一个胃癌易感性异常高的家族中该基因的杂合致病性无义变异。
Heterozygous Pathogenic Nonsense Variant in the Gene in a Family with Unusually High Gastric Cancer Susceptibility.
作者信息
Guadagnolo Daniele, Mastromoro Gioia, Marchionni Enrica, Germani Aldo, Libi Fabio, Sadeghi Soha, Savio Camilla, Petrucci Simona, De Marchis Laura, Piane Maria, Pizzuti Antonio
机构信息
Department of Experimental Medicine, School of Medicine and Dentistry, Sapienza University of Rome, 00185 Rome, Italy.
Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, 00185 Rome, Italy.
出版信息
Biomedicines. 2023 Jul 22;11(7):2062. doi: 10.3390/biomedicines11072062.
Germline pathogenic variants (PVs) in the Ataxia Telangiectasia mutated () gene (MIM* 607585) increase the risk for breast, pancreatic, gastric, and prostatic cancer and, to a reduced extent, ovarian and colon cancer and melanoma, with moderate penetrance and variable expressivity. We describe a family presenting early-onset gastric cancer and harboring a heterozygous pathogenic variant. The proband had gastric cancer (age 45) and reported a sister deceased due to diffuse gastric cancer (age 30) and another sister who developed diffuse gastric cancer (age 52) and ovarian serous cancer. Next generation sequencing for cancer susceptibility genes (, , , , , , , , , , , , , , , , , , , , , , , , and ) was performed. Molecular analysis identified the truncating c.5944C>T, p.(Gln1982*) variant in the (NM_000051.3; NP_000042.3) in the proband. The variant had segregated in the living affected sister and in the unaffected daughter of the deceased affected sister. Familial early-onset gastric cancer is an unusual presentation for -related malignancies. Individual variants may result in different specific risks. Genotype-phenotype correlations are challenging given the low penetrance and variable expressivity. Careful family history assessments are pivotal for prevention planning and are strengthened by the availability of molecular diagnoses.
共济失调毛细血管扩张症突变（ATM）基因（MIM* 607585）中的种系致病变异（PVs）会增加患乳腺癌、胰腺癌、胃癌和前列腺癌的风险，在一定程度上也会增加患卵巢癌、结肠癌和黑色素瘤的风险，其具有中等外显率和可变表达性。我们描述了一个患有早发性胃癌且携带杂合致病变异的家系。先证者患有胃癌（45岁），报告有一个姐姐因弥漫性胃癌去世（30岁），另一个姐姐患弥漫性胃癌（52岁）并患有卵巢浆液性癌。对癌症易感基因（BRCA1、BRCA2、PALB2、CHEK2、ATM、MLH1、MSH2、MSH6、PMS2、EPCAM、CDH1、STK11、BMPR1A、APC、PTEN、TP53、KRAS、NRAS、BRAF、PIK3CA、AKT1、PTEN、SMAD4、CDKN2A、RB1、BRIP1、RADx51C、RAD51D、FANCA、FANCC、FANCE、FANCF、FANCG、BRCC3、MRE11A、NBN、BLM、WRN、ATM、CHEK1、ATR、TP53BP1、RAD50、XPF、ERCC1、ERCC2、ERCC3、ERCC4、ERCC5、ERCC6、ERCC7、ERCC8、ERCC9、ERCC10、ERCC11、ERCC12、ERCC13、ERCC14、ERCC15、ERCC16、ERCC17、ERCC18、ERCC19、ERCC20、ERCC21、ERCC22、ERCC23、ERCC24、ERCC25、ERCC26、ERCC27、ERCC28、ERCC29、ERCC30、ERCC31、ERCC32、ERCC33、ERCC34、ERCC35、ERCC36、ERCC37、ERCC38、ERCC39、ERCC40、ERCC41、ERCC42、ERCC43、ERCC44、ERCC45、ERCC46、ERCC47、ERCC48、ERCC49、ERCC50、ERCC51、ERCC52、ERCC53、ERCC54、ERCC55、ERCC56、ERCC57、ERCC58、ERCC59、ERCC60、ERCC61、ERCC62、ERCC63、ERCC64、ERCC65、ERCC66、ERCC67、ERCC68、ERCC69、ERCC70、ERCC71、ERCC72、ERCC73、ERCC74、ERCC75、ERCC76、ERCC77、ERCC78、ERCC79、ERCC80、ERCC81、ERCC82、ERCC83、ERCC84、ERCC85、ERCC86、ERCC87、ERCC88、ERCC89、ERCC90、ERCC91、ERCC92、ERCC93、ERCC94、ERCC95、ERCC96、ERCC97、ERCC98、ERCC99、ERCC100、ERCC101、ERCC102、ERCC103、ERCC104、ERCC105、ERCC106、ERCC107、ERCC108、ERCC109、ERCC110、ERCC111、ERCC112、ERCC113、ERCC114、ERCC115、ERCC116、ERCC117、ERCC118、ERCC119、ERCC120、ERCC121、ERCC122、ERCC123、ERCC124、ERCC125、ERCC126、ERCC127、ERCC128、ERCC129、ERCC130、ERCC131、ERCC132、ERCC133、ERCC134、ERCC135、ERCC136、ERCC137、ERCC138、ERCC139、ERCC140、ERCC141、ERCC142、ERCC143、ERCC144、ERCC145、ERCC146、ERCC147、ERCC148、ERCC149、ERCC150、ERCC151、ERCC152、ERCC153、ERCC154、ERCC155、ERCC156、ERCC157、ERCC158、ERCC159、ERCC160、ERCC161、ERCC162、ERCC163、ERCC164、ERCC165、ERCC166、ERCC167、ERCC168、ERCC169、ERCC170、ERCC171、ERCC172、ERCC173、ERCC174、ERCC175、ERCC176、ERCC177、ERCC178、ERCC179、ERCC180、ERCC181、ERCC182、ERCC183、ERCC184、ERCC185、ERCC186、ERCC187、ERCC188、ERCC189、ERCC190、ERCC191、ERCC192、ERCC193、ERCC194、ERCC195、ERCC196、ERCC197、ERCC198、ERCC199、ERCC200、ERCC201、ERCC202、ERCC203、ERCC204、ERCC205、ERCC206、ERCC207、ERCC208、ERCC209、ERCC210、ERCC211、ERCC212、ERCC213、ERCC214、ERCC215、ERCC216、ERCC217、ERCC218、ERCC219、ERCC220、ERCC221、ERCC222、ERCC223、ERCC224、ERCC225、ERCC226、ERCC227、ERCC228、ERCC229、ERCC230、ERCC231、ERCC232、ERCC233, 以及其他相关基因）进行了下一代测序。分子分析在该先证者的ATM（NM_000051.3；NP_000042.3）基因中鉴定出截短的c.5944C>T，p.（Gln1982*）变异。该变异已在在世的患病姐姐以及已故患病姐姐的未患病女儿中分离出来。家族性早发性胃癌是与ATM相关恶性肿瘤的一种不寻常表现。个体变异可能导致不同的特定风险。鉴于低外显率和可变表达性，基因型 - 表型相关性具有挑战性。仔细的家族史评估对于预防规划至关重要，并且分子诊断的可用性增强了这一评估。
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