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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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CNAs in initial and recurrent tumors. (A) Gains; (B) losses. The top of each graph shows the initial tumors, and the bottom the recurrences. Partial loss of chromosomal arm 4q, 9p and 10q were more frequently detected in recurrences. Bins are ordered by genomic position and from chromosomes 1 to 22 on the x-axis; percentages of cases showing CNAs are depicted on the y-axis.
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Fig6: CNAs in initial and recurrent tumors. (A) Gains; (B) losses. The top of each graph shows the initial tumors, and the bottom the recurrences. Partial loss of chromosomal arm 4q, 9p and 10q were more frequently detected in recurrences. Bins are ordered by genomic position and from chromosomes 1 to 22 on the x-axis; percentages of cases showing CNAs are depicted on the y-axis.

Mentions: Forty-seven out of 98 patients were subjected to a second surgery because of tumor progression. Of 20 patients, 24 recurrent tumors could be retrieved from medical archives. Almost 50% of CNAs (99/207) in the initial and paired recurrent tumors were shared and 15% (31/207) were uniquely detected in the initial tumor. A substantial proportion (37%, 77/207) of CNAs was uniquely identified in the recurrent tumor, such as loss of genomic regions at chromosomes 4, 10 and 15 (Figures 5C and 6). 1p/19q co-deletion was consistently identified in initial as well as recurrent tumors and there were no cases with new 1p/19q co-deletion. In four patients, de novo loss of 10q (including distal 10q losses) surfaced in the recurrence. In hindsight, marginal deflection of 10q was observed in the initial tumor of one of these four patients, and was not detected by the calling algorithm [12]. In two out of four patients with new loss of 10q a higher malignancy grade (WHO grade III or IV) had been assigned to the recurrent tumor (Figure 5D). In one of the three patients for which both spatially distinct regions of the initial tumor and recurrences were analyzed, subclonal 10q loss was present in one of the regions of the initial tumor, but undetectable in the recurrence (Additional file 3). In the other two patients, 10q loss was detected in both the initial and paired recurrent tumor.Figure 6


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)

CNAs in initial and recurrent tumors. (A) Gains; (B) losses. The top of each graph shows the initial tumors, and the bottom the recurrences. Partial loss of chromosomal arm 4q, 9p and 10q were more frequently detected in recurrences. Bins are ordered by genomic position and from chromosomes 1 to 22 on the x-axis; percentages of cases showing CNAs are depicted on the y-axis.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig6: CNAs in initial and recurrent tumors. (A) Gains; (B) losses. The top of each graph shows the initial tumors, and the bottom the recurrences. Partial loss of chromosomal arm 4q, 9p and 10q were more frequently detected in recurrences. Bins are ordered by genomic position and from chromosomes 1 to 22 on the x-axis; percentages of cases showing CNAs are depicted on the y-axis.
Mentions: Forty-seven out of 98 patients were subjected to a second surgery because of tumor progression. Of 20 patients, 24 recurrent tumors could be retrieved from medical archives. Almost 50% of CNAs (99/207) in the initial and paired recurrent tumors were shared and 15% (31/207) were uniquely detected in the initial tumor. A substantial proportion (37%, 77/207) of CNAs was uniquely identified in the recurrent tumor, such as loss of genomic regions at chromosomes 4, 10 and 15 (Figures 5C and 6). 1p/19q co-deletion was consistently identified in initial as well as recurrent tumors and there were no cases with new 1p/19q co-deletion. In four patients, de novo loss of 10q (including distal 10q losses) surfaced in the recurrence. In hindsight, marginal deflection of 10q was observed in the initial tumor of one of these four patients, and was not detected by the calling algorithm [12]. In two out of four patients with new loss of 10q a higher malignancy grade (WHO grade III or IV) had been assigned to the recurrent tumor (Figure 5D). In one of the three patients for which both spatially distinct regions of the initial tumor and recurrences were analyzed, subclonal 10q loss was present in one of the regions of the initial tumor, but undetectable in the recurrence (Additional file 3). In the other two patients, 10q loss was detected in both the initial and paired recurrent tumor.Figure 6

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