Pathogenic Germline Variants in 10,389 Adult Cancers.,Cell

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Pathogenic Germline Variants in 10,389 Adult Cancers.
Cell ( IF 45.5 ) Pub Date : 2018-04-05 , DOI: 10.1016/j.cell.2018.03.039
Kuan-Lin Huang ₁ , R Jay Mashl ₁ , Yige Wu ₁ , Deborah I Ritter ₂ , Jiayin Wang ₃ , Clara Oh ₄ , Marta Paczkowska ₅ , Sheila Reynolds ₆ , Matthew A Wyczalkowski ₁ , Ninad Oak ₇ , Adam D Scott ₁ , Michal Krassowski ₅ , Andrew D Cherniack ₈ , Kathleen E Houlahan ₉ , Reyka Jayasinghe ₁ , Liang-Bo Wang ₁ , Daniel Cui Zhou ₁ , Di Liu ₄ , Song Cao ₁ , Young Won Kim ₇ , Amanda Koire ₇ , Joshua F McMichael ₁₀ , Vishwanathan Hucthagowder ₁₁ , Tae-Beom Kim ₁₂ , Abigail Hahn ₆ , Chen Wang ₁₃ , Michael D McLellan ₁₀ , Fahd Al-Mulla ₁₄ , Kimberly J Johnson ₁₅ , , Olivier Lichtarge ₇ , Paul C Boutros ₉ , Benjamin Raphael ₁₆ , Alexander J Lazar ₁₇ , Wei Zhang ₁₈ , Michael C Wendl ₁₉ , Ramaswamy Govindan ₄ , Sanjay Jain ₄ , David Wheeler ₇ , Shashikant Kulkarni ₂₀ , John F Dipersio ₂₁ , Jüri Reimand ₉ , Funda Meric-Bernstam ₂₂ , Ken Chen ₁₂ , Ilya Shmulevich ₆ , Sharon E Plon ₂₃ , Feng Chen ₂₁ , Li Ding ₂₄

Affiliation

Department of Medicine, Washington University in St. Louis, Saint Louis, MO 63108, USA; McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
School of Management, Xi'an Jiaotong University, Xi'an, Shanxi, China.
Department of Medicine, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Computational Biology Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Institute for Systems Biology, Seattle, WA 98109, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
The Broad Institute, Cambridge, MA 02142, USA.
Computational Biology Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Clinical Cytogenetics at Molecular Pathology Laboratory Network, Inc., Maryville, TN 37804, USA.
Departments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Health Sciences Research and Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, Rochester, MN 55905 USA.
Dasman Diabetes Institute and Molecular Pathology Laboratory, Kuwait University, Kuwait.
Brown School Master of Public Health Program, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Lewis-Sigler Institute, Princeton University, Princeton, NJ 08544, USA.
Departments of Pathology and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Cancer Biology and Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston Salem, NC 27157 USA.
McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO 63108, USA; Department of Genetics, Washington University in St. Louis, Saint Louis, MO 63108, USA; Department of Mathematics, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
Department of Medicine, Washington University in St. Louis, Saint Louis, MO 63108, USA; Siteman Cancer Center, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Medicine, Washington University in St. Louis, Saint Louis, MO 63108, USA; McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO 63108, USA; Department of Genetics, Washington University in St. Louis, Saint Louis, MO 63108, USA; Siteman Cancer Center, Washington University in St. Louis, Saint Louis, MO 63108, USA.

We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.

中文翻译：

10,389名成人癌症中的致病生殖细胞变异。

我们对癌症的易感性变异进行了迄今为止最大的调查，在来自33种癌症类型的10389例病例中，发现853个致病性或可能致病性变异。21个基因显示出单一或交叉癌症关联，包括黑色素瘤中SDHA和胃腺癌中PALB2的新型关联。包括ATM，BRCA1和NF1在内的肿瘤抑制因子中的659个易感变体和18个其他大缺失显示出低基因表达和频繁（43％）的杂合性或双等位基因两次击中事件。我们还发现了癌基因中的33个此类变异，包括与高基因表达相关的MET，RET和PTPN11中的错义。我们从优先级VUS提名了47个其他易感性变异体，并获得了多个证据，这些证据涉及病例控制频率，杂合性丧失，表达效果，以及与突变和修饰残基的共定位。我们的综合方法将罕见的易感变体与功能性后果联系起来，为癌症中变体分类和种系遗传测试的未来指南提供了依据。

更新日期：2018-04-06

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