Pathogenic Germline Variants in 10,389 Adult Cancers

K. L. Huang, R. J. Mashl, Y. Wu, D. I. Ritter, J. Wang, C. Oh, M. Paczkowska, S. Reynolds, M. A. Wyczalkowski, N. Oak, A. D. Scott, M. Krassowski, A. D. Cherniack, K. E. Houlahan, R. Jayasinghe, L. B. Wang, D. C. Zhou, D. Liu, S. Cao, Y. W. Kim & 29 others A. Koire, J. F. McMichael, V. Hucthagowder, T. B. Kim, A. Hahn, C. Wang, M. D. McLellan, F. Al-Mulla, K. J. Johnson, Cancer Genome Atlas Research Network, O. Lichtarge, P. C. Boutros, B. Raphael, A. J. Lazar, W. Zhang, M. C. Wendl, R. Govindan, S. Jain, D. Wheeler, S. Kulkarni, J. F. Dipersio, J. Reimand, F. Meric-Bernstam, K. Chen, I. Shmulevich, S. E. Plon, F. Chen, L. Ding, M. (come contributors) Marino

Research output: Contribution to journalArticle

Abstract

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.
Original languageEnglish
Pages (from-to)355-370.e14
JournalCell
Volume173
Issue number2
DOIs
Publication statusPublished - Apr 5 2018
Externally publishedYes

Fingerprint

Gene expression
Automatic teller machines
Loss of Heterozygosity
Tumors
Neoplasms
Genes
Testing
Gene Expression
Genetic Testing
Oncogenes
Melanoma
Stomach
Adenocarcinoma
Guidelines
Mutation

Keywords

  • LOH
  • cancer predisposition
  • germline and somatic genomes
  • variant pathogenicity

Cite this

Huang, K. L., Mashl, R. J., Wu, Y., Ritter, D. I., Wang, J., Oh, C., ... Marino, M. . C. (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

Pathogenic Germline Variants in 10,389 Adult Cancers. / Huang, K. L.; Mashl, R. J.; Wu, Y.; Ritter, D. I.; Wang, J.; Oh, C.; Paczkowska, M.; Reynolds, S.; Wyczalkowski, M. A.; Oak, N.; Scott, A. D.; Krassowski, M.; Cherniack, A. D.; Houlahan, K. E.; Jayasinghe, R.; Wang, L. B.; Zhou, D. C.; Liu, D.; Cao, S.; Kim, Y. W.; Koire, A.; McMichael, J. F.; Hucthagowder, V.; Kim, T. B.; Hahn, A.; Wang, C.; McLellan, M. D.; Al-Mulla, F.; Johnson, K. J.; Network, Cancer Genome Atlas Research; Lichtarge, O.; Boutros, P. C.; Raphael, B.; Lazar, A. J.; Zhang, W.; Wendl, M. C.; Govindan, R.; Jain, S.; Wheeler, D.; Kulkarni, S.; Dipersio, J. F.; Reimand, J.; Meric-Bernstam, F.; Chen, K.; Shmulevich, I.; Plon, S. E.; Chen, F.; Ding, L.; Marino, M. (come contributors).

In: Cell, Vol. 173, No. 2, 05.04.2018, p. 355-370.e14.

Research output: Contribution to journalArticle

Huang, KL, 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, LB, Zhou, DC, Liu, D, Cao, S, Kim, YW, Koire, A, McMichael, JF, Hucthagowder, V, Kim, TB, Hahn, A, Wang, C, McLellan, MD, Al-Mulla, F, Johnson, KJ, Network, CGAR, 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 & Marino, MC 2018, 'Pathogenic Germline Variants in 10,389 Adult Cancers', Cell, vol. 173, no. 2, pp. 355-370.e14. https://doi.org/10.1016/j.cell.2018.03.039
Huang KL, 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. https://doi.org/10.1016/j.cell.2018.03.039
Huang, K. L. ; Mashl, R. J. ; Wu, Y. ; Ritter, D. I. ; Wang, J. ; Oh, C. ; Paczkowska, M. ; Reynolds, S. ; Wyczalkowski, M. A. ; Oak, N. ; Scott, A. D. ; Krassowski, M. ; Cherniack, A. D. ; Houlahan, K. E. ; Jayasinghe, R. ; Wang, L. B. ; Zhou, D. C. ; Liu, D. ; Cao, S. ; Kim, Y. W. ; Koire, A. ; McMichael, J. F. ; Hucthagowder, V. ; Kim, T. B. ; Hahn, A. ; Wang, C. ; McLellan, M. D. ; Al-Mulla, F. ; Johnson, K. J. ; Network, Cancer Genome Atlas Research ; Lichtarge, O. ; Boutros, P. C. ; Raphael, B. ; Lazar, A. J. ; Zhang, W. ; Wendl, M. C. ; Govindan, R. ; Jain, S. ; Wheeler, D. ; Kulkarni, S. ; Dipersio, J. F. ; Reimand, J. ; Meric-Bernstam, F. ; Chen, K. ; Shmulevich, I. ; Plon, S. E. ; Chen, F. ; Ding, L. ; Marino, M. (come contributors). / Pathogenic Germline Variants in 10,389 Adult Cancers. In: Cell. 2018 ; Vol. 173, No. 2. pp. 355-370.e14.
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TY - JOUR

T1 - Pathogenic Germline Variants in 10,389 Adult Cancers

AU - Huang, K. L.

AU - Mashl, R. J.

AU - Wu, Y.

AU - Ritter, D. I.

AU - Wang, J.

AU - Oh, C.

AU - Paczkowska, M.

AU - Reynolds, S.

AU - Wyczalkowski, M. A.

AU - Oak, N.

AU - Scott, A. D.

AU - Krassowski, M.

AU - Cherniack, A. D.

AU - Houlahan, K. E.

AU - Jayasinghe, R.

AU - Wang, L. B.

AU - Zhou, D. C.

AU - Liu, D.

AU - Cao, S.

AU - Kim, Y. W.

AU - Koire, A.

AU - McMichael, J. F.

AU - Hucthagowder, V.

AU - Kim, T. B.

AU - Hahn, A.

AU - Wang, C.

AU - McLellan, M. D.

AU - Al-Mulla, F.

AU - Johnson, K. J.

AU - Network, Cancer Genome Atlas Research

AU - Lichtarge, O.

AU - Boutros, P. C.

AU - Raphael, B.

AU - Lazar, A. J.

AU - Zhang, W.

AU - Wendl, M. C.

AU - Govindan, R.

AU - Jain, S.

AU - Wheeler, D.

AU - Kulkarni, S.

AU - Dipersio, J. F.

AU - Reimand, J.

AU - Meric-Bernstam, F.

AU - Chen, K.

AU - Shmulevich, I.

AU - Plon, S. E.

AU - Chen, F.

AU - Ding, L.

AU - Marino, M. (come contributors)

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PY - 2018/4/5

Y1 - 2018/4/5

N2 - 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.

AB - 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.

KW - LOH

KW - cancer predisposition

KW - germline and somatic genomes

KW - variant pathogenicity

U2 - 10.1016/j.cell.2018.03.039

DO - 10.1016/j.cell.2018.03.039

M3 - Article

VL - 173

SP - 355-370.e14

JO - Cell

JF - Cell

SN - 0092-8674

IS - 2

ER -