The contribution of DNA mismatch repair gene defects to the burden of gynecological cancer

Drake, A.C.; Campbell, Harry; Porteous, Mary; Dunlop, Malcolm G.

doi:10.1046/j.1525-1438.2003.13194.x

Cited by 21 publications

(24 citation statements)

References 129 publications

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“…In our study, we found that six of seven patients whose family history fulfilled the Amsterdam criteria II were classified as presumptive Lynch syndrome. In 30% to 50% of Amsterdam criteria II families, a germ-line mutation cannot be found (16). Therefore, if the mutation detection level of Berends et al (13) represents f50% of Lynch Research.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it is likely that the approach taken in this study to use immunohistochemistry as a guide to selection of youngonset EC patients who might benefit from MMR mutation testing is a reasonable one. To seek mutations without initial tumor screening is likely to be expensive and inefficient due to the majority of young-onset patients having no indications of Lynch syndrome, the number of candidate genes, and the relatively poor success rate in the detection of mutations (16).…”

Section: Discussionmentioning

confidence: 99%

“…68 years (16). However, for patients with Lynch syndrome, the lifetime risk of EC increases to 40% to 60% (17,18), and the average age of onset falls to 48 years.…”

mentioning

confidence: 99%

“…However, not all reports have returned this finding (21). Individuals with Lynch syndrome are also more likely to develop multiple primary cancers during their lifetime; 54% to 61% of patients develop a second primary tumor and 15% to 23% have three or more primary tumors (16). Because of these high risks for cancer, screening and prophylactic surgery may be offered to individuals with Lynch syndrome (22 -24).…”

mentioning

confidence: 99%

“…Detection of deleterious mutations, in particular MMR genes, can unequivocally establish a diagnosis of Lynch syndrome. However, in 40% to 50% of putative Lynch syndrome families, no mutations can be found, and although such families are empirically at less risk than proven mutation carriers, their risk remains substantial (16).…”

mentioning

confidence: 99%

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Molecular, Pathologic, and Clinical Features of Early-Onset Endometrial Cancer: Identifying Presumptive Lynch Syndrome Patients

Walsh¹,

Cummings²,

Buchanan³

et al. 2008

Clinical Cancer Research

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Purpose: A woman with early-onset endometrial cancer (EC) may represent the ''sentinel''cancer event in a Lynch syndrome kindred.The aim of this study was to determine the incidence of Lynch syndrome in a series of young-onset EC, and to identify molecular, clinical, and pathologic features that may alert clinicians to the presence of this disorder. Experimental Design: Patients with EC, ages V50 years, were identified from the Queensland Centre for Gynaecological Cancer. Tumor sections underwent histopathology review and were immunostained for mismatch repair proteins. Tumor DNA was tested for microsatellite instability and methylation of MLH1. Patients were conservatively classified as presumptive Lynch syndrome if their tumors showed loss of at least one mismatch repair protein and were negative for methylation of MLH1. Personal and family history of cancer was reviewed where available. Results: Presumptive Lynch syndrome was seen in 26 of 146 (18%) tumors. These tumors were more likely to be poorly differentiated, International Federation of Gynecology and Obstetrics stage II and above, have tumor-infiltrating lymphocytes, have higher mitotic rate, and have deeper myometrial invasion (P < 0.05). Lynch syndrome cases were more likely to be associated with a positive family history when analyzed for Amsterdam criteria II, diagnosis of a Lynch syndrome spectrum cancer in at least one first-degree relative, and family history of any cancer (P < 0.05).Conclusion: Presumptive Lynch syndrome was identified in 18% of early-onset EC. A risk of this magnitude would argue for routine immunohistochemical testing of tumors in patients diagnosed with EC at or before the age of 50 years.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…68 years (16). However, for patients with Lynch syndrome, the lifetime risk of EC increases to 40% to 60% (17,18), and the average age of onset falls to 48 years.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Molecular, Pathologic, and Clinical Features of Early-Onset Endometrial Cancer: Identifying Presumptive Lynch Syndrome Patients

Walsh¹,

Cummings²,

Buchanan³

et al. 2008

Clinical Cancer Research

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Pathology of Malignancies Metastatic to the Ovary and of Synchronous Ovarian and Endometrial Carcinoma

Singh

2014

Pathology of the Ovary, Fallopian Tube and Peritoneum

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PMS2 expression in epithelial ovarian cancer is posttranslationally regulated by Akt and essential for platinum-induced apoptosis

et al. 2015

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Epithelial ovarian cancer (EOC) is the most lethal of the gynecologic malignancies, mainly due to the advanced stage at diagnosis and development of cisplatin resistance. The sensitivity of tumor cells to cisplatin is frequently affected by defect in DNA mismatch repair (MMR), which repairs mispaired DNA sequences and regulates DNA-damage-induced apoptosis. However, the role of postmeiotic segregation increased 2 (PMS2), a member of MMR protein family, in cisplatin resistance remains elusive. In the present study, we demonstrated the frequent deficiency of PMS2 and phosphorylation of Akt in EOC cell lines and tissues. Results of complex immunoprecipitation (co-IP) and protein stability assay indicated that activated Akt could directly bind to PMS2 and cause degradation of PMS2 in EOC cells. In addition, functional experiments revealed that PMS2 was required for cisplatin-induced apoptosis and cell cycle arrest in G2/M phase. These findings provide a novel insight into molecular mechanisms linking MMR with chemoresistance and suggest that stabilization of PMS2 expression may be useful in overcoming the cisplatin resistance in EOC.

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The contribution of DNA mismatch repair gene defects to the burden of gynecological cancer

Cited by 21 publications

References 129 publications

Molecular, Pathologic, and Clinical Features of Early-Onset Endometrial Cancer: Identifying Presumptive Lynch Syndrome Patients

Molecular, Pathologic, and Clinical Features of Early-Onset Endometrial Cancer: Identifying Presumptive Lynch Syndrome Patients

Pathology of Malignancies Metastatic to the Ovary and of Synchronous Ovarian and Endometrial Carcinoma

PMS2 expression in epithelial ovarian cancer is posttranslationally regulated by Akt and essential for platinum-induced apoptosis

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