Evaluating the performance of clinical criteria for predicting mismatch repair gene mutations in Lynch syndrome: a comprehensive analysis of 3,671 families.

Carriers of mismatch repair (MMR) gene mutations have a high lifetime risk for colorectal and endometrial cancers, as well as other malignancies. As mutation analysis to detect these patients is expensive and time-consuming, clinical criteria and tumor-tissue analysis are widely used as pre-screening methods. The aim of our study was to evaluate the performance of commonly applied clinical criteria (the Amsterdam I and II Criteria, and the original and revised Bethesda Guidelines) and the results of tumor-tissue analysis in predicting MMR gene mutations. We analyzed 3,671 families from the German HNPCC Registry and divided them into nine mutually exclusive groups with different clinical criteria. A total of 680 families (18.5%) were found to have a pathogenic MMR gene mutation. Among all 1,284 families with microsatellite instability-high (MSI-H) colorectal cancer, the overall mutation detection rate was 53.0%. Mutation frequencies and their distribution between the four MMR genes differed significantly between clinical groups (p < 0.001). The highest frequencies were found in families fulfilling the Amsterdam Criteria (46.4%). Families with loss of MSH2 expression had higher mutation detection rates (69.5%) than families with loss of MLH1 expression (43.1%). MMR mutations were found significantly more often in families with at least one MSI-H small-bowel cancer (p < 0.001). No MMR mutations were found among patients under 40-years-old with only colorectal adenoma. Familial clustering of Lynch syndrome-related tumors, early age of onset, and familial occurrence of small-bowel cancer were clinically relevant predictors for Lynch syndrome.

Steinke V ，Holzapfel S ，Loeffler M ，Holinski-Feder E ，Morak M ，Schackert HK ，Görgens H ，Pox C ，Royer-Pokora B ，von Knebel-Doeberitz M ，Büttner R ，Propping P ，Engel C ，German HNPCC Consortium ... -  《-》

Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics.

Lagerstedt Robinson K ，Liu T ，Vandrovcova J ，Halvarsson B ，Clendenning M ，Frebourg T ，Papadopoulos N ，Kinzler KW ，Vogelstein B ，Peltomäki P ，Kolodner RD ，Nilbert M ，Lindblom A ... -  《-》

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 ... -  《-》

Microsatellite instability and novel mismatch repair gene mutations in northern Chinese population with hereditary non-polyposis colorectal cancer.

Sheng JQ ，Chan TL ，Chan YW ，Huang JS ，Chen JG ，Zhang MZ ，Guo XL ，Mu H ，Chan AS ，Li SR ，Yuen ST ，Leung SY ... -  《-》

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》