1. Full name: Vu Dinh Quang                                          2. Sex: Male

3. Date of birth: 8th January 2018                                   4. Place of birth: Hanoi

5. Admission decision number: Number 4050/QĐ-KHTN-CTSV, dated on 19th September 2013 signed by Rector of VNU University of Science.

6. Changes in academic process: Extension according to: Decision No. 597/QĐ-ĐHKHTN date on 6th March 2018 signed by the Rector of VNU University of Science.

7. Official thesis title: “Study some genetic alterations and the relationship with clinical and treatment on neuroblastoma pediatric patients in Vietnam”

8. Major: Genetics                                                         9. Code: 62420121

10. Supervisors: 1st supervisor: Assoc.Prof.Dr. Nguyễn Thị Hồng Vân

                           2nd supervisor: Dr. MD. Phùng Tuyết Lan       

11. Summary of the new findings of the thesis

Detection of some genetic alterations on neuroblastoma pediatric patients.

The amplification of MYCN gene is found on 21 in 141 neuroblastomas by the fluorescent in-situ hybridization technique, with ratio is 14.89%.

The MLPA technique is done on 10 low-risk neuroblastoma patients to screen the abnormalities on chromosome 2 and 17. The aberrations of chromosome 17 are found on 2 patients: one has deletion in short arm and other have gain in long arm. There is no change in chromosome set found in the other patients.

The comparative genomic hybridization technique was used on 6 low-risk neuroblastomas. The results show that 2 patients are belong to the segmental chromosomal aberrations (SCA) group and 4 patients are in the numerical chromosomal aberrations (NCA) group. The common SCA are deletion in 1p and insertion in 17q. The common aberrations in NCA is loss of chromosome 4. 10, 14, 19, 21 and extra of chromosome 7.

There are 2 patients who are screened by both MLPA and CGH techniques. One case showed no any alteration by MLPA technique, but gain chromosome 17 by CGH technique. And the other shows deletion in 17q by MLPA technique but have both deletion 17p and gain 17q by CGH technique.

The comparative genomics hybridization technique displays some advantages than MLPA technique, like screening whole 23 chromosomes in one time, the higher specificity and sensitivity. So the CGH technique could replace for MLPA technique in detecting the copy number variation (CNV) in neuroblastoma.

The procedure of genetic analysis in neuroblastoma: the MYCN status is detected in all the patients by the fluorescent in-situ hybridization technique to risk group stratification. Next, the CNV is performed by the comparative genomics hybridization technique in the low-risk neuroblastoma to precise the treatment protocol.

Identification of relationship between some genetic alterations and some other prognostic factors, also the treatment on neuroblastoma patients.

In this study, 48.2% patients are under 1-year-old and 99.3% patients are under 5 years old. Only 5 in 21 amplified-MYCN patients are under 1-year-old, and the other cases are older. But the MYCN status don’t have the relationship with age at diagnosis (χ2 = 5.895 at p<0.05).

The sex ratio boy/girl was 1,56, and the MYCN amplification was more popular in boy than girl. But the MYCN status don't have the relationship with gender (t-Student = 0.574 at p<0.05).

There were 122 in 141 neuroblastomas at local stage (L1, L2), that accounts for 86.53% of the rate, 19 patients at metastasis stage (M, Ms), about 13.47% of the rate. The ratio of amplified MYCN is the highest at M stage (8/21 cases) and Ms (2/7 cases). But the MYCN status and stage don’t have any relationship (χ2 = 37.577 at p<0.05).

Urinary VMA was tested in 115 cases with 61.5% patients increased VMA level over 2.5 times than normal. Urinary HVA was tested in 117 cases with 50.4% patients increased HVA level over 2.5 times than normal. The ratio VMA/HVA above 1 was appeared in good prognosis patients. In this study, 13/14 amplified MYCN patients had that ration below 1. But the MYCN status don't have the relationship with gender (χ2 = 2.562 at p<0.05).

Approximate 52.48% patients didn’t increase LDH level at diagnosis and 15.6% patients had high LDH level. Most of MYCN amplification cases had increased LDH (16/21 patients). This result have proved the relationship between MYCN status and LDH level (χ2 = 69.123 at p<0.05).

Over 90% patients in this study were poorly differentiated neuroblastoma. Similarly, 85% MYCN amplification cases were same histology group. No amplified cases were differentiating neuroblastoma. This result show demonstrate the relationship between MYCN status and differentiation status (χ2 = 7.307 at p<0.05).

There are 64.7% tumors in favorable histology and 35.5% ones in unfavorable histology. About 75% amplified MYCN tumors were in the unfavorable histology group. But the MYCN status don't have the relationship with histological classification (χ2 = 16.187 at p<0.05).

In 21 MYCN amplification patients, 8 cases were in M stage, whose the treatment protocol has not been changed. 13 other cases in different stages had to change the treatment. One L1 stage patient was treated with intermediate risk protocol from the low risk protocol, and twelve L2 and Ms patients had to be treated with high risk protocol.

