Citations 2
DNA Mismatch Repair Gene Variant Classification: Evaluating the Utility of Somatic Mutations and Mismatch Repair Deficient Colonic Crypts and Endometrial Glands
Walker, Romy , Mahmood, Khalid , Como, Julia , Joo, Jihoon E. , Georgeson, Peter , Joseland, Sharelle , Preston, Susan , Pope, Bernard J. , Chan, James , Austin, Rachel , Bojadzieva, Jasmina , Campbell, Ainsley , Edwards, Emma, Goodwin, Annabel , Harris, Marion , Ip, Emilia , Kirk, Judy , Mansour, Julia, Fan, Helen Mar , Nichols, Cassandra , Pachter, Nicholas , Ragunathan, Abiramy, Spigelman, Allan D. , Susman, Rachel , Pai, Rish K. , Rosty, Christophe , Winship, Ingrid , Buchanan, Daniel D. , Pope, Bernard J , Chan, James M , Winship, Ingrid M , Buchanan, Daniel D , Rosty, Christophe , Georgeson, Peter , Clendenning, Mark , Gleeson, Margaret A. , Christie, Michael , Jenkins, Mark A. , Macrae, Finlay
Cancers | October 10, 2023 | Volume: 15 | Issue: 20 | Pages: 4925
Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. Lynch syndrome specific tumor features were evaluated for their ability to support the ACMG/InSiGHT framework in classifying variants of uncertain clinical significance (VUS) in the MMR genes. Twenty-eight CRC or EC tumors from 25 VUS carriers (6xMLH1, 9xMSH2, 6xMSH6, 4xPMS2), underwent targeted tumor sequencing for the presence of microsatellite instability/MMR-deficiency (MSI-H/dMMR) status and identification of a somatic MMR mutation (second hit). Immunohistochemical testing for the presence of dMMR crypts/glands in normal tissue was also performed. The ACMG/InSiGHT framework reclassified 7/25 (28%) VUS to likely pathogenic (LP), three (12%) to benign/likely benign, and 15 (60%) VUS remained unchanged. For the seven re-classified LP variants comprising nine tumors, tumor sequencing confirmed MSI-H/dMMR (8/9, 88.9%) and a second hit (7/9, 77.8%). Of these LP reclassified variants where normal tissue was available, the presence of a dMMR crypt/gland was found in 2/4 (50%). Furthermore, a dMMR endometrial gland in a carrier of an MSH2 exon 1-6 duplication provides further support for an upgrade of this VUS to LP. Our study confirmed that identifying these Lynch syndrome features can improve MMR variant classification, enabling optimal clinical care.
Frequency and Spectrum of Cancers in the Peutz-Jeghers Syndrome
Hearle, Nicholas, Schumacher, Valerié , Menko, Fred H. , Boardman, Lisa A., Gille, Johan J.P., Keller, Josbert J. , Westerman, Anne Marie, Scott, Rodney J. , Lim, Wendy , Trimbath, Jill D., Giardiello, Francis M., Gruber, Stephen B. , Offerhaus, G. Johan A. , Rooij, Felix W.M. de, Wilson, J. H. P. , Hansmann, Anika, Royer‐Pokora, Brigitte , Vogel, Tilman, Phillips, Robin, Spigelman, Allan D. , Houlston, Richard S. , Olschwang, Sylviane , Boardman, Lisa A., Gille, Johan J.P., Möslein, Gabriela , Houlston, Richard S
Clinical Cancer Research | May 17, 2006 | Volume: 12 | Issue: 10 | Pages: 3209-3215
Abstract Background: Although an increased cancer risk in Peutz-Jeghers syndrome is established, data on the spectrum of tumors associated with the disease and the influence of germ-line STK11/LKB1 (serine/threonine kinase) mutation status are limited. Experimental Design: We analyzed the incidence of cancer in 419 individuals with Peutz-Jeghers syndrome, and 297 had documented STK11/LKB1 mutations. Results: Ninety-six cancers were found among individuals with Peutz-Jeghers syndrome. The risk for developing cancer at ages 20, 30, 40, 50, 60, and 70 years was 2%, 5%, 17%, 31%, 60%, and 85%, respectively. The most common cancers represented in this analysis were gastrointestinal in origin, gastroesophageal, small bowel, colorectal, and pancreatic, and the risk for these cancers at ages 30, 40, 50, and 60 years was 1%, 9%, 15%, and 33%, respectively. In women with Peutz-Jeghers syndrome, the risk of breast cancer was substantially increased, being 8% and 31% at ages 40 and 60 years, respectively. Kaplan-Meier analysis showed that cancer risks were similar in Peutz-Jeghers syndrome patients with identified STK11/LKB1 mutations and those with no detectable mutation (log-rank test of difference χ2 = 0.62; 1 df; P = 0.43). Furthermore, the type or site of STK11/LKB1 mutation did not significantly influence cancer risk. Conclusions: The results from our study provide quantitative information on the spectrum of cancers and risks of specific cancer types associated with Peutz-Jeghers syndrome.