Pathogenic Germline Variants in 10,389 Adult Cancers

The Cancer Genome Atlas Research Network

Research output: Contribution to journalArticle

61 Citations (Scopus)

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. A pan-cancer analysis identifies hundreds of predisposing germline variants.

Original languageEnglish (US)
Pages (from-to)355-370.e14
JournalCell
Volume173
Issue number2
DOIs
StatePublished - Apr 5 2018

Fingerprint

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

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

The Cancer Genome Atlas Research Network (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. / The Cancer Genome Atlas Research Network.

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

Research output: Contribution to journalArticle

The Cancer Genome Atlas Research Network 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
The Cancer Genome Atlas Research Network. 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
The Cancer Genome Atlas Research Network. / Pathogenic Germline Variants in 10,389 Adult Cancers. In: Cell. 2018 ; Vol. 173, No. 2. pp. 355-370.e14.
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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. A pan-cancer analysis identifies hundreds of predisposing germline variants.",
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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. A pan-cancer analysis identifies hundreds of predisposing germline variants.

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