The Experts below are selected from a list of 66 Experts worldwide ranked by ideXlab platform
Daniel P Cahill - One of the best experts on this subject based on the ideXlab platform.
-
loss of the mismatch repair Protein MSH6 in glioblastomas recurrent after temozolomide
Cancer Research, 2007Co-Authors: Daniel P Cahill, Linsey Reavie, Candice Romany, David N LouisAbstract:1974 Glioblastomas are treated by surgical resection followed with radiotherapy (XRT) and the alkylating chemotherapeutic agent temozolomide (TMZ). Recently, inactivating mutations in the mismatch repair (MMR) gene MSH6 were identified in two glioblastomas recurrent post-TMZ. Since MMR pathway inactivation is a known mediator of alkylator resistance in vitro, these findings suggested MSH6 inactivation was causally linked to these two recurrences. However, the extent of involvement of MSH6 in glioblastoma is unknown. We sought to determine the overall frequency and clinical relevance of MSH6 alterations in glioblastomas. The MSH6 gene was sequenced in pre-treatment and recurrent glioblastomas. MSH6 mutation was not observed in any pre-treatment glioblastoma, while a significant subset of recurrent cases had somatic mutations. MSH6 and MGMT immunohistochemistry was systematically scored in a second panel of clinically well-characterized glioblastomas. MSH6 Protein expression was detected in all pre-treatment cases examined but, notably, expression was lost in significant subset of recurrences from matched post-XRT+TMZ cases. Loss of MSH6 was not associated with MGMT status. We conclude that loss of MSH6 occurs in post-XRT+TMZ glioblastoma recurrences, mirroring the MMR pathway inactivation observed during in vitro emergence of alkylator resistance. MSH6 deficiency may therefore contribute to the progression of recurrent glioblastomas during TMZ treatment.
-
loss of the mismatch repair Protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment
Clinical Cancer Research, 2007Co-Authors: Daniel P Cahill, Linsey Reavie, Candice Romany, K K Levine, Rebecca A Betensky, Patrick J Codd, Tracy T Batchelor, P A Futreal, Michael R Stratton, William T CurryAbstract:Purpose: Glioblastomas are treated by surgical resection followed by radiotherapy [X-ray therapy (XRT)] and the alkylating chemotherapeutic agent temozolomide. Recently, inactivating mutations in the mismatch repair gene MSH6 were identified in two glioblastomas recurrent post-temozolomide. Because mismatch repair pathway inactivation is a known mediator of alkylator resistance in vitro , these findings suggested that MSH6 inactivation was causally linked to these two recurrences. However, the extent of involvement of MSH6 in glioblastoma is unknown. We sought to determine the overall frequency and clinical relevance of MSH6 alterations in glioblastomas. Experimental Design: The MSH6 gene was sequenced in 54 glioblastomas. MSH6 and O 6 -methylguanine methyltransferase (MGMT) immunohistochemistry was systematically scored in a panel of 46 clinically well-characterized glioblastomas, and the corresponding patient response to treatment evaluated. Results: MSH6 mutation was not observed in any pretreatment glioblastoma (0 of 40), whereas 3 of 14 recurrent cases had somatic mutations ( P = 0.015). MSH6 Protein expression was detected in all pretreatment (17 of 17) cases examined but, notably, expression was lost in 7 of 17 (41%) recurrences from matched post–XRT + temozolomide cases ( P = 0.016). Loss of MSH6 was not associated with O 6 -methylguanine methyltransferase status. Measurements of in vivo tumor growth using three-dimensional reconstructed magnetic resonance imaging showed that MSH6-negative glioblastomas had a markedly increased rate of growth while under temozolomide treatment (3.17 versus 0.04 cc/mo for MSH6-positive tumors; P = 0.020). Conclusions: Loss of MSH6 occurs in a subset of post–XRT + temozolomide glioblastoma recurrences and is associated with tumor progression during temozolomide treatment, mirroring the alkylator resistance conferred by MSH6 inactivation in vitro . MSH6 deficiency may therefore contribute to the emergence of recurrent glioblastomas during temozolomide treatment.
