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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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Unsupervised clustering of CNAs in the discovery cohort. Histological subtypes and patients are color-coded on the x-axis and chromosomes are ordered on the y-axis, 1 to 22 from bottom to top. Shades of green enable visualization of individual chromosomal arms, their size varying by the number of regions. Hence, a chromosomal arm with many breakpoints based on CNAs is depicted as larger compared with one with fewer breakpoints. Red, copy number loss; blue, copy number gain; black, no CNA. OII, oligodendroglioma; OAII, oligoastrocytoma; AII, astrocytoma.
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Fig2: Unsupervised clustering of CNAs in the discovery cohort. Histological subtypes and patients are color-coded on the x-axis and chromosomes are ordered on the y-axis, 1 to 22 from bottom to top. Shades of green enable visualization of individual chromosomal arms, their size varying by the number of regions. Hence, a chromosomal arm with many breakpoints based on CNAs is depicted as larger compared with one with fewer breakpoints. Red, copy number loss; blue, copy number gain; black, no CNA. OII, oligodendroglioma; OAII, oligoastrocytoma; AII, astrocytoma.

Mentions: To obtain genome-wide copy numbers from the FFPE samples of our discovery cohort, we evaluated the use of shallow WGS. First, for sample LGG284 a paired-end 100 (PE100) sequence run was performed. Copy number profiles were produced by counting the unique sequence tags per 15 kb bin of the paired-end 100 bp reads from both ends (PE100 in Figure S1A in Additional file 1), the single 100 bp read from one end (SR100 in Figure S1B in Additional file 1) and the trimmed first single 50 bp read from the same end (SR50 in Figure S1C in Additional file 1). The noise (measured as variance) of the different profiles is very similar and CNAs observed are indistinguishable from each other, which implies that the uniqueness of the 50 bp sequence tags suffices to infer copy number levels, and longer reads are not necessary. Array comparative genomic hybridization (array CGH) was performed on the same DNA sample, which confirmed the CNAs detected (Figure S1D in Additional file 1). For an additional eight samples both 50 bp single-read (SR50) shallow WGS and array CGH were applied as technical validation. Shallow WGS and array analysis invariably yielded the same CNA profiles (Figure S2 in Additional file 1). Based on this information, all subsequent analyses were performed using 50 bp single-read (SR50) shallow WGS since it is more cost-effective and allows the use of samples with short DNA fragments, which are frequently obtained with FFPE materials. The most frequent CNAs, detected in more than 10% of cases, are whole or partial loss of chromosomal arms 9p, 10q, 12p, 13 and 14, as well as gain of chromosomal arms 7q, 8q, 10p and 11q. The most frequent CNAs in this cohort are co-deletion of 1p and 19q often accompanied by loss of whole chromosome 4, all commensurate with previous reports [11] (Figure 2).Figure 2


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)

Unsupervised clustering of CNAs in the discovery cohort. Histological subtypes and patients are color-coded on the x-axis and chromosomes are ordered on the y-axis, 1 to 22 from bottom to top. Shades of green enable visualization of individual chromosomal arms, their size varying by the number of regions. Hence, a chromosomal arm with many breakpoints based on CNAs is depicted as larger compared with one with fewer breakpoints. Red, copy number loss; blue, copy number gain; black, no CNA. OII, oligodendroglioma; OAII, oligoastrocytoma; AII, astrocytoma.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Unsupervised clustering of CNAs in the discovery cohort. Histological subtypes and patients are color-coded on the x-axis and chromosomes are ordered on the y-axis, 1 to 22 from bottom to top. Shades of green enable visualization of individual chromosomal arms, their size varying by the number of regions. Hence, a chromosomal arm with many breakpoints based on CNAs is depicted as larger compared with one with fewer breakpoints. Red, copy number loss; blue, copy number gain; black, no CNA. OII, oligodendroglioma; OAII, oligoastrocytoma; AII, astrocytoma.
Mentions: To obtain genome-wide copy numbers from the FFPE samples of our discovery cohort, we evaluated the use of shallow WGS. First, for sample LGG284 a paired-end 100 (PE100) sequence run was performed. Copy number profiles were produced by counting the unique sequence tags per 15 kb bin of the paired-end 100 bp reads from both ends (PE100 in Figure S1A in Additional file 1), the single 100 bp read from one end (SR100 in Figure S1B in Additional file 1) and the trimmed first single 50 bp read from the same end (SR50 in Figure S1C in Additional file 1). The noise (measured as variance) of the different profiles is very similar and CNAs observed are indistinguishable from each other, which implies that the uniqueness of the 50 bp sequence tags suffices to infer copy number levels, and longer reads are not necessary. Array comparative genomic hybridization (array CGH) was performed on the same DNA sample, which confirmed the CNAs detected (Figure S1D in Additional file 1). For an additional eight samples both 50 bp single-read (SR50) shallow WGS and array CGH were applied as technical validation. Shallow WGS and array analysis invariably yielded the same CNA profiles (Figure S2 in Additional file 1). Based on this information, all subsequent analyses were performed using 50 bp single-read (SR50) shallow WGS since it is more cost-effective and allows the use of samples with short DNA fragments, which are frequently obtained with FFPE materials. The most frequent CNAs, detected in more than 10% of cases, are whole or partial loss of chromosomal arms 9p, 10q, 12p, 13 and 14, as well as gain of chromosomal arms 7q, 8q, 10p and 11q. The most frequent CNAs in this cohort are co-deletion of 1p and 19q often accompanied by loss of whole chromosome 4, all commensurate with previous reports [11] (Figure 2).Figure 2

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