1894-1900.

7. Lo, Y. M. (2012). Fetal nucleic acids in maternal blood: the promises. Clinical Chemistry and Laboratory Medicine, 50(6), 995-998.

8. Lo, Y. M. (2012). Non-invasive prenatal diagnosis by massively parallel sequencing of maternal plasma DNA. Open Biology, 2(6), 120086.

9. Liao, G. J., Chan, K. C., Jiang, P., Sun, H., Leung, T. Y., Chiu, R. W., & Lo, Y. M. (2012). Noninvasive prenatal diagnosis of fetal trisomy 21 by allelic ratio analysis using targeted massively parallel sequencing of maternal plasma DNA. PLoS One, 7(5), e38154.

10. Lo, Y. M., Chan, K. C., & Chiu, R. W. (2012). Noninvasive fetal tr isomy 21 detection using chromosome-selective sequencing: a variation of the molecular counting theme. Expert Review of Molecular Diagnostics, 12(4), 329-331.

11. Chiu, R. W., & Lo, Y. M. (2012). Noninvasive prenatal diagnosis empowered by high-throughput sequencing. Prenatal Diagnosis, 32(4), 401-406.

12. Rifai, N., Diamandis, E. P., Lo, Y. M., Kricka, L. J., Wilding, P., Ladenson, J. H., & Wittwer, C. T. (2012). Advancing laboratory medicine through innovation: a tale of six inventors. Clinical Chemistry, 58(3), 502-510.

13. Zheng, Y. W., Chan, K. C., Sun, H., Jiang, P., Su, X., Chen, E. Z., Lun, F. M., Hung, E. C., Lee, V., Wong, J., Lai, P. B., Li, C. K., Chiu, R. W., & Lo, Y. M. (2012). Nonhematopoietically derived DNA is shorter than hematopoietically derived DNA in plasma: a transplantation model. Clinical Chemistry, 58(3), 549-558.

14. Liao, G. J., Chiu, R. W., & Lo, Y. M. (2012). Prenatal assessment of fetal chromosomal and genetic disorders through maternal plasma DNA analysis. Pathology, 44(2), 69-72.

15. Lo, Y. M., & Chiu, R. W. (2012). Genomic analysis of fetal nucleic acids in maternal blood. Annual Review of Genomics and Human Genetics, 13, 285-306.


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02 - chinese university of hong kong · landmark achievements have been made. first, the team...

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