Mutations in genes encoding PI3K-AKT and MAPK signaling define anogenital papillary hidradenoma.
Papillary hidradenoma (a.k.a. hidradenoma papilliferum) is a benign tumor of the anogenital region that almost exclusively arises in middle-aged Caucasian women. These tumors may recur and rare cases of malignant development have been reported. The genetic basis of papillary hidradenoma is currently unknown. Hence, we employed targeted high-coverage next generation sequencing interrogating 50 cancer-related genes and conventional Sanger sequencing to investigate the mutational landscape in a cohort of 15 cases. Additionally, we analyzed the HPV status of these tumors. Thirteen cases (87%) harbored mutations in cancer-related genes. Recurrent mutations in PIK3CA and AKT1 were present in 10 of the cases (67%). One PIK3CA mutated case had a concomitant STK11 mutation. Three cases harbored mutually exclusive mutations in BRAF, APC and ERBB4. The remaining two cases showed no mutations. None of the cases harbored DNA of human papilloma virus. Our results also provide evidence that--just as BRAF V600E mutations in hyperplastic polyps and benign nevi- a mutated driver gene does not imply malignant behavior per se but may set the basis for malignant transformation. The latter point may explain why rare cases of papillary hidradenoma have been reported to take a malignant course. Lastly, our genetic data may suggest treatment avenues beyond conventional surgery for some of these tumors.
Institute of Pathology, Technical University Munich (TUM), Trogerstrasse 18, Munich, 81675, Germany.
Nicole
N
Pfarr
Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany.
Hans-Peter
HP
Sinn
Institute of Pathology, Charité University Hospital, Berlin, 10117, Germany.
Frederick
F
Klauschen
Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany.
Christa
C
Flechtenmacher
Institute of Pathology, Charité University Hospital, Berlin, 10117, Germany.
Michael
M
Bockmayr
Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany.
Kathrin
K
Ridinger
Institute of Pathology, Charité University Hospital, Berlin, 10117, Germany.
Moritz
M
von Winterfeld
Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany.
Arne
A
Warth
Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany.
Katja
K
Lorenz
Institute of Pathology, Charité University Hospital, Berlin, 10117, Germany.
Jan
J
Budczies
Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany.
Roland
R
Penzel
Department of Pathology, Center for Integrated Diagnostics (CID), Massachusetts General Hospital/Harvard Medical School, Boston, MA, 02114.
Jochen K
JK
Lennerz
Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany.
Volker
V
Endris
Institute of Pathology, Technical University Munich (TUM), Trogerstrasse 18, Munich, 81675, Germany.|Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany.|National Center for Tumor Diseases (NCT), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
Wilko
W
Weichert
Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany.|National Center for Tumor Diseases (NCT), Heidelberg, Germany.|National Center of Tumor Diseases-Heidelberg School of Oncology (NCT-HSO), Heidelberg, Germany.
Albrecht
A
Stenzinger
D000091162:AMP-Activated Protein Kinase Kinases; D018250:Acrospiroma / Q000235:genetics*; D000328:Adult; D000368:Aged; D001005:Anus Neoplasms / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D020935:MAP Kinase Signaling System; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D014846:Vulvar Neoplasms / Q000235:genetics*
D000091162:AMP-Activated Protein Kinase Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; C484760:PIK3CA protein, human; C494918:AKT1 protein, human; C109790:STK11 protein, human