Frequent PIK3CA Mutations in Colorectal and Endometrial Tumors With 2 or More Somatic Mutations in Mismatch Repair Genes.
Some colorectal and endometrial tumors with microsatellite instability not attributable to MLH1 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.



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 PIK3CA, BRAF, KRAS, NRAS, and PTEN by targeted next-generation sequencing and used logistic-regression models to compare them with those from patients with Lynch syndrome, MLH1-hypermethylated, or microsatellite-stable tumors. We validated our findings using independent data sets from The Cancer Genome Atlas.



Among colorectal cancer cases, we found that 14 of 21 (67%) patients with double somatic tumors also had PIK3CA mutations, compared with 4 of 18 (22%) tumors from patients with Lynch syndrome, 2 of 10 (20%) tumors with MLH1 hypermethylation, and 12 of 78 (15%) tumors with microsatellite stability (P < .0001 for patients with double somatic tumors vs other subgroups). Mutations in PIK3CA were detected in all 13 patients with double somatic endometrial cancers (P = .04 compared with other subgroups). We did not detect BRAF 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 PIK3CA (P < .0001 compared with other subgroups).



Most patients with colorectal or endometrial tumors with 2 or more somatic (but not germline) mutations in MMR proteins also have mutations in PIK3CA; mutations in PIK3CA are detected at substantially higher frequencies in these double somatic tumors than in other microsatellite-instability subgroups. PIK3CA mutation status might be used to identify a specific group of colorectal tumors, and to select treatment or determine prognosis.
Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, Washington; Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, Washington.
Stacey A
SA
Cohen
Department of Laboratory Medicine, University of Washington, Seattle, Washington.
Emily H
EH
Turner
Department of Laboratory Medicine, University of Washington, Seattle, Washington.
Mallory B
MB
Beightol
Department of Laboratory Medicine, University of Washington, Seattle, Washington.
Angela
A
Jacobson
Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, Washington.
Ted A
TA
Gooley
Department of Laboratory Medicine, University of Washington, Seattle, Washington.
Stephen J
SJ
Salipante
Division of Medical Oncology, Department of Medicine, Stanford University, Stanford, California.
Sigurdis
S
Haraldsdottir
Department of Laboratory Medicine, University of Washington, Seattle, Washington.
Christina
C
Smith
Department of Laboratory Medicine, University of Washington, Seattle, Washington.
Sheena
S
Scroggins
Department of Laboratory Medicine, University of Washington, Seattle, Washington.
Jonathan F
JF
Tait
Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, Washington; Division of Gastroenterology, University of Washington, Seattle, Washington.
William M
WM
Grady
Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, Washington; Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, Washington.
Edward H
EH
Lin
Division of Gynecologic Oncology, The Ohio State University, Columbus, Ohio.
David E
DE
Cohn
Division of Gynecologic Oncology, The Ohio State University, Columbus, Ohio.
Paul J
PJ
Goodfellow
Department of Surgery, The Ohio State University College of Medicine, Columbus, Ohio.
Mark W
MW
Arnold
Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio.
Albert
A
de la Chapelle
Division of Human Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
Rachel
R
Pearlman
Division of Human Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
Heather
H
Hampel
Department of Laboratory Medicine, University of Washington, Seattle, Washington. Electronic address: cpritch@uw.edu.
Colin C
CC
Pritchard
D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D053843:DNA Mismatch Repair / Q000235:genetics*; D004252:DNA Mutational Analysis; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D053842:Microsatellite Instability; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics
C117307:KRAS protein, human; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
Lynch-Like Syndrome; MMR; MSI; PI3K