Limits...
Epigenetic Modifications and Accumulation of DNA Double-Strand Breaks in Oral Lichen Planus Lesions Presenting Poor Response to Therapy.

Dillenburg CS, Martins MA, Almeida LO, Meurer L, Squarize CH, Martins MD, Castilho RM - Medicine (Baltimore) (2015)

Bottom Line: Although an exciting prospect, the identification of early epigenetic markers associated with clinical outcome in premalignant and malignant disorders remains elusive.We analyzed 42 OLP patients, who had different responses to therapy, for acetyl-histone H3 at lys9 (H3K9ac), which is associated with enhanced transcription and nuclear decondensation, and the presence of DSBs, as determined by accumulation of phosphorylated γH2AX foci.Patients with high levels of H3K9ac acetylation failed to respond to therapy or experienced disease recurrence shortly after therapy.

View Article: PubMed Central - PubMed

Affiliation: From the Department of Oral Pathology (CSD, MDM), School of Dentistry; Department of Oral Medicine (MATM), Hospital de Clínicas de Porto Alegre (HCPA/UFRGS); Department of Pathology (LM), School of Medicine, Hospital de Clínicas de Porto Alegre (HCPA/UFRGS), Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; and Laboratory of Epithelial Biology (CSD, MATM, LOA, CHS, MDM, RMC), Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.

ABSTRACT
Epigenetics refers to changes in cell characteristics that occur independently of modifications to the deoxyribonucleic acid (DNA) sequence. Alterations mediated by epigenetic mechanisms are important factors in cancer progression. Although an exciting prospect, the identification of early epigenetic markers associated with clinical outcome in premalignant and malignant disorders remains elusive. We examined alterations in chromatin acetylation in oral lichen planus (OLP) with distinct clinical behavior and compared the alterations to the levels of DNA double-strand breaks (DSBs). We analyzed 42 OLP patients, who had different responses to therapy, for acetyl-histone H3 at lys9 (H3K9ac), which is associated with enhanced transcription and nuclear decondensation, and the presence of DSBs, as determined by accumulation of phosphorylated γH2AX foci. Patients with high levels of H3K9ac acetylation failed to respond to therapy or experienced disease recurrence shortly after therapy. Similar to H3K9ac, patients who responded poorly to therapy had increased accumulation of DNA DSB, indicating genomic instability. These findings suggest that histone modifications occur in OLP, and H3K9ac and γH2AX histones may serve as epigenetic markers for OLP recurrence.

Show MeSH

Related in: MedlinePlus

OLP cases exhibit differential responses to therapy. (A) Clinical aspects of response of OLP patients after outcome period (8 wk after the discontinuation of treatment—day 90). Type I patients (50%) have complete remission of erosive lesions. Type II patients (32%) have partial clinical resolution. Type III patients (18%) are nonresponsive to therapy. (B) H&E-stained sections of OLP lesions from patients with differential responses to therapy depict similar histological aspects. Upper panel illustrates the presence of a well-defined band-like zone of inflammatory cell infiltration (∗) (40× magnification). Lower panel shows signs of degeneration of the basal cell layer (arrows) associated with lymphocytes infiltrate and exocytosis and absence of epithelial dysplasia (200× magnification). H&E = hematoxylin and eosin, OLP = oral lichen planus.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4554108&req=5

Figure 1: OLP cases exhibit differential responses to therapy. (A) Clinical aspects of response of OLP patients after outcome period (8 wk after the discontinuation of treatment—day 90). Type I patients (50%) have complete remission of erosive lesions. Type II patients (32%) have partial clinical resolution. Type III patients (18%) are nonresponsive to therapy. (B) H&E-stained sections of OLP lesions from patients with differential responses to therapy depict similar histological aspects. Upper panel illustrates the presence of a well-defined band-like zone of inflammatory cell infiltration (∗) (40× magnification). Lower panel shows signs of degeneration of the basal cell layer (arrows) associated with lymphocytes infiltrate and exocytosis and absence of epithelial dysplasia (200× magnification). H&E = hematoxylin and eosin, OLP = oral lichen planus.

Mentions: Current therapeutic strategies for OLP patients include corticosteroids, immunosuppressors, retinoids, antifungal agents, and low-level laser therapy, among others.13,33,34 All of these treatments improve symptomatic OLP, but none are curative. The clinical response to therapy is heterogeneous, and disease relapse and resistance to treatment is common in OLP patients.13 OLP lesions have a range of clinical appearances that vary from reticular to atrophic and erosive lesions. With the goal of identifying markers associated with disease progression, we classified the patients treated into 3 groups based on response to therapy. We found that half of patients had a complete clinical resolution of symptoms (Type I), which was determined by total absence of symptoms and remission of all atrophic/erosive lesions regardless of persisting hyperkeratotic lesions. This group of patients was classified as responsive to therapy. Thirty-two percent of patients achieved partial clinical resolution (Type II), which was determined by a decrease in, but not the complete remission of, atrophic/erosive areas and symptoms; these patients were classified as partially responsive. Finally, all remaining patients were nonresponsive (Type III) and did not benefit from therapy and/or experienced worsening of symptoms (Figure 1A). Histologically, all patients enrolled in this trial had clinical manifestations and histological findings compatible with OLP (Figure 1A).