Joel Couprie - One of the best experts on this subject based on the ideXlab platform.
-
human mismatch repair Protein MSH6 contains a pwwp domain that targets double stranded dna
Biochemistry, 2008Co-Authors: Ce Dric Laguri, Isabelle Dubandgoulet, Nikolas Friedrich, Pascal Belin, Isabelle Callebaut, Bernard Gilquin, Sophie Zinnjustin, Joel CouprieAbstract:The eukaryotic mismatch repair (MMR) Protein MSH6 exhibits a core region structurally and functionally similar to bacterial MutS. However, it possesses an additional N-terminal region (NTR), comprising a PCNA binding motif, a large region of unknown function and a nonspecific DNA binding fragment. Yeast NTR was recently described as an extended tether between PCNA and the core of MSH6 (1). In contrast, we show that human NTR presents a globular PWWP domain in the region of unknown function. We demonstrate that this PWWP domain binds double-stranded DNA, without any preference for mismatches or nicks, whereas its apparent affinity for single-stranded DNA is about 20 times lower. The S144I mutation, which in human MSH6 causes inherited somatic defects in MMR resulting in increased development of hereditary non polyposis colorectal cancer (2), is located in the DNA binding surface of the PWWP domain. However, it only moderately affects domain stability, and it does not perturb DNA binding in Vitro.
William T Curry - One of the best experts on this subject based on the ideXlab platform.
-
loss of the mismatch repair Protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment
Clinical Cancer Research, 2007Co-Authors: Daniel P Cahill, Linsey Reavie, Candice Romany, K K Levine, Rebecca A Betensky, Patrick J Codd, Tracy T Batchelor, P A Futreal, Michael R Stratton, William T CurryAbstract:Purpose: Glioblastomas are treated by surgical resection followed by radiotherapy [X-ray therapy (XRT)] and the alkylating chemotherapeutic agent temozolomide. Recently, inactivating mutations in the mismatch repair gene MSH6 were identified in two glioblastomas recurrent post-temozolomide. Because mismatch repair pathway inactivation is a known mediator of alkylator resistance in vitro , these findings suggested that MSH6 inactivation was causally linked to these two recurrences. However, the extent of involvement of MSH6 in glioblastoma is unknown. We sought to determine the overall frequency and clinical relevance of MSH6 alterations in glioblastomas. Experimental Design: The MSH6 gene was sequenced in 54 glioblastomas. MSH6 and O 6 -methylguanine methyltransferase (MGMT) immunohistochemistry was systematically scored in a panel of 46 clinically well-characterized glioblastomas, and the corresponding patient response to treatment evaluated. Results: MSH6 mutation was not observed in any pretreatment glioblastoma (0 of 40), whereas 3 of 14 recurrent cases had somatic mutations ( P = 0.015). MSH6 Protein expression was detected in all pretreatment (17 of 17) cases examined but, notably, expression was lost in 7 of 17 (41%) recurrences from matched post–XRT + temozolomide cases ( P = 0.016). Loss of MSH6 was not associated with O 6 -methylguanine methyltransferase status. Measurements of in vivo tumor growth using three-dimensional reconstructed magnetic resonance imaging showed that MSH6-negative glioblastomas had a markedly increased rate of growth while under temozolomide treatment (3.17 versus 0.04 cc/mo for MSH6-positive tumors; P = 0.020). Conclusions: Loss of MSH6 occurs in a subset of post–XRT + temozolomide glioblastoma recurrences and is associated with tumor progression during temozolomide treatment, mirroring the alkylator resistance conferred by MSH6 inactivation in vitro . MSH6 deficiency may therefore contribute to the emergence of recurrent glioblastomas during temozolomide treatment.
Candice Romany - One of the best experts on this subject based on the ideXlab platform.
