The status of Her2 amplification and Kras mutations in mucinous ovarian carcinoma

Human Genomics, Dec 2016

Jayson GC et al. remarked in Lancet that nearly 100% of mucinous ovarian cancer cases have Kras mutation as well as a high frequency of Her2 amplification. Using the Abbott PathVysion Her2 DNA Probe Kit and Kras mutant-enriched PCR Kits (FemtoPath®), 21 samples of primary ovarian mucinous cystadenocarcinomas from Taiwanese patients were examined to determine the status of Her2 amplification and Kras mutations. Our results showed the Her2 amplification rates were 33.33%, while the Kras mutation rates were 61.90%. We present here our results in order to enlighten the readership that the ~100% Kras mutant frequency and the high Her2 amplification rate reported by Jayson et al. may be too exaggerated to be applicable into all populations. Additionally, we report another 2 novel Kras mutations (A11V, V14I).

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

http://www.humgenomics.com/content/pdf/s40246-016-0096-9.pdf

The status of Her2 amplification and Kras mutations in mucinous ovarian carcinoma

Chang et al. Human Genomics The status of Her2 amplification and Kras mutations in mucinous ovarian carcinoma Kuang-Leei Chang 2 Ming-Yung Lee 1 Wan-Ru Chao 0 Chih-Ping Han 0 3 0 Department of Pathology, Chung-Shan Medical University and Chung Shan Medical University Hospital , Taichung , Taiwan 1 Department of Statistics and Informatics Science, Providence University , Taichung , Taiwan 2 Department of Emergency Medicine, Chung-Shan Medical University and Chung Shan Medical University Hospital , Taichung , Taiwan 3 Department of Obstetrics and Gynecology, Chung-Shan Medical University and Chung-Shan Medical University Hospital , No 110, Sec 1, Chien Kuo N. Rd, Taichung 40201 , Taiwan Jayson GC et al. remarked in Lancet that nearly 100% of mucinous ovarian cancer cases have Kras mutation as well as a high frequency of Her2 amplification. Using the Abbott PathVysion Her2 DNA Probe Kit and Kras mutantenriched PCR Kits (FemtoPath®), 21 samples of primary ovarian mucinous cystadenocarcinomas from Taiwanese patients were examined to determine the status of Her2 amplification and Kras mutations. Our results showed the Her2 amplification rates were 33.33%, while the Kras mutation rates were 61.90%. We present here our results in order to enlighten the readership that the ~100% Kras mutant frequency and the high Her2 amplification rate reported by Jayson et al. may be too exaggerated to be applicable into all populations. Additionally, we report another 2 novel Kras mutations (A11V, V14I). Kras mutation; Her2 amplification; Mucinous ovarian carcinoma - Oncology/College of American Pathologists (ASCO/CAP) breast cancer scoring methods were used to examine for Her2 FISH ratio. The Kras mutant-enriched polymerase chain reaction (PCR) Kits (FemtoPath®) and a following direct sequencing method were applied to analyze exon 2 of the Kras gene. The reason why we choose Kras exon 2 to analyze is because Kras gene mutations are mainly known to cluster in several hotspots, with exon 2 (codons 12 and 13) being most commonly affected [6–9]. The prevalence of Kras mutations and Her2 amplification within 21 Taiwanese mucinous ovarian carcinoma cases is shown in Table 1, which indicates that the amplification rate of Her2 was 33.33% (n = 7), while the mutation rate of Kras was 61.90% (n = 13). Additionally, the rates of co-existing Kras mutations and Her2 amplification were 9.52% (n = 2) (Table 1). However, there was a lack of statistically significant association between Her2 amplification and Kras mutations (p = 0.057). Of the 13 cases of mucinous ovarian carcinoma with Kras mutations, 12 cases had a single missense mutation, which was composed of G12V in 4 cases, G12D in 5 cases, G12A in 1 case and A11V in 2 cases. The remaining 1 case had triple missense mutations—A11V, G13N and V14I. Moreover, both A11V and V14I were novel discoveries, based on the Catalogue of Somatic Mutations in Cancer (COSMIC) database [10]. © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Table 1 The prevalence and relationship of Kras mutations and Her2 amplification in