JAMA：研究发现与胃癌有关的新基因突变

生物谷

胃癌是我国最常见的恶性肿瘤之一 ,在我国其发病率居各类肿瘤的首位 ,每年约有 17 万人死于胃癌 ,几乎接近全部恶性肿瘤死亡人数的1/4 ,且每年还有 2 万以上新的胃癌病人产生出来 ,胃癌确实是一种严重威胁人民身体健康的疾病。

    发表在6月6日的JAMA杂志上的一项研究结果显示，研究人员确定出一种与遗传性弥散型胃癌有关的新基因突变。

    胃癌是全世界因癌症死亡病例的第二大原因，主要有两种类型：一种肠型，另一种是弥散型。遗传性弥散型胃癌（HDGC）是有CDH1基因的突变引起的。CDH1突变的确定增加了研发降低癌症风险的治疗方法的机会。

    Pardeep  Kaurah和同事对CDH1基因的突变频率进行了评估，并且还对这些突变是因为独立突变事件或共同血统而导致的问题进行了研究。该研究对38个有患有HDGC成员的家庭进行了CDH1突变分析。

    研究证实30％到40％的具有胃癌史的家庭和超过50％的出现过两个弥散型胃癌病例的家庭携带了CDH1基因突变。接下来，研究人员将会进行更多范围的研究。而这些初步的数据则显示出了CDH1基因突变与胃癌的相关程度。

原始出处:

Founder and Recurrent CDH1 Mutations in Families With Hereditary Diffuse Gastric Cancer

Pardeep Kaurah, MSc; Andrée MacMillan, MSc; Niki Boyd, MSc, PhD; Janine Senz, BSc; Alessandro De Luca, BSc; Nicki Chun, MS; Gianpaolo Suriano, PhD; Sonya Zaor, MSc; Lori Van Manen, MS; Cathy Gilpin, MS; Sarah Nikkel, MD; Mary Connolly-Wilson, Med; Scott Weissman, MS; Wendy S. Rubinstein, MD; Courtney Sebold, MS; Robert Greenstein, MD; Jennifer Stroop, MS; Dwight Yim, MD; Benoit Panzini, MD; Wendy McKinnon, MS; Marc Greenblatt, MD; Debrah Wirtzfeld, MD; Daniel Fontaine, MD; Daniel Coit, MD; Sam Yoon, MD; Daniel Chung, MD; Gregory Lauwers, MD; Antonio Pizzuti, MD; Carlos Vaccaro, MD; Maria Ana Redal, PhD; Carla Oliveira, PhD; Marc Tischkowitz, MD; Sylviane Olschwang, MD; Steven Gallinger, MD; Henry Lynch, MD; Jane Green, PhD; James Ford, MD; Paul Pharoah, PhD; Bridget Fernandez, MD; David Huntsman, MD

JAMA. 2007;297:2360-2372. Published online June 3, 2007 (doi:10.1001/jama.297.21.2360).

Context Hereditary diffuse gastric cancer is caused by germline mutations in the epithelial cadherin (CDH1) gene and is characterized by an increased risk for diffuse gastric cancer and lobular breast cancer.

Objective To determine whether recurring germline CDH1 mutations occurred due to independent mutational events or common ancestry.

Design, Setting, and Patients Thirty-eight families diagnosed clinically with hereditary diffuse gastric cancer were accrued between November 2004 and January 2006 and were analyzed for CDH1 mutations as part of an ongoing study at the British Columbia Cancer Agency. Twenty-six families had at least 2 gastric cancer cases with 1 case of diffuse gastric cancer in a person younger than 50 years; 12 families had either a single case of diffuse gastric cancer diagnosed in a person younger than 35 years or multiple cases of diffuse gastric cancer diagnosed in persons older than 50 years.

Main Outcome Measures Classification of family members as carriers or noncarriers of CDH1 mutations. Haplotype analysis to assess recurring mutations for common ancestry was performed on 7 families from this study and 7 previously reported families with the same mutations.

Results Thirteen mutations (6 novel) were identified in 15 of the 38 families (40% detection rate). The 1137G>A splicing mutation and the 1901C>T (A634V) missense/splicing mutation occurred on common haplotypes in 2 families but on different haplotypes in a third family. The 2195G>A (R732Q) missense/splicing mutation occurred in 2 families on different haplotypes. The 2064-2065delTG mutation occurred on a common haplotype in 2 families. Two families from this study plus 2 additional families carrying the novel 2398delC mutation shared a common haplotype, suggesting a founder effect. All 4 families originate from the southeast coast of Newfoundland. Due to concentrations of lobular breast cancer cases, 2 branches of this family had been diagnosed as having hereditary breast cancer and were tested for BRCA mutations. Within these 4 families, the cumulative risk by age 75 years in mutation carriers for clinically detected gastric cancer was 40% (95% confidence interval [CI], 12%-91%) for males and 63% (95% CI, 19%-99%) for females and the risk for breast cancer in female mutation carriers was 52% (95% CI, 29%-94%).

Conclusions Recurrent CDH1 mutations in families with hereditary diffuse gastric cancer are due to both independent mutational events and common ancestry. The presence of a founder mutation from Newfoundland is strongly supported.

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