Integrated analysis of germline and somatic variants in ovarian cancer

Krishna L. Kanchi; Kimberly J. Johnson; Charles Lu; Michael D. McLellan; Mark D.M. Leiserson; Michael Wendl; Qunyuan Zhang; Daniel C. Koboldt; Mingchao Xie; Cyriac Kandoth; Joshua F. McMichael; Matthew A. Wyczalkowski; David E. Larson; Heather K. Schmidt; Christopher Miller; Robert Fulton; Paul T. Spellman; Elaine R. Mardis; Todd Druley; Timothy A. Graubert; Paul J. Goodfellow; Benjamin J. Raphael; Richard K. Wilson; Li Ding

doi:10.1038/ncomms4156

Integrated analysis of germline and somatic variants in ovarian cancer

Krishna L. Kanchi, Kimberly J. Johnson, Charles Lu, Michael D. McLellan, Mark D.M. Leiserson, Michael Wendl, Qunyuan Zhang, Daniel C. Koboldt, Mingchao Xie, Cyriac Kandoth, Joshua F. McMichael, Matthew A. Wyczalkowski, David E. Larson, Heather K. Schmidt, Christopher Miller, Robert Fulton, Paul T. Spellman, Elaine R. Mardis, Todd Druley, Timothy A. GraubertPaul J. Goodfellow, Benjamin J. Raphael, Richard K. Wilson, Li Ding

Research output: Contribution to journal › Article › peer-review

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Abstract

We report the first large-scale exome-wide analysis of the combined germline-somatic landscape in ovarian cancer. Here we analyse germline and somatic alterations in 429 ovarian carcinoma cases and 557 controls. We identify 3,635 high confidence, rare truncation and 22,953 missense variants with predicted functional impact. We find germline truncation variants and large deletions across Fanconi pathway genes in 20% of cases. Enrichment of rare truncations is shown in BRCA1, BRCA2 and PALB2. In addition, we observe germline truncation variants in genes not previously associated with ovarian cancer susceptibility (NF1, MAP3K4, CDKN2B and MLL3). Evidence for loss of heterozygosity was found in 100 and 76% of cases with germline BRCA1 and BRCA2 truncations, respectively. Germline-somatic interaction analysis combined with extensive bioinformatics annotation identifies 222 candidate functional germline truncation and missense variants, including two pathogenic BRCA1 and 1 TP53 deleterious variants. Finally, integrated analyses of germline and somatic variants identify significantly altered pathways, including the Fanconi, MAPK and MLL pathways.

Original language	English
Article number	3156
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms4156
State	Published - Jan 22 2014

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Kanchi, K. L., Johnson, K. J., Lu, C., McLellan, M. D., Leiserson, M. D. M., Wendl, M., Zhang, Q., Koboldt, D. C., Xie, M., Kandoth, C., McMichael, J. F., Wyczalkowski, M. A., Larson, D. E., Schmidt, H. K., Miller, C., Fulton, R., Spellman, P. T., Mardis, E. R., Druley, T., ... Ding, L. (2014). Integrated analysis of germline and somatic variants in ovarian cancer. Nature communications, 5, [3156]. https://doi.org/10.1038/ncomms4156

Kanchi, Krishna L. ; Johnson, Kimberly J. ; Lu, Charles ; McLellan, Michael D. ; Leiserson, Mark D.M. ; Wendl, Michael ; Zhang, Qunyuan ; Koboldt, Daniel C. ; Xie, Mingchao ; Kandoth, Cyriac ; McMichael, Joshua F. ; Wyczalkowski, Matthew A. ; Larson, David E. ; Schmidt, Heather K. ; Miller, Christopher ; Fulton, Robert ; Spellman, Paul T. ; Mardis, Elaine R. ; Druley, Todd ; Graubert, Timothy A. ; Goodfellow, Paul J. ; Raphael, Benjamin J. ; Wilson, Richard K. ; Ding, Li. / Integrated analysis of germline and somatic variants in ovarian cancer. In: Nature communications. 2014 ; Vol. 5.

@article{5cb99c4dcee2456e9101727a6ce93b38,

title = "Integrated analysis of germline and somatic variants in ovarian cancer",

abstract = "We report the first large-scale exome-wide analysis of the combined germline-somatic landscape in ovarian cancer. Here we analyse germline and somatic alterations in 429 ovarian carcinoma cases and 557 controls. We identify 3,635 high confidence, rare truncation and 22,953 missense variants with predicted functional impact. We find germline truncation variants and large deletions across Fanconi pathway genes in 20% of cases. Enrichment of rare truncations is shown in BRCA1, BRCA2 and PALB2. In addition, we observe germline truncation variants in genes not previously associated with ovarian cancer susceptibility (NF1, MAP3K4, CDKN2B and MLL3). Evidence for loss of heterozygosity was found in 100 and 76% of cases with germline BRCA1 and BRCA2 truncations, respectively. Germline-somatic interaction analysis combined with extensive bioinformatics annotation identifies 222 candidate functional germline truncation and missense variants, including two pathogenic BRCA1 and 1 TP53 deleterious variants. Finally, integrated analyses of germline and somatic variants identify significantly altered pathways, including the Fanconi, MAPK and MLL pathways.",