mucinous ovarian carcinoma n (%) number (percentage) aFisher’s exact test Conclusion Both Her2 amplification and Kras activating mutations are not mutually exclusive, which indicates that Her2/Kras/ mitogen-activated protein kinases (MAPK) is a crucial pathway in the carcinogenesis of mucinous ovarian neoplasms. Targeting this pathway seems to be a viable therapeutic option for patients with recurrent or advanced stage mucinous ovarian carcinoma. Treatment selection based on the molecular alterations of Her2 and Kras can possibly produce superior therapeutic effects compared with nonselective treatments. Additionally, functional impacts of these 2 novel Kras mutations (A11V, V14I) are still unknown; further studies using bioinformatics tools and molecular modeling are encouraged. Abbreviations ASCO/CAP: American Society of Clinical Oncology/College of American Pathologists; COSMIC: Catalogue of Somatic Mutations in Cancer; Her2: Human epidermal growth factor receptor 2 gene; ICH: International Conference on Harmonization; Kras: V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog gene; MAPK: Mitogen-activated protein kinases; PCR: Polymerase chain reaction Acknowledgements This work was supported by Prof. Hao-Ping Liu, DVM, PhD, National Chung Hsing University and Chung Shan Medical University, Taichung, Taiwan (Grant: NCHU-CSMU-10501). We are very much thankful to Prof. Heung Tat Ng, MD, Female Cancer Foundation, Taipei, Taiwan, for his keen interest and valuable guidance. We are extremely grateful to Jennie Cheng, RN, PhD; Alexandra Ruan, MD; and Bernard A (HHS/OPHS) Schwetz, DVM, PhD, for their expertise and patience in English correction and helpful comments. Availability of data and materials Please contact the author for data requests. Ethics approval and consent to participate Our research was conducted in accordance with the International Conference on Harmonization (ICH) guidelines and compliant with all applicable regulations for the protection of human subjects for research, including review and approval by the Institutional Review Board of the Chung-Shan Medical University Hospital, Taichung, Taiwan. 1. Jayson GC , Kohn EC , Kitchener HC , Ledermann JA . Ovarian cancer . Lancet . 2014 ; 384 : 1376 - 88 . 2. Chao WR , Lee MY , Lin WL , Koo CL , Sheu GT , Han CP . Assessing the HER2 status in mucinous epithelial ovarian cancer on the basis of the 2013 ASCO/ CAP guideline update . Am J Surg Pathol . 2014 ; 38 : 1227 - 34 . 3. Li XS , Sun J , He XL . Expression of c-myc and mutation of the Kras gene in patients with ovarian mucinous tumors . Genet Mol Res . 2015 ; 14 : 10752 - 9 . doi:10.4238/ 2015 .September.9. 14 . 4. Auner V , Kriegshäuser G , Tong D , et al. Kras mutation analysis in ovarian samples using a high sensitivity biochip assay . BMC Cancer . 2009 ; 9 : 111 . 5. Perren TJ . Mucinous epithelial ovarian carcinoma . Ann Oncol . 2016 ; 27 suppl 1:i53-7 . doi:10.1093/annonc/mdw087. 6. Zinsky R , Bölükbas S , Bartsch H , et al. Analysis of Kras mutations of Exon 2 Codons 12 and 13 by SNaPshot analysis in comparison to common DNA sequencing . Gastroenterol Res Pract . 2010 ; 2010 :789363. doi:10.1155/2010/789363. 7. Prior IA , Lewis PD , Mattos C. A comprehensive survey of Ras mutations in cancer . Cancer Res . 2012 ; 72 : 2457 - 67 . 8. Bos JL . Ras oncogenes in human cancer: a review . Cancer Res . 1989 ; 49 : 4682 - 9 . 9. Stolze B , Reinhart S , Bulllinger L , et al. Comparative analysis of Kras codon 12 , 13 , 18 , 61, and 117 mutations using human MCF10A isogenic cell lines . Sci Rep . 2015 ; 5 :8535. doi:10.1038/srep08535. 10. Lee YJ , Lee MY , Ruan A , et al. Multipoint Kras oncogene mutations potentially indicate mucinous carcinoma on the entire spectrum of mucinous ovarian neoplasms . Oncotarget . https://www.ncbi. nlm.nih.gov/ pubmed/27888800. Advance Online Publications . 2016 . doi:10.18632/ oncotarget.13449.


This is a preview of a remote PDF: http://www.humgenomics.com/content/pdf/s40246-016-0096-9.pdf

Kuang-Leei Chang, Ming-Yung Lee, Wan-Ru Chao, Chih-Ping Han. The status of Her2 amplification and Kras mutations in mucinous ovarian carcinoma, Human Genomics, 2016, 40, DOI: 10.1186/s40246-016-0096-9