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Pathogenic Germline Variants in 10,389 Adult Cancers.

Publication ,  Journal Article
Huang, K-L; Mashl, RJ; Wu, Y; Ritter, DI; Wang, J; Oh, C; Paczkowska, M; Reynolds, S; Wyczalkowski, MA; Oak, N; Scott, AD; Krassowski, M ...
Published in: Cell
April 5, 2018

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.

Duke Scholars

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Published In

Cell

DOI

EISSN

1097-4172

Publication Date

April 5, 2018

Volume

173

Issue

2

Start / End Page

355 / 370.e14

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Proto-Oncogene Proteins c-ret
  • Proto-Oncogene Proteins c-met
  • Polymorphism, Single Nucleotide
  • Neoplasms
  • Mutation, Missense
  • Loss of Heterozygosity
  • Humans
  • Germ-Line Mutation
  • Germ Cells
 

Citation

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Huang, K.-L., Mashl, R. J., Wu, Y., Ritter, D. I., Wang, J., Oh, C., … Ding, L. (2018). Pathogenic Germline Variants in 10,389 Adult Cancers. Cell, 173(2), 355-370.e14. https://doi.org/10.1016/j.cell.2018.03.039
Huang, Kuan-Lin, R Jay Mashl, Yige Wu, Deborah I. Ritter, Jiayin Wang, Clara Oh, Marta Paczkowska, et al. “Pathogenic Germline Variants in 10,389 Adult Cancers.Cell 173, no. 2 (April 5, 2018): 355-370.e14. https://doi.org/10.1016/j.cell.2018.03.039.
Huang K-L, Mashl RJ, Wu Y, Ritter DI, Wang J, Oh C, et al. Pathogenic Germline Variants in 10,389 Adult Cancers. Cell. 2018 Apr 5;173(2):355-370.e14.
Huang, Kuan-Lin, et al. “Pathogenic Germline Variants in 10,389 Adult Cancers.Cell, vol. 173, no. 2, Apr. 2018, pp. 355-370.e14. Pubmed, doi:10.1016/j.cell.2018.03.039.
Huang K-L, Mashl RJ, Wu Y, Ritter DI, Wang J, Oh C, Paczkowska M, Reynolds S, Wyczalkowski MA, Oak N, Scott AD, Krassowski M, Cherniack AD, Houlahan KE, Jayasinghe R, Wang L-B, Zhou DC, Liu D, Cao S, Kim YW, Koire A, McMichael JF, Hucthagowder V, Kim T-B, Hahn A, Wang C, McLellan MD, Al-Mulla F, Johnson KJ, Cancer Genome Atlas Research Network, Lichtarge O, Boutros PC, Raphael B, Lazar AJ, Zhang W, Wendl MC, Govindan R, Jain S, Wheeler D, Kulkarni S, Dipersio JF, Reimand J, Meric-Bernstam F, Chen K, Shmulevich I, Plon SE, Chen F, Ding L. Pathogenic Germline Variants in 10,389 Adult Cancers. Cell. 2018 Apr 5;173(2):355-370.e14.
Journal cover image

Published In

Cell

DOI

EISSN

1097-4172

Publication Date

April 5, 2018

Volume

173

Issue

2

Start / End Page

355 / 370.e14

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Proto-Oncogene Proteins c-ret
  • Proto-Oncogene Proteins c-met
  • Polymorphism, Single Nucleotide
  • Neoplasms
  • Mutation, Missense
  • Loss of Heterozygosity
  • Humans
  • Germ-Line Mutation
  • Germ Cells