Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors

被引：100

作者：

Rodrigues, Manuel ^{[1
,2
]}

Mobuchon, Lenha ^{[1
]}

Houy, Alexandre ^{[1
]}

Fievet, Alice ^{[1
,3
]}

Gardrat, Sophie ^{[4
]}

Barnhill, Raymond L. ^{[4
,5
]}

Popova, Tatiana ^{[1
]}

Servois, Vincent ^{[6
]}

Rampanou, Aurore ^{[7
]}

Mouton, Aurore ^{[8
]}

Dayot, Stephane ^{[1
]}

Raynal, Virginie ^{[9
,10
]}

Galut, Michele ^{[11
]}

Putterman, Marc ^{[12
]}

Tick, Sarah ^{[13
]}

Cassoux, Nathalie ^{[5
,14
]}

Roman-Roman, Sergio ^{[15
]}

Bidard, Francois-Clement ^{[2
,7
,16
]}

Lantz, Olivier ^{[8
]}

Mariani, Pascale ^{[17
]}

Piperno-Neumann, Sophie ^{[2
]}

Stern, Marc-Henri ^{[1
,3
]}

机构：

[1] PSL Res Univ, Inst Curie, INSERM U830, DRUM,Equipe Labellisee Ligue Natl Canc, F-75248 Paris, France

[2] PSL Res Univ, Inst Curie, Dept Med Oncol, F-75248 Paris, France

[3] PSL Res Univ, Inst Curie, Dept Genet, F-75248 Paris, France

[4] PSL Res Univ, Inst Curie, Dept Biopathol, F-75248 Paris, France

[5] Univ Paris 05, Fac Med, F-75006 Paris, France

[6] PSL Res Univ, Inst Curie, Dept Med Imaging, F-75248 Paris, France

[7] PSL Res Univ, Inst Curie, Lab Circulating Tumor Biomarkers, SiRIC, F-75248 Paris, France

[8] PSL Res Univ, Inst Curie, INSERM CIC BT 1428, F-75248 Paris, France

[9] PSL Res Univ, Inst Curie, INSERM U830, F-75248 Paris, France

[10] Inst Curie Genom Excellence ICGex Platform, F-75248 Paris, France

[11] PSL Res Univ, Inst Curie, Biol Resource Ctr, F-75248 Paris, France

[12] Quinze Vingts Natl Ophthalmol Hosp, Dept Pathol, F-75012 Paris, France

[13] Quinze Vingts Natl Ophthalmol Hosp, Dept Ophthalmol 3, F-75012 Paris, France

[14] PSL Res Univ, Inst Curie, Dept Ocular Oncol, F-75248 Paris, France

[15] PSL Res Univ, Inst Curie, Dept Translat Res, F-75248 Paris, France

[16] Paris Saclay Univ, UVSQ, F-78035 St Quentin en Yvelines, France

[17] PSL Res Univ, Inst Curie, Dept Surg Oncol, F-75248 Paris, France

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

关键词：

CANCER; DNA; IDENTIFICATION; BLOCKADE; DATABASE; CELLS; PD-1;

D O I：

10.1038/s41467-018-04322-5

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Metastatic uveal melanoma is a deadly disease with no proven standard of care. Here we present a metastatic uveal melanoma patient with an exceptional high sensitivity to a PD-1 inhibitor associated with outlier CpG>TpG mutation burden, MBD4 germline deleterious mutation, and somatic MBD4 inactivation in the tumor. We identify additional tumors in The Cancer Genome Atlas (TCGA) cohorts with similar hypermutator profiles in patients carrying germline deleterious MBD4 mutations and somatic loss of heterozygosity. This MBD4-related hypermutator phenotype may explain unexpected responses to immune checkpoint inhibitors.

引用

页数：6

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