摘要
目的探讨壶腹癌患者中KRAS和HER家族基因变异及共变异特征。方法收集北京协和医院2019年4月至2024年10月存档的甲醛固定石蜡包埋壶腹癌标本37例,采用二代测序方法分析其KRAS和HER家族基因的突变特征,并采用免疫组织化学(IHC)和荧光原位杂交(FISH)方法对HER2基因变异的标本分别进行HER2蛋白表达和基因状态(针对IHC 2+)检测。结果37例患者中男性22例,女性15例,年龄31~82岁。在51.4%(19/37)的病例中检测到KRAS基因突变,其中G12D突变最为常见,占比为7/19,其次为G12V(5/19)和Q61R(3/19),G12C、A146T、N116H及Q61H的突变占比均为1/19。HER家族基因变异率为27.0%(10/37),以HER2(6/10)和HER3基因的错义突变为主。在此队列中,发现3例(8.1%,3/37)KRAS和HER家族基因共突变患者,分别是KRAS p.G12D/HER2 p.V842I/HER2 p.V777L(c.2329 G>T)/HER3 p.Asp581Asn、KRAS p.Q61R/HER4 p.D1018H及KRAS p.G12C/HER2 p.R678Q。另外,确认了1例HER3 p.V104L(c.310 G>C)突变。同时还检出4种新突变,即HER3 p.V296E、HER3 p.V920L(c.2758 G>T)、HER3 p.Asp581Asn和HER4 p.D1018H。在6例HER2基因变异的样本(16.2%,6/37)中检出5种突变类型,以HER2 p.S310Y最常见(3/6)。1例HER2 p.S310Y样本(HER2 IHC 2+)经二代测序及FISH检测均提示为HER2基因扩增,而另1例HER2 p.L755S突变样本(HER2 IHC 2+)的FISH结果也显示HER2基因扩增。结论壶腹癌中可发生KRAS和HER家族基因共突变。在HER家族基因变异的肿瘤中HER2基因突变占一半以上,后者可与基因扩增并存。
Objective To investigate the variations and co-alteration of KRAS and HER-family genes in the patients with ampullary carcinoma.Methods A total of 37 formalin-fixed paraffin-embedded primary ampullary carcinoma specimens,which were collected at Peking Union Medical College Hospital from April 2019 to October 2024 were analyzed for KRAS and HER-family gene mutations using next-generation sequencing(NGS).Immunohistochemistry(IHC)was performed for HER2 protein expression in HER2 mutation cases and fluorescence in situ hybridization(FISH)for further gene status in HER2 IHC 2+cases.Results In our cohort(22 males,15 females;31-82 years old),KRAS gene mutations were detected in 51.4%(19/37)of cases,with G12D being the most frequent abnormality(7/19),followed by G12V(5/19)and Q61R(3/19).Other variants of KRAS gene included G12C,A146T,N116H,and Q61H(each 1/19).In this cohort,27.0%(10/37)of cases harbored HER-family gene alterations with most frequently in HER2(6/10)and HER3 genes(missense mutations mainly).Notably,3 cases(8.1%,3/37)with coexistence of KRAS and HER-family genes mutations were recognized in our series,including KRAS p.G12D/HER2 p.V842I/HER2 p.V777L(c.2329 G>T)/HER3 p.Asp581Asn,KRAS p.Q61R/HER4 p.D1018H and KRAS p.G12C/HER2 p.R678Q.Additionally,a mutation of HER3 p.V104L(c.310 G>C)was identified in our population.Moreover,4 novel mutations including HER3 p.V296E,HER3 p.V920L(c.2758 G>T),HER3 p.Asp581Asn,and HER4 p.D1018H were detected.In 6 tumors with HER2 gene changes(16.2%,6/37),5 variants with the high proportion of HER2 p.S310Y(3/6)were revealed.A tumor(HER2 IHC 2+)with HER2 p.S310Y presented HER2 gene amplification confirmed by NGS and FISH,and another one(also HER2 IHC 2+)with HER2 p.L755S possessed HER2 gene amplification determined by FISH assay.Conclusion In ampullary carcinoma,co-alteration of KRAS and HER-family genes is observed,and HER2 gene mutations account for more than half of HER-family gene abnormities,which may be accompanied by gene amplification.
作者
曾玲丽
武莎斐
周炜洵
刘媛媛
李凯咪
莫胜崴
刘梦琳
曾瑄
Zeng Lingli;Wu Shafei;Zhou Weixun;Liu Yuanyuan;Li Kaimi;Mo Shengwei;Liu Menglin;Zeng Xuan(Department of Pathology,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100730,China)
出处
《中华病理学杂志》
北大核心
2025年第7期762-768,共7页
Chinese Journal of Pathology
基金
中央高水平医院临床科研业务费(2022-PUMCH-B-063)
北京市希思科临床肿瘤学研究基金(Y-2022HER2AZMS-0375)。
关键词
肝胰管壶腹
癌
基因
变异
Ampulla of vater
Carcinoma
Genes
Variation