-
loss of the mismatch repair Protein MSH6 in glioblastomas recurrent after temozolomide
Cancer Research, 2007Co-Authors: Daniel P Cahill, Linsey Reavie, Candice Romany, David N LouisAbstract:1974 Glioblastomas are treated by surgical resection followed with radiotherapy (XRT) and the alkylating chemotherapeutic agent temozolomide (TMZ). Recently, inactivating mutations in the mismatch repair (MMR) gene MSH6 were identified in two glioblastomas recurrent post-TMZ. Since MMR pathway inactivation is a known mediator of alkylator resistance in vitro, these findings suggested MSH6 inactivation was causally linked to these two recurrences. However, the extent of involvement of MSH6 in glioblastoma is unknown. We sought to determine the overall frequency and clinical relevance of MSH6 alterations in glioblastomas. The MSH6 gene was sequenced in pre-treatment and recurrent glioblastomas. MSH6 mutation was not observed in any pre-treatment glioblastoma, while a significant subset of recurrent cases had somatic mutations. MSH6 and MGMT immunohistochemistry was systematically scored in a second panel of clinically well-characterized glioblastomas. MSH6 Protein expression was detected in all pre-treatment cases examined but, notably, expression was lost in significant subset of recurrences from matched post-XRT+TMZ cases. Loss of MSH6 was not associated with MGMT status. We conclude that loss of MSH6 occurs in post-XRT+TMZ glioblastoma recurrences, mirroring the MMR pathway inactivation observed during in vitro emergence of alkylator resistance. MSH6 deficiency may therefore contribute to the progression of recurrent glioblastomas during TMZ treatment.
-
loss of the mismatch repair Protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment
Clinical Cancer Research, 2007Co-Authors: Daniel P Cahill, Linsey Reavie, Candice Romany, K K Levine, Rebecca A Betensky, Patrick J Codd, Tracy T Batchelor, P A Futreal, Michael R Stratton, William T CurryAbstract:Purpose: Glioblastomas are treated by surgical resection followed by radiotherapy [X-ray therapy (XRT)] and the alkylating chemotherapeutic agent temozolomide. Recently, inactivating mutations in the mismatch repair gene MSH6 were identified in two glioblastomas recurrent post-temozolomide. Because mismatch repair pathway inactivation is a known mediator of alkylator resistance in vitro , these findings suggested that MSH6 inactivation was causally linked to these two recurrences. However, the extent of involvement of MSH6 in glioblastoma is unknown. We sought to determine the overall frequency and clinical relevance of MSH6 alterations in glioblastomas. Experimental Design: The MSH6 gene was sequenced in 54 glioblastomas. MSH6 and O 6 -methylguanine methyltransferase (MGMT) immunohistochemistry was systematically scored in a panel of 46 clinically well-characterized glioblastomas, and the corresponding patient response to treatment evaluated. Results: MSH6 mutation was not observed in any pretreatment glioblastoma (0 of 40), whereas 3 of 14 recurrent cases had somatic mutations ( P = 0.015). MSH6 Protein expression was detected in all pretreatment (17 of 17) cases examined but, notably, expression was lost in 7 of 17 (41%) recurrences from matched post–XRT + temozolomide cases ( P = 0.016). Loss of MSH6 was not associated with O 6 -methylguanine methyltransferase status. Measurements of in vivo tumor growth using three-dimensional reconstructed magnetic resonance imaging showed that MSH6-negative glioblastomas had a markedly increased rate of growth while under temozolomide treatment (3.17 versus 0.04 cc/mo for MSH6-positive tumors; P = 0.020). Conclusions: Loss of MSH6 occurs in a subset of post–XRT + temozolomide glioblastoma recurrences and is associated with tumor progression during temozolomide treatment, mirroring the alkylator resistance conferred by MSH6 inactivation in vitro . MSH6 deficiency may therefore contribute to the emergence of recurrent glioblastomas during temozolomide treatment.
Linsey Reavie - One of the best experts on this subject based on the ideXlab platform.
