Frequent PIK3CA Mutations in Colorectal and Endometrial Tumors With 2 or More Somatic Mutations in Mismatch Repair Genes

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• 作者：Stacey A. Cohen¹ ; ² ; ^&lowast ; ; Emily H. Turner³ ; ^&lowast ; ; Mallory B. Beightol³ ; Angela Jacobson³ ; Ted A. Gooley² ; Stephen J. Salipante³ ; Sigurdis Haraldsdottir⁴ ; Christina Smith³ ; Sheena Scroggins³ ; Jonathan F. Tait³ ; William M. Grady² ; ⁵ ; Edward H. Lin¹ ; ² ; David E. Cohn⁶ ; Paul J. Goodfellow⁶ ; Mark W. Arnold⁷ ; Albert de la Chapelle⁸ ; Rachel Pearlman⁹ ; Heather Hampel⁹ ; Colin C. Pritchard³ ; ^{cpritch@uw.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：MSI ; MMR ; Lynch-Like Syndrome ; PI3K
• 刊名：Gastroenterology
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：151
• 期：3
• 页码：440-447.e1
• 全文大小：966 K

文摘

Some colorectal and endometrial tumors with microsatellite instability not attributable to <em>MLH1em> hypermethylation or germline mutations contain 2 or more somatic mutations in genes encoding mismatch repair (MMR) proteins. We sought to define the molecular phenotype of this newly recognized tumor subtype.

ec_2">Methods

From 2 prospective studies of the efficacy of screening for Lynch syndrome, we identified patients with colorectal and endometrial tumors who had 2 or more somatic (but not germline) mutations in genes encoding MMR proteins (double somatic). We determined the frequencies of tumor mutations in <em>PIK3CAem>, <em>BRAFem>, <em>KRASem>, <em>NRASem>, and <em>PTENem> by targeted next-generation sequencing and used logistic-regression models to compare them with those from patients with Lynch syndrome, <em>MLH1em>-hypermethylated, or microsatellite-stable tumors. We validated our findings using independent data sets from The Cancer Genome Atlas.

ec_3">Results

Among colorectal cancer cases, we found that 14 of 21 (67%) patients with double somatic tumors also had <em>PIK3CAem> mutations, compared with 4 of 18 (22%) tumors from patients with Lynch syndrome, 2 of 10 (20%) tumors with <em>MLH1em> hypermethylation, and 12 of 78 (15%) tumors with microsatellite stability (<em>Pem> < .0001 for patients with double somatic tumors vs other subgroups). Mutations in <em>PIK3CAem> were detected in all 13 patients with double somatic endometrial cancers (<em>Pem> = .04 compared with other subgroups). We did not detect <em>BRAFem> mutations in patients with double somatic colorectal tumors or Lynch syndrome. We found highly similar results in a validation cohort from The Cancer Genome Atlas (113 patients with colorectal tumors, 178 endometrial tumors); 100% of double somatic cases had a somatic mutation in <em>PIK3CAem> (<em>Pem> < .0001 compared with other subgroups).

ec_4">Conclusions

Most patients with colorectal or endometrial tumors with 2 or more somatic (but not germline) mutations in MMR proteins also have mutations in <em>PIK3CAem>; mutations in <em>PIK3CAem> are detected at substantially higher frequencies in these double somatic tumors than in other microsatellite-instability subgroups. <em>PIK3CAem> mutation status might be used to identify a specific group of colorectal tumors, and to select treatment or determine prognosis.