There are 6 low risk patients who were screened CNVs by comparative genomic hybridization technique. The numerical chromosomal aberrations (NCA) group had 4 cases; in which, a new patient, 2 following up patients after 2 chemotherapy courses, one patient after 3 courses of chemotherapy. By their genetic profiles, the new patient didn’t need the chemotherapy; 3 other patients had stopped the chemotherapy and just followed up. The segmental chromosomal aberrations (SCA) group 2 cases; in which, a L2 stage case and a M stage case. Following their CGH results, the L2 stage patient needed more chemotherapy and the M stage case had 50% chance of successful cure with high risk protocol. At this moment, the status of those patients is stable.

12. Practical applicability, if any:

This result was and is using in risk-group stratification as well as the treatment tailoring for neuroblastoma in National Children’s Hospital.

13. Further research directions, if any:

Implementation the comparative genomics hybridization technique in non-amplified MYCN neuroblastoma, not only the low risk but also the intermediate risk and high risk to achieve the full database of the neuroblastoma in Vietnam.

Study the mutations on some genes correlated neuroblastoma, such as ALK, PHOX2B, MDM2 etc. by sequencing technique, aiming at targeted therapy and personalized medicine in treatment for pediatric cancer patients.

14. Thesis-related publications:

[1] Vũ Đình Quang, Nguyễn Xuân Huy, Phùng Tuyết Lan, Trần Đức Hậu, Trần Ngọc Sơn, Hoàng Ngọc Thạch, Lê Đình Công, Ngô Diễm Ngọc (21014), “Đánh giá khuếch đại gen MYCN trên bệnh nhân UNBTK”, Tạp chí Y Dược Lâm Sàng 108(9), trang 283-288.

[2] Vũ Đình Quang, Nguyễn Thị Hồng Vân, Phùng Tuyết Lan, Trần Ngọc Sơn, Lê Đình Công, Hoàng Ngọc Thạch, Nguyễn Xuân Huy, Ngô Diễm Ngọc (2015), “Nghiên cứu mối quan hệ giữa trạng thái gen MYCN với một số yếu tố tiên lượng khác trên 41 bệnh nhân UNBTK”, Tạp chí Khoa học ĐHQG: Khoa học Tự nhiên và Công nghệ 31(4S), trang 288-293.

[3] Vu Dinh Quang, Nguyen Thi Hong Van, Phung Tuyet Lan, Tran Ngoc Son, Le Dinh Cong, Hoang Ngoc Thach, Nguyen Xuan Huy, Ngo Diem Ngoc (2016),“Study on the Relationship Between MYCN Status and Certain Prognostic Factors in 131 Patients with Neuroblastoma”, Journal of Clinical Medicine 36, pp 30-36.

[4] Vũ Đình Quang, Nguyễn Thị Hồng Vân, Phùng Tuyết Lan, Trần Ngọc Sơn, Lê Đình Công, Hoàng Ngọc Thạch, Nguyễn Xuân Huy, Ngô Diễm Ngọc (2016), “Nghiên cứu mối quan hệ giữa trạng thái gen MYCN với tuổi và kết quả mô bệnh học trên 41 bệnh nhân UNBTK”, Tạp chí Nhi khoa 9(3), trang 46-50.

[5] Q.D. Vu, V.T.H. Nguyen, N.D. Ngo, N.X. Huy, L.T. Phung, C.D. Le, T.N. Hoang, M.T.C. Tran, H.T. Le (2016), “Association of MYCN Status with Certain Prognosis Factors of Vietnamese Neuroblastoma from 2013-2015”, Pediatric Blood and Cancer 63, pp S205-S206.

[6] Q. Vu, N. Nguyen, L. Bui, H. Pham, C. Le, N. Le, T. Hoang, N. Ngo, H. Nguyen, L. Phung, V. Nguyen, H. Le (2017), “Treatment of non high risk neuroblastoma patients following SIOPEL protocol in Vietnam from 2013 to 2015”, Pediatric Blood and Cancer 64, pp S448-S449.

[7] Vũ Đình Quang, Nguyễn Thị Hồng Vân, Phùng Tuyết Lan, Nguyễn Xuân Huy, Ngô Diễm Ngọc, Bùi Ngọc Lan, Phạm Duy Hiền, Lê Đình Công, Hoàng Ngọc Thạch, Dương Hồng Quân, Nguyễn Thanh Liêm, Lê Thanh Hải (2017), “Ứng dụng kỹ thuật lai so sánh hệ gen trong xác định biến đổi di truyền ở bệnh nhân UNBTK không khuếch đại gen MYCN”, Tạp chí Khoa học ĐHQGHN: Khoa học Tự nhiên và Công nghệ 33(2S), trang 109-113.