Epigenetic Modifications and Accumulation of DNA Double-Strand Breaks in Oral Lichen Planus Lesions Presenting Poor Response to Therapy.

Dillenburg CS, Martins MA, Almeida LO, Meurer L, Squarize CH, Martins MD, Castilho RM - Medicine (Baltimore) (2015)

OLP cases exhibit differential responses to therapy. (A) Clinical aspects of response of OLP patients after outcome period (8 wk after the discontinuation of treatment—day 90). Type I patients (50%) have complete remission of erosive lesions. Type II patients (32%) have partial clinical resolution. Type III patients (18%) are nonresponsive to therapy. (B) H&E-stained sections of OLP lesions from patients with differential responses to therapy depict similar histological aspects. Upper panel illustrates the presence of a well-defined band-like zone of inflammatory cell infiltration (∗) (40× magnification). Lower panel shows signs of degeneration of the basal cell layer (arrows) associated with lymphocytes infiltrate and exocytosis and absence of epithelial dysplasia (200× magnification). H&E = hematoxylin and eosin, OLP = oral lichen planus.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4554108&req=5

Figure 1: OLP cases exhibit differential responses to therapy. (A) Clinical aspects of response of OLP patients after outcome period (8 wk after the discontinuation of treatment—day 90). Type I patients (50%) have complete remission of erosive lesions. Type II patients (32%) have partial clinical resolution. Type III patients (18%) are nonresponsive to therapy. (B) H&E-stained sections of OLP lesions from patients with differential responses to therapy depict similar histological aspects. Upper panel illustrates the presence of a well-defined band-like zone of inflammatory cell infiltration (∗) (40× magnification). Lower panel shows signs of degeneration of the basal cell layer (arrows) associated with lymphocytes infiltrate and exocytosis and absence of epithelial dysplasia (200× magnification). H&E = hematoxylin and eosin, OLP = oral lichen planus.
Mentions: Current therapeutic strategies for OLP patients include corticosteroids, immunosuppressors, retinoids, antifungal agents, and low-level laser therapy, among others.13,33,34 All of these treatments improve symptomatic OLP, but none are curative. The clinical response to therapy is heterogeneous, and disease relapse and resistance to treatment is common in OLP patients.13 OLP lesions have a range of clinical appearances that vary from reticular to atrophic and erosive lesions. With the goal of identifying markers associated with disease progression, we classified the patients treated into 3 groups based on response to therapy. We found that half of patients had a complete clinical resolution of symptoms (Type I), which was determined by total absence of symptoms and remission of all atrophic/erosive lesions regardless of persisting hyperkeratotic lesions. This group of patients was classified as responsive to therapy. Thirty-two percent of patients achieved partial clinical resolution (Type II), which was determined by a decrease in, but not the complete remission of, atrophic/erosive areas and symptoms; these patients were classified as partially responsive. Finally, all remaining patients were nonresponsive (Type III) and did not benefit from therapy and/or experienced worsening of symptoms (Figure 1A). Histologically, all patients enrolled in this trial had clinical manifestations and histological findings compatible with OLP (Figure 1A).

Bottom Line: Although an exciting prospect, the identification of early epigenetic markers associated with clinical outcome in premalignant and malignant disorders remains elusive.We analyzed 42 OLP patients, who had different responses to therapy, for acetyl-histone H3 at lys9 (H3K9ac), which is associated with enhanced transcription and nuclear decondensation, and the presence of DSBs, as determined by accumulation of phosphorylated γH2AX foci.Patients with high levels of H3K9ac acetylation failed to respond to therapy or experienced disease recurrence shortly after therapy.

View Article: PubMed Central - PubMed

Affiliation: From the Department of Oral Pathology (CSD, MDM), School of Dentistry; Department of Oral Medicine (MATM), Hospital de Clínicas de Porto Alegre (HCPA/UFRGS); Department of Pathology (LM), School of Medicine, Hospital de Clínicas de Porto Alegre (HCPA/UFRGS), Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; and Laboratory of Epithelial Biology (CSD, MATM, LOA, CHS, MDM, RMC), Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.

ABSTRACT
Epigenetics refers to changes in cell characteristics that occur independently of modifications to the deoxyribonucleic acid (DNA) sequence. Alterations mediated by epigenetic mechanisms are important factors in cancer progression. Although an exciting prospect, the identification of early epigenetic markers associated with clinical outcome in premalignant and malignant disorders remains elusive. We examined alterations in chromatin acetylation in oral lichen planus (OLP) with distinct clinical behavior and compared the alterations to the levels of DNA double-strand breaks (DSBs). We analyzed 42 OLP patients, who had different responses to therapy, for acetyl-histone H3 at lys9 (H3K9ac), which is associated with enhanced transcription and nuclear decondensation, and the presence of DSBs, as determined by accumulation of phosphorylated γH2AX foci. Patients with high levels of H3K9ac acetylation failed to respond to therapy or experienced disease recurrence shortly after therapy. Similar to H3K9ac, patients who responded poorly to therapy had increased accumulation of DNA DSB, indicating genomic instability. These findings suggest that histone modifications occur in OLP, and H3K9ac and γH2AX histones may serve as epigenetic markers for OLP recurrence.

Show MeSH
Related in: MedlinePlus