Targeted sequencing in DLBCL, molecular subtypes, and outcomes: a Haematological Malignancy Research Network report

被引：370

作者：

Lacy, Stuart E. ^{[1
]}

Barrans, Sharon L. ^{[2
]}

Beer, Philip A. ^{[3
]}

Painter, Daniel ^{[1
]}

Smith, Alexandra G. ^{[1
]}

Roman, Eve ^{[1
]}

Cooke, Susanna L. ^{[4
]}

Ruiz, Camilo ^{[3
]}

Glover, Paul ^{[2
]}

Van Hoppe, Suzan J. L. ^{[2
]}

Webster, Nichola ^{[2
]}

Campbell, Peter J. ^{[3
]}

Tooze, Reuben M. ^{[5
]}

Patmore, Russell ^{[6
]}

Burton, Cathy ^{[2
]}

Crouch, Simon ^{[1
]}

Hodson, Daniel J. ^{[7
]}

机构：

[1] Univ York, Dept Hlth Sci, Epidemiol & Canc Stat Grp, York YO10 5DD, N Yorkshire, England

[2] St Jamess Inst Oncol, Haematol Malignancy Diagnost Serv, Leeds, W Yorkshire, England

[3] Wellcome Trust Sanger Inst, Cambridge, England

[4] Univ Glasgow, Inst Canc Sci, Glasgow, Lanark, Scotland

[5] Univ Leeds, Leeds Inst Mol Med, Sect Expt Haematol, Leeds, W Yorkshire, England

[6] Castle Hill Hosp, Queens Ctr Oncol & Haematol, Cottingham, England

[7] Univ Cambridge, Wellcome MRC Cambridge Stem Cell Inst, Cambridge, England

来源：

BLOOD | 2020年 / 135卷 / 20期

基金：

英国医学研究理事会;

关键词：

B-CELL LYMPHOMA; GENOME; DISCOVERY; MUTATION; GENETICS; REVEALS; GENES;

D O I：

10.1182/blood.2019003535

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Based on the profile of genetic alterations occurring in tumor samples from selected diffuse large B-cell lymphoma (DLBCL) patients, 2 recent whole-exome sequencing studies proposed partially overlapping classification systems. Using clustering techniques applied to targeted sequencing data derived from a large unselected population-based patient cohort with full clinical follow-up (n = 928), we investigated whether molecular subtypes can be robustly identified using methods potentially applicable in routine clinical practice. DNA extracted from DLBCL tumors diagnosed in patients residing in a catchment population of similar to 4 million (14 centers) were sequenced with a targeted 293-gene hematological-malignancy panel. Bernoulli mixture-model clustering was applied and the resulting subtypes analyzed in relation to their clinical characteristics and outcomes. Five molecular subtypes were resolved, termed MYD88, BCL2, SOCS1/SGK1, TET2/SGK1, and NOTCH2, along with an unclassified group. The subtypes characterized by genetic alterations of BCL2, NOTCH2, and MYD88 recapitulated recent studies showing good, intermediate, and poor prognosis, respectively. The SOCS1/SGK1 subtype showed biological overlap with primary mediastinal B-cell lymphoma and conferred excellent prognosis. Although not identified as a distinct cluster, NOTCH1 mutation was associated with poor prognosis. The impact of TP53 mutation varied with genomic subtypes, conferring no effect in the NOTCH2 subtype and poor prognosis in the MYD88 subtype. Our findings confirm the existence of molecular subtypes of DLBCL, providing evidence that genomic tests have prognostic significance in non-selected DLBCL patients. The identification of both good and poor risk subtypes in patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) clearly show the clinical value of the approach, confirming the need for a consensus classification.

引用

页码：1759 / 1771

页数：13

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