Marjolijn D Trietsch1, Vivian M Spaans2, Natalja T ter Haar3, Elisabeth M Osse3, Alexander A W Peters4, Katja N Gaarenstroom4, Gert Jan Fleuren3. 1. Department of Pathology, Leiden University Medical Center, The Netherlands. Electronic address: M.D.Trietsch@LUMC.nl. 2. Department of Pathology, Leiden University Medical Center, The Netherlands; Department of Gynecology, Leiden University Medical Center, The Netherlands. 3. Department of Pathology, Leiden University Medical Center, The Netherlands. 4. Department of Gynecology, Leiden University Medical Center, The Netherlands.
Abstract
BACKGROUND: Two etiologic pathways of vulvar cancer are known, a human papillomavirus (HPV)- and a TP53-associated route, respectively, but other genetic changes may also play a role. Studies on somatic mutations in vulvar cancer other than TP53 are limited in number and size. In this study, we investigated the prevalence of genetic mutations in 107 vulvar squamous cell carcinomas (VSCCs). METHODS: A total of 107 paraffin-embedded tissue samples of primarily surgically treated VSCCs were tested for HPV infection and screened for mutations in 14 genes (BRAF, CDKN2A(p16), CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, PTEN, and TP53) using Sanger sequencing and mass spectrometry. RESULTS: Mutations were detected in 7 genes. Of 107 VSCCs, 66 tumors (62%) contained at least one mutation (TP53=58, CDKN2A(p16)=14, HRAS=10, PIK3CA=7, PPP2R1A=3, KRAS=1, PTEN=1). Mutations occurred most frequently in HPV-negative samples. Five-year survival was significantly worse for patients with a mutation (47% vs 59%, P=.035), with a large effect from patients carrying HRAS-mutations. CONCLUSION: Somatic mutations were detected in 62% of VSCCs. As expected, HPV infection and TP53-mutations play a key role in the development of VSCC, but CDKN2A(p16), HRAS, and PIK3CA-mutations were also frequently seen in HPV-negative patients. Patients with somatic mutations, especially HRAS-mutations, have a significantly worse prognosis than patients lacking these changes, which could be of importance for the development of targeted therapy.
BACKGROUND: Two etiologic pathways of vulvar cancer are known, a human papillomavirus (HPV)- and a TP53-associated route, respectively, but other genetic changes may also play a role. Studies on somatic mutations in vulvar cancer other than TP53 are limited in number and size. In this study, we investigated the prevalence of genetic mutations in 107 vulvar squamous cell carcinomas (VSCCs). METHODS: A total of 107 paraffin-embedded tissue samples of primarily surgically treated VSCCs were tested for HPV infection and screened for mutations in 14 genes (BRAF, CDKN2A(p16), CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, PTEN, and TP53) using Sanger sequencing and mass spectrometry. RESULTS: Mutations were detected in 7 genes. Of 107 VSCCs, 66 tumors (62%) contained at least one mutation (TP53=58, CDKN2A(p16)=14, HRAS=10, PIK3CA=7, PPP2R1A=3, KRAS=1, PTEN=1). Mutations occurred most frequently in HPV-negative samples. Five-year survival was significantly worse for patients with a mutation (47% vs 59%, P=.035), with a large effect from patients carrying HRAS-mutations. CONCLUSION: Somatic mutations were detected in 62% of VSCCs. As expected, HPV infection and TP53-mutations play a key role in the development of VSCC, but CDKN2A(p16), HRAS, and PIK3CA-mutations were also frequently seen in HPV-negative patients. Patients with somatic mutations, especially HRAS-mutations, have a significantly worse prognosis than patients lacking these changes, which could be of importance for the development of targeted therapy.
Authors: Anastasiya Atanasova Chokoeva; Georgi Tchernev; Elena Castelli; Elisabetta Orlando; Shyam B Verma; Markus Grebe; Uwe Wollina Journal: Wien Med Wochenschr Date: 2015-05-01
Authors: Vivian M Spaans; Marjolijn D Trietsch; Alexander A W Peters; Michelle Osse; Natalja Ter Haar; Gert J Fleuren; Ekaterina S Jordanova Journal: PLoS One Date: 2015-07-21 Impact factor: 3.240
Authors: Marjolijn D Trietsch; Maaike H M Oonk; Lukas J A C Hawinkels; Rosalie Bor; Jaap D H van Eendenburg; Zina Ivanova; Alexander A W Peters; Hans W Nijman; Katja N Gaarenstroom; Tjalling Bosse Journal: Oncotarget Date: 2016-05-03
Authors: Michael K Kiessling; Alessandra Curioni-Fontecedro; Panagiotis Samaras; Kirstin Atrott; Jesus Cosin-Roger; Silvia Lang; Michael Scharl; Gerhard Rogler Journal: Oncotarget Date: 2015-12-08