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一个有早发性透明细胞肾细胞癌家族史的种系变异的相互作用。

Interaction of germline variants in a family with a history of early-onset clear cell renal cell carcinoma.

作者信息

Nicolas Emmanuelle, Demidova Elena V, Iqbal Waleed, Serebriiskii Ilya G, Vlasenkova Ramilia, Ghatalia Pooja, Zhou Yan, Rainey Kim, Forman Andrea F, Dunbrack Roland L, Golemis Erica A, Hall Michael J, Daly Mary B, Arora Sanjeevani

机构信息

Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

出版信息

Mol Genet Genomic Med. 2019 Mar;7(3):e556. doi: 10.1002/mgg3.556. Epub 2019 Jan 24.

DOI:10.1002/mgg3.556
PMID:30680959
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6418363/
Abstract

BACKGROUND

Identification of genetic factors causing predisposition to renal cell carcinoma has helped improve screening, early detection, and patient survival.

METHODS

We report the characterization of a proband with renal and thyroid cancers and a family history of renal and other cancers by whole-exome sequencing (WES), coupled with WES analysis of germline DNA from additional affected and unaffected family members.

RESULTS

This work identified multiple predicted protein-damaging variants relevant to the pattern of inherited cancer risk. Among these, the proband and an affected brother each had a heterozygous Ala45Thr variant in SDHA, a component of the succinate dehydrogenase (SDH) complex. SDH defects are associated with mitochondrial disorders and risk for various cancers; immunochemical analysis indicated loss of SDHB protein expression in the patient's tumor, compatible with SDH deficiency. Integrated analysis of public databases and structural predictions indicated that the two affected individuals also had additional variants in genes including TGFB2, TRAP1, PARP1, and EGF, each potentially relevant to cancer risk alone or in conjunction with the SDHA variant. In addition, allelic imbalances of PARP1 and TGFB2 were detected in the tumor of the proband.

CONCLUSION

Together, these data suggest the possibility of risk associated with interaction of two or more variants.

摘要

背景

确定导致肾细胞癌易感性的遗传因素有助于改善筛查、早期检测和患者生存率。

方法

我们报告了通过全外显子组测序（WES）对一名患有肾癌和甲状腺癌且有肾癌及其他癌症家族史的先证者进行的特征分析，并对其他受影响和未受影响的家庭成员的种系DNA进行了WES分析。

结果

这项研究确定了多个与遗传性癌症风险模式相关的预测性蛋白质损伤变体。其中，先证者和一名受影响的兄弟在琥珀酸脱氢酶（SDH）复合物的一个组成部分SDHA中均有一个杂合的Ala45Thr变体。SDH缺陷与线粒体疾病和各种癌症风险相关；免疫化学分析表明患者肿瘤中SDHB蛋白表达缺失，与SDH缺乏相符。对公共数据库的综合分析和结构预测表明，这两名受影响的个体在包括TGFB2、TRAP1、PARP1和EGF在内的基因中也有其他变体，每个变体单独或与SDHA变体一起都可能与癌症风险相关。此外，在先证者的肿瘤中检测到PARP1和TGFB2的等位基因失衡。

结论

总之，这些数据表明两个或更多变体相互作用可能存在风险。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb85/6418363/12ffad537b7d/MGG3-7-na-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb85/6418363/f4414a536884/MGG3-7-na-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb85/6418363/2f7108fd35fa/MGG3-7-na-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb85/6418363/1527c15d9256/MGG3-7-na-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb85/6418363/9c8559f18c7f/MGG3-7-na-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb85/6418363/e5a17438928e/MGG3-7-na-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb85/6418363/12ffad537b7d/MGG3-7-na-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb85/6418363/f4414a536884/MGG3-7-na-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb85/6418363/2f7108fd35fa/MGG3-7-na-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb85/6418363/1527c15d9256/MGG3-7-na-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb85/6418363/9c8559f18c7f/MGG3-7-na-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb85/6418363/e5a17438928e/MGG3-7-na-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb85/6418363/12ffad537b7d/MGG3-7-na-g006.jpg

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