<i>CREBBP</i>and<i>STAT6</i>co-mutation and 16p13 and 1p36 loss define the t(14;18)-negative diffuse variant of follicular lymphoma

Xian, Rena R.; Xie, Youhua; Haley, Lisa; Yonescu, Raluca; Pallavajjala, Aparna; Pittaluga, Stefania; Jaffe, Elaine S.; Duffield, Amy S.; McCall, Chad M.; Gheith, Shereen M F; Gocke, Christopher D.

doi:10.1101/2020.05.28.120212

Cited by 4 publications

(7 citation statements)

References 60 publications

(105 reference statements)

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“…STAT6 mutation has been found to be enriched in selected series of FL with diffuse growth pattern, CD23 expression, and/or absence of t(14;18). [36][37][38][39] Our analysis identifies the FL_STAT6 cluster independent of such criteria but sharing associated molecular features, providing further evidence for this as a distinct molecular subtype of FL. In these prior studies of FL enrichment of STAT6 with CREBBP and TNFRSF14 mutation has been a consistent finding which is shared with our analysis.…”

Section: Discussionsupporting

confidence: 51%

“…We note that this does not exclude the potential for selective enrichment of STAT6 mutation among BCL2 translocation-negative FL, as has been previously reported, but argues that STAT6 mutation may occur as a feature of both BCL2 translocation-positive and -negative FL cases. [36][37][38][39] Mutational profiles in FL subgroups BIC clustering only on aSHM targets (excluding BCL2) confirmed the segregation based on these features alone, supporting the conclusion that a significant subset of FL is characterized by a mutational pattern consistent with higher aSHM activity. Seeking further evidence of differential mutational mechanisms between FL subsets, we carried out a mutational signature analysis.…”

Section: Fl Genetic Subclusterssupporting

confidence: 59%

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Molecular Subclusters of Follicular Lymphoma: A Report From the Uk's Haematological Malignancy Research Network

Crouch

Painter

Barrans

et al. 2021

Hematological Oncology

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= 43, 70, 124, by age respectively). All NHL sub-types were more common in males except for Mediastinal B-cell (PMBL) more common in females. For all NHLs combined, survival was not influenced by gender or age but differed by place of care. 2y OS of patients aged 15-24y treated at the 29 Consented Study hospitals was 86% and 74% at other, mostly smaller district hospitals, Hazard Ratio 1.75 (0.94, 3.26). Consented Study Cohort 392 patients were recruited , 15-19y (n = 111), 20-24y (n = 148), 25-29y (n = 133). 27 NHL sub-types were recorded. Presentation with advanced disease was common; of 104 DLBCLs, 15% had NCCI IPI score of 4-5 and 18% had ≥3 extranodal disease sites.Unexpected was frequent failure to respond to first-line therapy in DLBCL and PMBL. 8/81 (10%) DLBCLs with complete treatment records died with refractory disease and 9 (11%) required ≥2 lines to achieve remission. 4/60 (7%) PMBLs died with refractory disease and 19 (32%) remained PET positive after first-line chemotherapy, needing further chemotherapy or radiotherapy to achieve remission.There was variation between hospitals in treatment regimens used for individual diseases. The effect of treatment on survival being most marked for Burkitt's Lymphoma aged 15-24y. Of a total 32 cases, 23 were treated with (R)CODOX-M±IVAC, 7 died (OS 69%); 9 treated on the (R)FAB/LMB96 protocol, 1 died (OS 89%). This observation needs investigation in a randomised trial.Conclusions: NHL in teenage and young adult patients is challenging to manage. Advanced disease and resistance to first line treatment is common. Our findings support treatment of these cases guided by experienced cancer centres. The detailed information gained by this national collaboration provides the evidence base for future trials and treatment strategies.

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Section: Discussionsupporting

confidence: 51%

Section: Fl Genetic Subclusterssupporting

confidence: 59%

Molecular Subclusters of Follicular Lymphoma: A Report From the Uk's Haematological Malignancy Research Network

Crouch

Painter

Barrans

et al. 2021

Hematological Oncology

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“…In this study, we performed a genetic analysis of the largest series of t(14;18) 2 FL reported to date, with previous studies limited by a low number of cases 6,21 or focused on cases with BCL2 expression 11 or particular morphological features. [20][21][22]33 We found that t(14;18) 2 FL is genetically a heterogeneous disease that is most common in women, usually presents in early clinical stages (stages I/II) at diagnosis, and has an excellent prognosis. Morphologically, cases with a pure follicular growth pattern predominated (60%), although a diffuse component was frequently observed (40%).…”

