Limits...
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.

Show MeSH

Related in: MedlinePlus

Kaplan Meier plots for distal 10q loss and 1p/19q co-deletion in (A) discovery, (B) validation and (C) confirmation cohorts. The dark blue line indicates loss of distal 10q without 1p/19q co-deletion versus the rest of the cohort (n =15, P-value =0.001 in (A), n =8, P-value =0.018 in (B), and n =14, P-value =0.0018 in (C). The green line indicates 1p/19q co-deletion without distal loss of 10q (n =38, P-value =0.0001 in (A), n =41, P-value =0.0005 in (B), and n =47, P-value =0.74 in (C). The light blue line indicates 10q loss and 1p/19q co-deletion (n =3, P-value =0.39 in (A), n =4, P-value =0.94 in (B), and n =0 in (C). The grey line indicates neither 10q deletion nor 1p/19q co-deletion (n =42 in (A), n =73 in (B), and n =123 in (C). The y-axis represents the fraction of patients alive, cumulative survival (Cum. Surv.), and the x-axis time in months. Censored patients are indicated with a vertical bar.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: Kaplan Meier plots for distal 10q loss and 1p/19q co-deletion in (A) discovery, (B) validation and (C) confirmation cohorts. The dark blue line indicates loss of distal 10q without 1p/19q co-deletion versus the rest of the cohort (n =15, P-value =0.001 in (A), n =8, P-value =0.018 in (B), and n =14, P-value =0.0018 in (C). The green line indicates 1p/19q co-deletion without distal loss of 10q (n =38, P-value =0.0001 in (A), n =41, P-value =0.0005 in (B), and n =47, P-value =0.74 in (C). The light blue line indicates 10q loss and 1p/19q co-deletion (n =3, P-value =0.39 in (A), n =4, P-value =0.94 in (B), and n =0 in (C). The grey line indicates neither 10q deletion nor 1p/19q co-deletion (n =42 in (A), n =73 in (B), and n =123 in (C). The y-axis represents the fraction of patients alive, cumulative survival (Cum. Surv.), and the x-axis time in months. Censored patients are indicated with a vertical bar.

Mentions: Association of survival with CNAs detected in the discovery cohort was tested. In addition to the known prognostically favorable 1p/19q co-deletion, five further chromosomal losses at chromosomes 9p, distal 10q, 11p, 13q, and 22q presented with statistical significance (Table 2). No associations were observed with gains. Significant regions were verified in the French validation cohort of 126 diffuse LGG patients (Table 1). Loss of distal 10q was an unfavorable CNA in both cohorts, whereas losses of chromosomal regions at 9p, 11p, 13q and 22q were not substantiated in the validation cohort (Table 2). In the discovery cohort, median overall survival for patients with or without loss of whole or distal 10q was respectively 6.6 years versus 16.7 years (18/98, P-value =0.009). The size of chromosome 10 deletion varies from whole chromosome loss (5/18) to 22.5 Mbp distal loss (10q25.2- 10qter). An association between loss of this region with overall survival was finally tested in the TCGA dataset of LGG. Despite the limited number of patients deceased in this cohort (Table 1), a significant association with overall survival was observed (P-value =0.0018) (Figure 3), which confirms that distal 10q is a prognostically unfavorable chromosomal aberration.Table 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)

Kaplan Meier plots for distal 10q loss and 1p/19q co-deletion in (A) discovery, (B) validation and (C) confirmation cohorts. The dark blue line indicates loss of distal 10q without 1p/19q co-deletion versus the rest of the cohort (n =15, P-value =0.001 in (A), n =8, P-value =0.018 in (B), and n =14, P-value =0.0018 in (C). The green line indicates 1p/19q co-deletion without distal loss of 10q (n =38, P-value =0.0001 in (A), n =41, P-value =0.0005 in (B), and n =47, P-value =0.74 in (C). The light blue line indicates 10q loss and 1p/19q co-deletion (n =3, P-value =0.39 in (A), n =4, P-value =0.94 in (B), and n =0 in (C). The grey line indicates neither 10q deletion nor 1p/19q co-deletion (n =42 in (A), n =73 in (B), and n =123 in (C). The y-axis represents the fraction of patients alive, cumulative survival (Cum. Surv.), and the x-axis time in months. Censored patients are indicated with a vertical bar.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: Kaplan Meier plots for distal 10q loss and 1p/19q co-deletion in (A) discovery, (B) validation and (C) confirmation cohorts. The dark blue line indicates loss of distal 10q without 1p/19q co-deletion versus the rest of the cohort (n =15, P-value =0.001 in (A), n =8, P-value =0.018 in (B), and n =14, P-value =0.0018 in (C). The green line indicates 1p/19q co-deletion without distal loss of 10q (n =38, P-value =0.0001 in (A), n =41, P-value =0.0005 in (B), and n =47, P-value =0.74 in (C). The light blue line indicates 10q loss and 1p/19q co-deletion (n =3, P-value =0.39 in (A), n =4, P-value =0.94 in (B), and n =0 in (C). The grey line indicates neither 10q deletion nor 1p/19q co-deletion (n =42 in (A), n =73 in (B), and n =123 in (C). The y-axis represents the fraction of patients alive, cumulative survival (Cum. Surv.), and the x-axis time in months. Censored patients are indicated with a vertical bar.
Mentions: Association of survival with CNAs detected in the discovery cohort was tested. In addition to the known prognostically favorable 1p/19q co-deletion, five further chromosomal losses at chromosomes 9p, distal 10q, 11p, 13q, and 22q presented with statistical significance (Table 2). No associations were observed with gains. Significant regions were verified in the French validation cohort of 126 diffuse LGG patients (Table 1). Loss of distal 10q was an unfavorable CNA in both cohorts, whereas losses of chromosomal regions at 9p, 11p, 13q and 22q were not substantiated in the validation cohort (Table 2). In the discovery cohort, median overall survival for patients with or without loss of whole or distal 10q was respectively 6.6 years versus 16.7 years (18/98, P-value =0.009). The size of chromosome 10 deletion varies from whole chromosome loss (5/18) to 22.5 Mbp distal loss (10q25.2- 10qter). An association between loss of this region with overall survival was finally tested in the TCGA dataset of LGG. Despite the limited number of patients deceased in this cohort (Table 1), a significant association with overall survival was observed (P-value =0.0018) (Figure 3), which confirms that distal 10q is a prognostically unfavorable chromosomal aberration.Table 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