-
loss of the mismatch repair Protein MSH6 in glioblastomas recurrent after temozolomide
Cancer Research, 2007Co-Authors: Daniel P Cahill, Linsey Reavie, Candice Romany, David N LouisAbstract:1974 Glioblastomas are treated by surgical resection followed with radiotherapy (XRT) and the alkylating chemotherapeutic agent temozolomide (TMZ). Recently, inactivating mutations in the mismatch repair (MMR) gene MSH6 were identified in two glioblastomas recurrent post-TMZ. Since MMR pathway inactivation is a known mediator of alkylator resistance in vitro, these findings suggested MSH6 inactivation was causally linked to these two recurrences. However, the extent of involvement of MSH6 in glioblastoma is unknown. We sought to determine the overall frequency and clinical relevance of MSH6 alterations in glioblastomas. The MSH6 gene was sequenced in pre-treatment and recurrent glioblastomas. MSH6 mutation was not observed in any pre-treatment glioblastoma, while a significant subset of recurrent cases had somatic mutations. MSH6 and MGMT immunohistochemistry was systematically scored in a second panel of clinically well-characterized glioblastomas. MSH6 Protein expression was detected in all pre-treatment cases examined but, notably, expression was lost in significant subset of recurrences from matched post-XRT+TMZ cases. Loss of MSH6 was not associated with MGMT status. We conclude that loss of MSH6 occurs in post-XRT+TMZ glioblastoma recurrences, mirroring the MMR pathway inactivation observed during in vitro emergence of alkylator resistance. MSH6 deficiency may therefore contribute to the progression of recurrent glioblastomas during TMZ treatment.
-
loss of the mismatch repair Protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment
Clinical Cancer Research, 2007Co-Authors: Daniel P Cahill, Linsey Reavie, Candice Romany, K K Levine, Rebecca A Betensky, Patrick J Codd, Tracy T Batchelor, P A Futreal, Michael R Stratton, William T CurryAbstract:Purpose: Glioblastomas are treated by surgical resection followed by radiotherapy [X-ray therapy (XRT)] and the alkylating chemotherapeutic agent temozolomide. Recently, inactivating mutations in the mismatch repair gene MSH6 were identified in two glioblastomas recurrent post-temozolomide. Because mismatch repair pathway inactivation is a known mediator of alkylator resistance in vitro , these findings suggested that MSH6 inactivation was causally linked to these two recurrences. However, the extent of involvement of MSH6 in glioblastoma is unknown. We sought to determine the overall frequency and clinical relevance of MSH6 alterations in glioblastomas. Experimental Design: The MSH6 gene was sequenced in 54 glioblastomas. MSH6 and O 6 -methylguanine methyltransferase (MGMT) immunohistochemistry was systematically scored in a panel of 46 clinically well-characterized glioblastomas, and the corresponding patient response to treatment evaluated. Results: MSH6 mutation was not observed in any pretreatment glioblastoma (0 of 40), whereas 3 of 14 recurrent cases had somatic mutations ( P = 0.015). MSH6 Protein expression was detected in all pretreatment (17 of 17) cases examined but, notably, expression was lost in 7 of 17 (41%) recurrences from matched post–XRT + temozolomide cases ( P = 0.016). Loss of MSH6 was not associated with O 6 -methylguanine methyltransferase status. Measurements of in vivo tumor growth using three-dimensional reconstructed magnetic resonance imaging showed that MSH6-negative glioblastomas had a markedly increased rate of growth while under temozolomide treatment (3.17 versus 0.04 cc/mo for MSH6-positive tumors; P = 0.020). Conclusions: Loss of MSH6 occurs in a subset of post–XRT + temozolomide glioblastoma recurrences and is associated with tumor progression during temozolomide treatment, mirroring the alkylator resistance conferred by MSH6 inactivation in vitro . MSH6 deficiency may therefore contribute to the emergence of recurrent glioblastomas during temozolomide treatment.