Section: Discussionmentioning

confidence: 90%

“…Independent variables for cluster analysis patterns, either alone 20,33 or with the expression of CD23 21 or the presence of 1p36 deletion. 22 In the present study, we did not preselect the cases according to morphological characteristics and included all cases with a lack of t( compared with previous studies.…”

Section: A1mentioning

confidence: 99%

Follicular lymphoma t(14;18)-negative is genetically a heterogeneous disease

et al. 2020

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Fifty-five cases of t(14;18)− follicular lymphoma (FL) were genetically characterized by targeted sequencing and copy number (CN) arrays. t(14;18)− FL predominated in women (M/F 1:2); patients often presented during early clinical stages (71%), and had excellent prognoses. Overall, t(14;18)− FL displayed CN alterations (CNAs) and gene mutations carried by conventional t(14;18)+ FL (cFL), but with different frequencies. The most frequently mutated gene was STAT6 (57%) followed by CREBBP (49%), TNFRSF14 (39%), and KMT2D (27%). t(14;18)− FL showed significantly more STAT6 mutations and lacked MYD88, NOTCH2, MEF2B, and MAP2K1 mutations compared with cFL, nodal marginal zone lymphoma (NMZL), and pediatric-type FL (PTFL). We identified 2 molecular clusters. Cluster A was characterized by TNFRSF14 mutations/1p36 alterations (96%) and frequent mutations in epigenetic regulators, with recurrent loss of 6q21-24 sharing many features with cFL. Cluster B showed few genetic alterations; however, a subgroup with STAT6 mutations concurrent with CREBBP mutations/16p alterations without TNFRSF14 and EZH2 mutations was noted (65%). These 2 molecular clusters did not distinguish cases by inguinal localization, growth pattern, or presence of STAT6 mutations. BCL6 rearrangements were demonstrated in 10 of 45 (22%) cases and did not cluster together. Cases with predominantly inguinal presentation (20 of 50; 40%) had a higher frequency of diffuse growth pattern, STAT6 mutations, CD23 expression, and a lower number of CNAs, in comparison with noninguinal cases (5.1 vs 9.1 alterations per case; P < .05). STAT6 mutations showed a positive correlation with CD23 expression (P < .001). In summary, t(14;18)− FL is genetically a heterogeneous disorder with features that differ from cFL, NMZL, and PTFL.

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“…For example, TP53:KRAS co-mutation in NSCLC was found to confer clinical benefit to PD-1 inhibitors [7]. CREBBP:STAT6 co-mutation supports the diagnosis of the diffuse variant of follicular lymphoma [8]. NSCLC patients with EGFR:TP53 or EGFR:PIK3CA co-mutation are more likely to be resistant to the first-generation EGFR tyrosine kinase inhibitors [9].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of Co-Mutations Identifies Cooperating Mechanisms of Tumorigenesis

Jiang

Ness

et al. 2021

Preprint

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Somatic mutations are one of the most important factors in tumorigenesis and are the focus of most cancer sequencing efforts. The co-occurrence of multiple mutations in one tumor has gained increasing attention as a means of identifying cooperating mutations or pathways that contribute to cancer.Using multi-omics, phenotypical, and clinical data from 29,559 cancer subjects and 1,747 cancer cell lines covering 78 distinct cancer types, we show that co-mutations are associated with prognosis, drug sensitivity, and disparities in sex, age, and race. Some co-mutation combinations displayed stronger effects than their corresponding single mutations. For example, co-mutation TP53:KRAS in pancreatic adenocarcinoma is significantly associated with disease specific survival (hazard ratio = 2.87, adjusted p-value = 0.0003) and its prognostic predictive power is greater than either TP53 or KRAS as individually mutated genes. Functional analyses revealed that co-mutations with higher prognostic values have higher potential impact and cause greater dysregulation of gene expression. Furthermore, many of the prognostically significant co-mutations caused gains or losses of binding sequences of RNA binding proteins or micro RNAs with known cancer associations. Thus, detailed analyses of co-mutations can identify mechanisms that cooperate in tumorigenesis.

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CREBBPandSTAT6co-mutation and 16p13 and 1p36 loss define the t(14;18)-negative diffuse variant of follicular lymphoma

Cited by 4 publications

References 60 publications

Molecular Subclusters of Follicular Lymphoma: A Report From the Uk's Haematological Malignancy Research Network

Molecular Subclusters of Follicular Lymphoma: A Report From the Uk's Haematological Malignancy Research Network

Follicular lymphoma t(14;18)-negative is genetically a heterogeneous disease

Comprehensive Analysis of Co-Mutations Identifies Cooperating Mechanisms of Tumorigenesis

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