PURPOSE: To determine the frequency of mismatch repair (MMR) gene germline mutations in endometrial cancer patients who were diagnosed at less than 50 years of age; to relate the presence of mutations to family history, histopathologic data, presence of tumor microsatellite instability (MSI), and immunostaining; and to formulate criteria for genetic testing in these patients. PATIENTS AND METHODS: Endometrial cancer patients (N = 58), who were diagnosed at less than 50 years of age, were included and questioned about their family history. Mutation analysis of the MLH1, MSH2, and MSH6 genes was performed (denaturing gradient gel electrophoresis and sequence analysis to detect small mutations and multiplex ligation-dependent probe amplification to detect large deletions or duplications). For MSI analysis, five consensus markers were used, and immunostaining of the three MMR proteins was performed. RESULTS: In five of 22 patients with a positive first-degree family history for hereditary nonpolyposis colorectal cancer (HNPCC)-related cancers, pathogenic germline mutations were found (one MLH1, three MSH2, and one MSH6). Four mutation carriers belonged to families fulfilling the revised Amsterdam criteria. No mutations were found in the 35 patients without such family history (P =.006). MSI was detected in 20 of 57 cancers, among which four were from mutation carriers. In 23 of 51 cancers, one or more MMR protein was absent; in all five mutation carriers, immunostaining indicated the involved MMR gene. CONCLUSION: In 23% of the young endometrial cancer patients with at least one first-degree relative with an HNPCC-related cancer, an MMR gene mutation was detected. Therefore, presence of an HNPCC-related cancer in a first-degree relative seems to be an important selection criterion for mutation analysis. Subsequent immunostaining of MMR proteins will point to the gene(s) that should be analyzed.
PURPOSE: To determine the frequency of mismatch repair (MMR) gene germline mutations in endometrial cancerpatients who were diagnosed at less than 50 years of age; to relate the presence of mutations to family history, histopathologic data, presence of tumor microsatellite instability (MSI), and immunostaining; and to formulate criteria for genetic testing in these patients. PATIENTS AND METHODS: Endometrial cancerpatients (N = 58), who were diagnosed at less than 50 years of age, were included and questioned about their family history. Mutation analysis of the MLH1, MSH2, and MSH6 genes was performed (denaturing gradient gel electrophoresis and sequence analysis to detect small mutations and multiplex ligation-dependent probe amplification to detect large deletions or duplications). For MSI analysis, five consensus markers were used, and immunostaining of the three MMR proteins was performed. RESULTS: In five of 22 patients with a positive first-degree family history for hereditary nonpolyposis colorectal cancer (HNPCC)-related cancers, pathogenic germline mutations were found (one MLH1, three MSH2, and one MSH6). Four mutation carriers belonged to families fulfilling the revised Amsterdam criteria. No mutations were found in the 35 patients without such family history (P =.006). MSI was detected in 20 of 57 cancers, among which four were from mutation carriers. In 23 of 51 cancers, one or more MMR protein was absent; in all five mutation carriers, immunostaining indicated the involved MMR gene. CONCLUSION: In 23% of the young endometrial cancerpatients with at least one first-degree relative with an HNPCC-related cancer, an MMR gene mutation was detected. Therefore, presence of an HNPCC-related cancer in a first-degree relative seems to be an important selection criterion for mutation analysis. Subsequent immunostaining of MMR proteins will point to the gene(s) that should be analyzed.
Authors: Stefano Uccella; Stephen S Cha; L Joseph Melton; Eric J Bergstralh; Lisa A Boardman; Gary L Keeney; Karl C Podratz; Fabio Francesco Ciancio; Andrea Mariani Journal: Int J Gynecol Cancer Date: 2011-07 Impact factor: 3.437
Authors: Rajani Bharati; Mark A Jenkins; Noralane M Lindor; Loïc Le Marchand; Steven Gallinger; Robert W Haile; Polly A Newcomb; John L Hopper; Aung Ko Win Journal: Gynecol Oncol Date: 2014-03-11 Impact factor: 5.482
Authors: Laura Baglietto; Noralane M Lindor; James G Dowty; Darren M White; Anja Wagner; Encarna B Gomez Garcia; Annette H J T Vriends; Nicola R Cartwright; Rebecca A Barnetson; Susan M Farrington; Albert Tenesa; Heather Hampel; Daniel Buchanan; Sven Arnold; Joanne Young; Michael D Walsh; Jeremy Jass; Finlay Macrae; Yoland Antill; Ingrid M Winship; Graham G Giles; Jack Goldblatt; Susan Parry; Graeme Suthers; Barbara Leggett; Malinda Butz; Melyssa Aronson; Jenny N Poynter; John A Baron; Loic Le Marchand; Robert Haile; Steve Gallinger; John L Hopper; John Potter; Albert de la Chapelle; Hans F Vasen; Malcolm G Dunlop; Stephen N Thibodeau; Mark A Jenkins Journal: J Natl Cancer Inst Date: 2009-12-22 Impact factor: 13.506
Authors: Daniel D Buchanan; Yen Y Tan; Michael D Walsh; Mark Clendenning; Alexander M Metcalf; Kaltin Ferguson; Sven T Arnold; Bryony A Thompson; Felicity A Lose; Michael T Parsons; Rhiannon J Walters; Sally-Ann Pearson; Margaret Cummings; Martin K Oehler; Penelope B Blomfield; Michael A Quinn; Judy A Kirk; Colin J Stewart; Andreas Obermair; Joanne P Young; Penelope M Webb; Amanda B Spurdle Journal: J Clin Oncol Date: 2013-12-09 Impact factor: 44.544
Authors: Kellie S Matthews; Jacob M Estes; Michael G Conner; Upender Manne; Jenny M Whitworth; Warner K Huh; Ronald D Alvarez; J Michael Straughn; Mack N Barnes; Rodney P Rocconi Journal: Obstet Gynecol Date: 2008-05 Impact factor: 7.661