Biallelic mutation of MSH2 in primary human cells is associated with sensitivity to irradiation and altered RAD51 foci kinetics

Barwell, Julian; Pangon, Laurent; Hodgson, Shirley; Georgiou, Anne; Kesterton, Ian; Slade, T.A.; Taylor, Michelle; Payne, Stewart J.; Brinkman, Heike; Smythe, Jon; Sebire, Neil J.; Solomon, Ellen; Docherty, Zoe; Camplejohn, Richard S.; Homfray, Tessa; Morris, Joanna R.

doi:10.1136/jmg.2006.048660

Cited by 15 publications

(4 citation statements)

References 17 publications

(8 reference statements)

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“…Studies on cell lines with MSI, however, have suggested an increased sensitivity to radiation [22, 23]. An MLH1 knockout mouse model did show increased tumor growth as a late effect of radiation, suggesting the possibility of an increased risk of secondary cancers in individuals with Lynch syndrome treated with radiation [24].…”

Section: Discussionmentioning

confidence: 99%

Microsatellite instability and survival in rectal cancer

Samowitz

Curtin

Wolff

et al. 2009

Cancer Causes Control

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Objective-High levels of microsatellite instability (MSI-H) have been associated in many studies with improved prognosis in colon cancer. Very few studies have evaluated the effect of MSI-H on rectal cancer survival. We assessed MSI-H and other genetic and epigenetic changes on survival of 990 individuals diagnosed with first primary rectal cancer.Methods-MSI was assessed primarily by instability in the mononucleotide repeat BAT-26. The BRAF V600E mutation was assessed by TaqMan assay. The CpG island methylator phenotype (CIMP) was determined by methylation-specific PCR of CpG islands in MLH1, methylated in tumors (MINT)1, (MINT)2, (MINT)31 and CDKN2A. KRAS2 codons 12 and 13 mutations, and TP53 mutations in exons 5-8 were determined by sequencing.Results-Multivariate analysis revealed that MSI-H (HRR 2.47, 95% CI 1.13-5.40) and KRAS2 mutations (HRR 1.37, 95% CI 1.04-1.81) were associated with a significantly higher risk of dying of rectal cancer. Only one of 22 MSI-H tumors showed a BRAF V600E mutation. Of 15 MSI-H rectal cancers evaluated for methylation, two exhibited MLH1 methylation and four exhibited CIMP. Conclusion-The genetic and epigenetic characteristics of MSI-H rectal cancers suggest that they are enriched for Lynch-associated tumors; adverse prognosis associated with MSI-H in these tumors may reflect the relatively high frequency of Lynch-associated cancers and/or the effect of radiation or chemotherapy on Lynch-associated rectal cancers or MSI tumors in general.

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Section: Discussionmentioning

confidence: 99%

Microsatellite instability and survival in rectal cancer

Samowitz

Curtin

Wolff

et al. 2009

Cancer Causes Control

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“…The response to radiotherapy in relation to MMR deficiency is complex and depends on several factors including radiation dose (35). Caution in the use of radiotherapy for treatment of malignancies arising in patients with functional loss of MSH2 or possibly other MMR genes has also been suggested (36). However, an excellent response to radiotherapy in a primitive neuroectodermal tumour arising in a patient with a heterozygous MSH2 mutation has been documented (37).…”

Section: Discussionmentioning

confidence: 99%

Childhood brain tumours due to germline bi-allelic mismatch repair gene mutations

et al. 2011

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Childhood brain tumours may be due to germline bi-allelic mismatch repair (MMR) gene mutations in MLH1, MSH2, MSH6 or PMS2. These mutations can also lead to colorectal neoplasia and haematological malignancies. Here, we review this syndrome and present siblings with early-onset rectal adenoma and papillary glioneural brain tumour, respectively, due to novel germline bi-allelic PMS2 mutations. Identification of MMR protein defects can lead to early diagnosis of this condition. In addition, assays for these defects may help to classify brain tumours for research protocols aimed at targeted therapies.

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“…Despite the general agreement that MSI predicts poor response to adjuvant 5-fluouracil-based chemotherapy (89), its impact on response to 5-fluouracil given as part of nCRT is controversial (90). In MSI with LARC, an increased sensitivity to radiotherapy has been observed in preclinical studies (91)(92)(93). Initial underpowered series with little clinicopathologic detail and considerable heterogeneity have described pCR rates of between 0 and 60% (59).…”

Section: Clinical Implications Of Rectal Cancer Molecular Pathogenesimentioning

confidence: 99%

Delivery of Personalized Care for Locally Advanced Rectal Cancer: Incorporating Pathological, Molecular Genetic, and Immunological Biomarkers Into the Multimodal Paradigm

2020

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Biallelic mutation of MSH2 in primary human cells is associated with sensitivity to irradiation and altered RAD51 foci kinetics

Cited by 15 publications

References 17 publications

Microsatellite instability and survival in rectal cancer

Microsatellite instability and survival in rectal cancer

Childhood brain tumours due to germline bi-allelic mismatch repair gene mutations

Delivery of Personalized Care for Locally Advanced Rectal Cancer: Incorporating Pathological, Molecular Genetic, and Immunological Biomarkers Into the Multimodal Paradigm

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