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Spatial and temporal evolution of distal 10q deletion, a prognostically unfavorable event in diffuse low-grade gliomas.

van Thuijl HF, Scheinin I, Sie D, Alentorn A, van Essen HF, Cordes M, Fleischeuer R, Gijtenbeek AM, Beute G, van den Brink WA, Meijer GA, Havenith M, Idbaih A, Hoang-Xuan K, Mokhtari K, Verhaak RG, van der Valk P, van de Wiel MA, Heimans JJ, Aronica E, Reijneveld JC, Wesseling P, Ylstra B - Genome Biol. (2014)

Bottom Line: Loss of 10q25.2-qter is a frequent subclonal event and significantly correlates with an unfavorable prognosis.A significant correlation is furthermore observed in a validation set of 126 and confirmation set of 184 patients.Intratumoral heterogeneity and higher frequencies of distal 10q loss in recurrences suggest this event is involved in outgrowth to the recurrent tumor.

View Article: PubMed Central - PubMed

ABSTRACT

Background: The disease course of patients with diffuse low-grade glioma is notoriously unpredictable. Temporal and spatially distinct samples may provide insight into the evolution of clinically relevant copy number aberrations (CNAs). The purpose of this study is to identify CNAs that are indicative of aggressive tumor behavior and can thereby complement the prognostically favorable 1p/19q co-deletion.

Results: Genome-wide, 50 base pair single-end sequencing was performed to detect CNAs in a clinically well-characterized cohort of 98 formalin-fixed paraffin-embedded low-grade gliomas. CNAs are correlated with overall survival as an endpoint. Seventy-five additional samples from spatially distinct regions and paired recurrent tumors of the discovery cohort were analyzed to interrogate the intratumoral heterogeneity and spatial evolution. Loss of 10q25.2-qter is a frequent subclonal event and significantly correlates with an unfavorable prognosis. A significant correlation is furthermore observed in a validation set of 126 and confirmation set of 184 patients. Loss of 10q25.2-qter arises in a longitudinal manner in paired recurrent tumor specimens, whereas the prognostically favorable 1p/19q co-deletion is the only CNA that is stable across spatial regions and recurrent tumors.

Conclusions: CNAs in low-grade gliomas display extensive intratumoral heterogeneity. Distal loss of 10q is a late onset event and a marker for reduced overall survival in low-grade glioma patients. Intratumoral heterogeneity and higher frequencies of distal 10q loss in recurrences suggest this event is involved in outgrowth to the recurrent tumor.

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Related in: MedlinePlus

Accrual of samples and clinical data of the discovery cohort. Samples were selected based on criteria listed in the boxes connected with vertical arrows. Reasons for exclusion of samples are listed in boxes in the right panel, connected with horizontal arrows. The number below each box represents the number of patients. Boxes below the dotted line list criteria for collection of recurrent tumors and spatially distinct regions of LGGs. AII, astrocytoma; H&E, hematoxylin and eosin; OII, oligodendroglioma; OAII, oligoastrocytoma.
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Fig1: Accrual of samples and clinical data of the discovery cohort. Samples were selected based on criteria listed in the boxes connected with vertical arrows. Reasons for exclusion of samples are listed in boxes in the right panel, connected with horizontal arrows. The number below each box represents the number of patients. Boxes below the dotted line list criteria for collection of recurrent tumors and spatially distinct regions of LGGs. AII, astrocytoma; H&E, hematoxylin and eosin; OII, oligodendroglioma; OAII, oligoastrocytoma.

Mentions: We studied 173 formalin-fixed paraffin-embedded (FFPE) samples from 98 LGG patients, including spatially distinct regions and paired recurrent tumors, by shallow WGS. Patients had either deceased or had passed the median survival time of six years for LGGs. Other inclusion criteria and patient characteristics of this discovery cohort are summarized in Figure 1 and Table 1. Age at diagnosis, overall survival and postoperative treatment (type and timing) varied extensively between patients, but not between the five participating hospitals, which contributed nearly equal numbers of cases. Comparison of overall survival between patients treated immediately after surgery and those for whom postoperative treatment was withheld did not reveal statistically significant differences. Characteristics of the LGG patients of the French validation (n =126) [5] and confirmation cohorts (n =184), the latter from publicly available data from The Cancer Genome Atlas (TCGA) [10], are also listed in Table 1. Due to the retrospective character of this study, the cohorts are not matched; there is considerable variation in duration of follow-up and the percentage of patients deceased and for which information on overall survival is available, as well as in the distribution of histological subgroups.Figure 1