author = "Kanchi, {Krishna L.} and Johnson, {Kimberly J.} and Charles Lu and McLellan, {Michael D.} and Leiserson, {Mark D.M.} and Michael Wendl and Qunyuan Zhang and Koboldt, {Daniel C.} and Mingchao Xie and Cyriac Kandoth and McMichael, {Joshua F.} and Wyczalkowski, {Matthew A.} and Larson, {David E.} and Schmidt, {Heather K.} and Christopher Miller and Robert Fulton and Spellman, {Paul T.} and Mardis, {Elaine R.} and Todd Druley and Graubert, {Timothy A.} and Goodfellow, {Paul J.} and Raphael, {Benjamin J.} and Wilson, {Richard K.} and Li Ding",

year = "2014",

month = jan,

day = "22",

doi = "10.1038/ncomms4156",

language = "English",

volume = "5",

journal = "Nature Communications",

issn = "2041-1723",

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Kanchi, KL, Johnson, KJ, Lu, C, McLellan, MD, Leiserson, MDM, Wendl, M, Zhang, Q, Koboldt, DC, Xie, M, Kandoth, C, McMichael, JF, Wyczalkowski, MA, Larson, DE, Schmidt, HK, Miller, C , Fulton, R, Spellman, PT, Mardis, ER, Druley, T, Graubert, TA, Goodfellow, PJ, Raphael, BJ, Wilson, RK & Ding, L 2014, 'Integrated analysis of germline and somatic variants in ovarian cancer', Nature communications, vol. 5, 3156. https://doi.org/10.1038/ncomms4156

Integrated analysis of germline and somatic variants in ovarian cancer. / Kanchi, Krishna L.; Johnson, Kimberly J.; Lu, Charles; McLellan, Michael D.; Leiserson, Mark D.M.; Wendl, Michael; Zhang, Qunyuan; Koboldt, Daniel C.; Xie, Mingchao; Kandoth, Cyriac; McMichael, Joshua F.; Wyczalkowski, Matthew A.; Larson, David E.; Schmidt, Heather K.; Miller, Christopher ; Fulton, Robert; Spellman, Paul T.; Mardis, Elaine R.; Druley, Todd; Graubert, Timothy A.; Goodfellow, Paul J.; Raphael, Benjamin J.; Wilson, Richard K.; Ding, Li.

In: Nature communications, Vol. 5, 3156, 22.01.2014.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Integrated analysis of germline and somatic variants in ovarian cancer

AU - Kanchi, Krishna L.

AU - Johnson, Kimberly J.

AU - Lu, Charles

AU - McLellan, Michael D.

AU - Leiserson, Mark D.M.

AU - Wendl, Michael

AU - Zhang, Qunyuan

AU - Koboldt, Daniel C.

AU - Xie, Mingchao

AU - Kandoth, Cyriac

AU - McMichael, Joshua F.

AU - Wyczalkowski, Matthew A.

AU - Larson, David E.

AU - Schmidt, Heather K.

AU - Miller, Christopher

AU - Fulton, Robert

AU - Spellman, Paul T.

AU - Mardis, Elaine R.

AU - Druley, Todd

AU - Graubert, Timothy A.

AU - Goodfellow, Paul J.

AU - Raphael, Benjamin J.

AU - Wilson, Richard K.

AU - Ding, Li

PY - 2014/1/22

Y1 - 2014/1/22

N2 - We report the first large-scale exome-wide analysis of the combined germline-somatic landscape in ovarian cancer. Here we analyse germline and somatic alterations in 429 ovarian carcinoma cases and 557 controls. We identify 3,635 high confidence, rare truncation and 22,953 missense variants with predicted functional impact. We find germline truncation variants and large deletions across Fanconi pathway genes in 20% of cases. Enrichment of rare truncations is shown in BRCA1, BRCA2 and PALB2. In addition, we observe germline truncation variants in genes not previously associated with ovarian cancer susceptibility (NF1, MAP3K4, CDKN2B and MLL3). Evidence for loss of heterozygosity was found in 100 and 76% of cases with germline BRCA1 and BRCA2 truncations, respectively. Germline-somatic interaction analysis combined with extensive bioinformatics annotation identifies 222 candidate functional germline truncation and missense variants, including two pathogenic BRCA1 and 1 TP53 deleterious variants. Finally, integrated analyses of germline and somatic variants identify significantly altered pathways, including the Fanconi, MAPK and MLL pathways.

AB - We report the first large-scale exome-wide analysis of the combined germline-somatic landscape in ovarian cancer. Here we analyse germline and somatic alterations in 429 ovarian carcinoma cases and 557 controls. We identify 3,635 high confidence, rare truncation and 22,953 missense variants with predicted functional impact. We find germline truncation variants and large deletions across Fanconi pathway genes in 20% of cases. Enrichment of rare truncations is shown in BRCA1, BRCA2 and PALB2. In addition, we observe germline truncation variants in genes not previously associated with ovarian cancer susceptibility (NF1, MAP3K4, CDKN2B and MLL3). Evidence for loss of heterozygosity was found in 100 and 76% of cases with germline BRCA1 and BRCA2 truncations, respectively. Germline-somatic interaction analysis combined with extensive bioinformatics annotation identifies 222 candidate functional germline truncation and missense variants, including two pathogenic BRCA1 and 1 TP53 deleterious variants. Finally, integrated analyses of germline and somatic variants identify significantly altered pathways, including the Fanconi, MAPK and MLL pathways.

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DO - 10.1038/ncomms4156

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AN - SCOPUS:84892968131

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JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

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