HNPCC 的突变筛查复旦大学附属肿瘤医院

大肠外科刘方奇

2010-4-29

Contents

1.研究背景

2.材料与方法

3.结果及讨论

研究背景

研究背景介绍• 何为 HNPCC ？• 常染色体显性遗传病； 5-10% 发生率； MMR 缺陷引起

• 如何研究？• 临床标准；选择 MLH1 和 MSH2 基因筛查突变

• 研究现状• 欧洲多，亚洲少• 90% 突变出现在 MLH1 和 MSH2• 无热点突变

研究背景介绍• 临床标准• Amsterdam I&II ； Bethesda ；

• 数据库• 最权威—— InSight (http://www.insight-group.org)

• 研究的意义是什么？• 遗传性疾病，早预防早治疗• 中国研究较少• 希望找到亚洲或中国的热点突变• 为中国的临床检测提供指导

材料与方法

材料与方法

结果与讨论

结果与讨论

临床资料归纳与整理1.

突变结果讨论2.

临床•左半 > 右半64.7% vs. 35.3%

　 Amsterdam I&II criteria Bethesda criteria Alln(%) 15(15.3%) 83(84.7%) 98(100%)Age(median, range) years 48.1(35-67) 47.6(19-82) 47.7(19-82)Sex n(%) male 12(80.0%) 45(54.2%) 57(58.2%) female 3(20.0%) 38(45.8%) 41(41.8%)Location n(%) Ascending colon 5(23.8%) 20(20.4%) 25(21.0%) Hepatic flexure 2(9.5%) 2(2.0%) 4(3.4%) Transverse colon 2(9.5%) 8(8.2%) 10(8.4%) Splenic flexure 2(9.5%) 1(1.0%) 3(2.5%) Descending colon 4(19.0%) 8(8.2%) 12(10.1%) Sigmoid colon 3(14.3%) 15(15.3%) 18(15.1%) Rectum 3(14.3%) 44(44.9%) 47(39.5%)Multiple cancer synchronous tumours 3(20.0%) 3(3.6%) 6(6.1%)

metachronous tumour 4(26.7%) 17(20.5%) 21(21.4%)Pathology adenocarcinoma 13(86.7%) 69(83.1%) 82(83.7%) mucinous carcinoma 2(13.3%) 11(13.2%) 13(13.3%) Others 0(0.0%) 3(3.6%) 3(3.1%)Family history 15 51 66

同时异时肿瘤发生率高

粘液腺癌 >10%

• 31 CRC happened, 11 were left side and 20 were right (64.5% vs. 35.5%),

• 20 related cancers happened, most of them were gastric cancer and endometrial carcinoma, 5 each

(25%).

Family ID

CRC number

CRC frequency

Cancer number

Cancer frequency Male Female

Onset age of CRC

Onset age of cancer

Multiple primary

CRC

Multiple primary tumors

Right site

Left site

Extracolonic cancer (type)

Mucinous carcinoma

H9 4 6 4 6 3 1 48 48 2 2 5 1 0 0H76 5 5 5 5 4 1 37 37 0 0 1 4 0 0

H86 1 2 3 5 2 1 47 47 1 1 1 1 3(1St, 1Es, 1E) 1

H88 1 1 3 3 3 0 19 19 0 0 1 0 2(2L) 0H166 4 5 4 5 2 2 36 36 1 1 2 3 0 0H167 4 6 5 7 3 2 29 29 2 2 1 5 1(1E) 0

H224 1 1 5 7 2 3 44 51 0 2 0 1 6(2St, 2E, 2Br) 0

H231 1 1 2 3 1 1 47 44 0 1 0 1 2(1L, 1Br) 0H236 3 3 3 4 1 2 40 40 0 1 0 3 1(1E) 1

H245 1 1 3 6 1 2 56 50 0 1 0 15(2St, 1Li, 1L,

1O)0

• AC 组 15 例，突变 4 例

• 如在肠外肿瘤中加入胃癌，符合 30 例，突变 8 例

• 检出率相同，避免遗漏

• 复旦推荐标准

突变Family

ID

MutationClinical criteria

Having been reported (times)Gene Exon Nucleotide Consequence Type

H9 MSH2 1 c.23C>T p.Thr8Met Missense Amsterdam Yes (5)

H76 MLH1 2c.157del GAGG

Frameshift Amsterdam No

H86 MLH1 1 c.-64G>T Uncertain Bethesda NoH88 MSH2 7 c.1168C>T p.Phe390Leu Missense Bethesda Yes (34)

H166 MLH1 8 c.655A>G p.Ile219Val Missense Amsterdam Yes (224)

H167 MLH1 17 c.1989G>AAberrant splicing

Amsterdam Yes (2)

H224 MLH1 19 c.2159insG FrameshiftBethesda

NoMSH2 7 c.1168C>T p.Phe390Leu Missense Yes (34)

H231 MSH2 7 c.1168C>T p.Phe390Leu Missense Bethesda Yes (34)H236 MLH1 18 c.2042C>T p.Ala681Val Missense Bethesda Yes (1)H245 MSH2 7 c.1168C>T p.Phe390Leu Missense Bethesda Yes (34)

该患者同时有两个突变，且满足复旦推荐标准

• 四个患者突变一致—— MSH2 c.1168C>T

• InSight 数据库中该位点报道结果——亚洲占绝大多数• 潜在亚洲人种热点突变 or SNP

参考文献1. Lee S-C, Guo J-Y, Lim R et al. Clinical and molecular characteristics of hereditary non-polyposis colorectal

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2. Landis SH, Murray T, Bolden S et al. Cancer statistics, 1999. CA Cancer J Clin 1999: 49: 8-31, 31.

3. Lynch HT, Smyrk T. Hereditary nonpolyposis colorectal cancer (Lynch syndrome): An updated review. Cancer 1996: 78: 1149-1167.

4. Ricciardiello L, Boland C. Lynch syndrome (hereditary non-polyposis colorectal cancer): Current concepts and approaches to management. Current Gastroenterology Reports 2005: 7: 412-420.

5. Lynch HT, Lynch JF, Lynch PM. Toward a consensus in molecular diagnosis of hereditary nonpolyposis colorectal cancer (Lynch syndrome). J Natl Cancer Inst 2007: 99: 261-263.

6. Lynch HT, de la Chapelle A. Hereditary Colorectal Cancer. The New England Journal of Medicine 2003: 348: 919-932.

7. Vasen HFA, Watson P, Mecklin J-P et al. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 1999: 116: 1453-1456.

8. Lynch HT, de la Chapelle A. Genetic susceptibility to non-polyposis colorectal cancer. Journal of Medical Genetics 1999: 36: 801-818.

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10. Aarnio M, Mecklin J-P, Aaltonen LA et al. Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. International Journal of Cancer 1995: 64: 430-433.

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Thank you ！