Spatial and temporal evolution of distal 10q deletion, a prognostically unfavorable event in diffuse low-grade gliomas.

van Thuijl HF, Scheinin I, Sie D, Alentorn A, van Essen HF, Cordes M, Fleischeuer R, Gijtenbeek AM, Beute G, van den Brink WA, Meijer GA, Havenith M, Idbaih A, Hoang-Xuan K, Mokhtari K, Verhaak RG, van der Valk P, van de Wiel MA, Heimans JJ, Aronica E, Reijneveld JC, Wesseling P, Ylstra B - Genome Biol. (2014)

Accrual of samples and clinical data of the discovery cohort. Samples were selected based on criteria listed in the boxes connected with vertical arrows. Reasons for exclusion of samples are listed in boxes in the right panel, connected with horizontal arrows. The number below each box represents the number of patients. Boxes below the dotted line list criteria for collection of recurrent tumors and spatially distinct regions of LGGs. AII, astrocytoma; H&E, hematoxylin and eosin; OII, oligodendroglioma; OAII, oligoastrocytoma.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4195855&req=5

Fig1: Accrual of samples and clinical data of the discovery cohort. Samples were selected based on criteria listed in the boxes connected with vertical arrows. Reasons for exclusion of samples are listed in boxes in the right panel, connected with horizontal arrows. The number below each box represents the number of patients. Boxes below the dotted line list criteria for collection of recurrent tumors and spatially distinct regions of LGGs. AII, astrocytoma; H&E, hematoxylin and eosin; OII, oligodendroglioma; OAII, oligoastrocytoma.
Mentions: We studied 173 formalin-fixed paraffin-embedded (FFPE) samples from 98 LGG patients, including spatially distinct regions and paired recurrent tumors, by shallow WGS. Patients had either deceased or had passed the median survival time of six years for LGGs. Other inclusion criteria and patient characteristics of this discovery cohort are summarized in Figure 1 and Table 1. Age at diagnosis, overall survival and postoperative treatment (type and timing) varied extensively between patients, but not between the five participating hospitals, which contributed nearly equal numbers of cases. Comparison of overall survival between patients treated immediately after surgery and those for whom postoperative treatment was withheld did not reveal statistically significant differences. Characteristics of the LGG patients of the French validation (n =126) [5] and confirmation cohorts (n =184), the latter from publicly available data from The Cancer Genome Atlas (TCGA) [10], are also listed in Table 1. Due to the retrospective character of this study, the cohorts are not matched; there is considerable variation in duration of follow-up and the percentage of patients deceased and for which information on overall survival is available, as well as in the distribution of histological subgroups.Figure 1

Bottom Line: Loss of 10q25.2-qter is a frequent subclonal event and significantly correlates with an unfavorable prognosis.A significant correlation is furthermore observed in a validation set of 126 and confirmation set of 184 patients.Intratumoral heterogeneity and higher frequencies of distal 10q loss in recurrences suggest this event is involved in outgrowth to the recurrent tumor.

View Article: PubMed Central - PubMed

ABSTRACT

Background: The disease course of patients with diffuse low-grade glioma is notoriously unpredictable. Temporal and spatially distinct samples may provide insight into the evolution of clinically relevant copy number aberrations (CNAs). The purpose of this study is to identify CNAs that are indicative of aggressive tumor behavior and can thereby complement the prognostically favorable 1p/19q co-deletion.

Results: Genome-wide, 50 base pair single-end sequencing was performed to detect CNAs in a clinically well-characterized cohort of 98 formalin-fixed paraffin-embedded low-grade gliomas. CNAs are correlated with overall survival as an endpoint. Seventy-five additional samples from spatially distinct regions and paired recurrent tumors of the discovery cohort were analyzed to interrogate the intratumoral heterogeneity and spatial evolution. Loss of 10q25.2-qter is a frequent subclonal event and significantly correlates with an unfavorable prognosis. A significant correlation is furthermore observed in a validation set of 126 and confirmation set of 184 patients. Loss of 10q25.2-qter arises in a longitudinal manner in paired recurrent tumor specimens, whereas the prognostically favorable 1p/19q co-deletion is the only CNA that is stable across spatial regions and recurrent tumors.

Conclusions: CNAs in low-grade gliomas display extensive intratumoral heterogeneity. Distal loss of 10q is a late onset event and a marker for reduced overall survival in low-grade glioma patients. Intratumoral heterogeneity and higher frequencies of distal 10q loss in recurrences suggest this event is involved in outgrowth to the recurrent tumor.

Show MeSH
Related in: MedlinePlus