Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents.

Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain tumors. There is no satisfactory method for diagnosis of CMMRD because screens for mutations in MMR genes are noninformative for 30% of patients. MMR-deficient cancer cells are resistant to genotoxic agents and have microsatellite instability (MSI), due to accumulation of errors in repetitive DNA sequences. We investigated whether these features could be used to identify patients with CMMRD. We examined MSI by PCR analysis and tolerance to methylating or thiopurine agents (functional characteristics of MMR-deficient tumor cells) in lymphoblastoid cells (LCs) from 3 patients with CMMRD and 5 individuals with MMR-proficient LCs (controls). Using these assays, we defined experimental parameters that allowed discrimination of a series of 14 patients with CMMRD from 52 controls (training set). We then used the same parameters to assess 23 patients with clinical but not genetic features of CMMRD. In the training set, we identified parameters, based on MSI and LC tolerance to methylation, that detected patients with CMMRD vs controls with 100% sensitivity and 100% specificity. Among 23 patients suspected of having CMMRD, 6 had MSI and LC tolerance to methylation (CMMRD highly probable), 15 had neither MSI nor LC tolerance to methylation (unlikely to have CMMRD), and 2 were considered doubtful for CMMRD based on having only 1 of the 2 features. The presence of MSI and tolerance to methylation in LCs identified patients with CMMRD with 100% sensitivity and specificity. These features could be used in diagnosis of patients.

Bodo S ，Colas C ，Buhard O ，Collura A ，Tinat J ，Lavoine N ，Guilloux A ，Chalastanis A ，Lafitte P ，Coulet F ，Buisine MP ，Ilencikova D ，Ruiz-Ponte C ，Kinzel M ，Grandjouan S ，Brems H ，Lejeune S ，Blanché H ，Wang Q ，Caron O ，Cabaret O ，Svrcek M ，Vidaud D ，Parfait B ，Verloes A ，Knappe UJ ，Soubrier F ，Mortemousque I ，Leis A ，Auclair-Perrossier J ，Frébourg T ，Fléjou JF ，Entz-Werle N ，Leclerc J ，Malka D ，Cohen-Haguenauer O ，Goldberg Y ，Gerdes AM ，Fedhila F ，Mathieu-Dramard M ，Hamelin R ，Wafaa B ，Gauthier-Villars M ，Bourdeaut F ，Sheridan E ，Vasen H ，Brugières L ，Wimmer K ，Muleris M ，Duval A ，European Consortium “Care for CMMRD” ... -  《-》

Functional Repair Assay for the Diagnosis of Constitutional Mismatch Repair Deficiency From Non-Neoplastic Tissue.

Shuen AY ，Lanni S ，Panigrahi GB ，Edwards M ，Yu L ，Campbell BB ，Mandel A ，Zhang C ，Zhukova N ，Alharbi M ，Bernstein M ，Bowers DC ，Carroll S ，Cole KA ，Constantini S ，Crooks B ，Dvir R ，Farah R ，Hijiya N ，George B ，Laetsch TW ，Larouche V ，Lindhorst S ，Luiten RC ，Magimairajan V ，Mason G ，Mason W ，Mordechai O ，Mushtaq N ，Nicholas G ，Oren M ，Palma L ，Pedroza LA ，Ramdas J ，Samuel D ，Wolfe Schneider K ，Seeley A ，Semotiuk K ，Shamvil A ，Sumerauer D ，Toledano H ，Tomboc P ，Wierman M ，Van Damme A ，Lee YY ，Zapotocky M ，Bouffet E ，Durno C ，Aronson M ，Gallinger S ，Foulkes WD ，Malkin D ，Tabori U ，Pearson CE ... -  《-》

Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer.

Southey MC ，Jenkins MA ，Mead L ，Whitty J ，Trivett M ，Tesoriero AA ，Smith LD ，Jennings K ，Grubb G ，Royce SG ，Walsh MD ，Barker MA ，Young JP ，Jass JR ，St John DJ ，Macrae FA ，Giles GG ，Hopper JL ... -  《JOURNAL OF CLINICAL ONCOLOGY》

Screening for germline mutations of MLH1, MSH2, MSH6 and PMS2 genes in Slovenian colorectal cancer patients: implications for a population specific detection strategy of Lynch syndrome.

Berginc G ，Bracko M ，Ravnik-Glavac M ，Glavac D ... -  《-》

Combined Microsatellite Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic Oncology Group Study.

The best screening practice for Lynch syndrome (LS) in endometrial cancer (EC) remains unknown. We sought to determine whether tumor microsatellite instability (MSI) typing along with immunohistochemistry (IHC) and MLH1 methylation analysis can help identify women with LS. ECs from GOG210 patients were assessed for MSI, MLH1 methylation, and mismatch repair (MMR) protein expression. Each tumor was classified as having normal MMR, defective MMR associated with MLH1 methylation, or probable MMR mutation (ie, defective MMR but no methylation). Cancer family history and demographic and clinical features were compared for the three groups. Lynch mutation testing was performed for a subset of women. Analysis of 1,002 ECs suggested possible MMR mutation in 11.8% of tumors. The number of patients with a family history suggestive of LS was highest among women whose tumors were classified as probable MMR mutation (P = .001). Lynch mutations were identified in 41% of patient cases classified as probable mutation (21 of 51 tested). One of the MSH6 Lynch mutations was identified in a patient whose tumor had intact MSH6 expression. Age at diagnosis was younger for mutation carriers than noncarriers (54.3 v 62.3 years; P < .01), with five carriers diagnosed at age > 60 years. Combined MSI, methylation, and IHC analysis may prove useful in Lynch screening in EC. Twenty-four percent of mutation carriers presented with ECs at age > 60 years, and one carrier had an MSI-positive tumor with no IHC defect. Restricting Lynch testing to women diagnosed at age < 60 years or to women with IHC defects could result in missing a substantial fraction of genetic disease.

Goodfellow PJ ，Billingsley CC ，Lankes HA ，Ali S ，Cohn DE ，Broaddus RJ ，Ramirez N ，Pritchard CC ，Hampel H ，Chassen AS ，Simmons LV ，Schmidt AP ，Gao F ，Brinton LA ，Backes F ，Landrum LM ，Geller MA ，DiSilvestro PA ，Pearl ML ，Lele SB ，Powell MA ，Zaino RJ ，Mutch D ... -  《-》