title: Genetic alterations in quadruple malignancies of a patient with multiple sclerosis: their role in malignancy development and response to therapy.
abstract: Multiple cancers represent 2.42% of all human cancers and are mainly double or triple cancers. Many possible causes of multiple malignancies have been reported such as genetic alterations, exposure to anti-cancer chemotherapy, radiotherapy, immunosuppressive therapy and reduced immunologic response. We report a female patient with multiple sclerosis and quadruple cancers of different embryological origin. Patient was diagnosed with stage III (T3, N1a, MO) medullary thyroid carcinoma (MTC), multicentric micropapillary thyroid carcinoma, scapular and lumbar melanomas (Clark II, Breslow II), and lobular invasive breast carcinoma (T1a, NO, MO). All tumors present in our patient except micropapillary thyroid carcinomas were investigated for gene alterations known to have a key role in cancer promotion and progression. Tumor samples were screened for the p16 alterations (loss of heterozygosity and homozygous deletions), loss of heterozygosity of PTEN, p53 alterations (mutational status and loss of heterozygosity) and mutational status of RET, HRAS and KRAS. Each type of tumor investigated had specific pattern of analyzed genetic alterations. The most prominent genetic changes were mutual alterations in PTEN and p53 tumor suppressors present in breast cancer and two melanomas. These co-alterations could be crucial for promoting development of multiple malignancies. Moreover the insertion in 4(th) codon of HRAS gene was common for all tumor types investigated. It represents frameshift mutation introducing stop codon at position 5 which prevents synthesis of a full-length protein. Since the inactivated RAS enhances sensitivity to tamoxifen and radiotherapy this genetic alteration could be considered as a good prognostic factor for this patient.
authors.affiliation: Institute for Biological Research "Sinisa Stankovic", University of Belgrade Bulevar Despota Stefana 142, 11060 Belgrade, Serbia.
authors.forename: Zorica
authors.initials: Z
authors.lastname: Milosevic
authors.affiliation: Institute for Biological Research "Sinisa Stankovic", University of Belgrade Bulevar Despota Stefana 142, 11060 Belgrade, Serbia.
authors.forename: Nikola
authors.initials: N
authors.lastname: Tanic
authors.affiliation: Institute for Biological Research "Sinisa Stankovic", University of Belgrade Bulevar Despota Stefana 142, 11060 Belgrade, Serbia.
authors.forename: Jasna
authors.initials: J
authors.lastname: Bankovic
authors.affiliation: Institute for Biological Research "Sinisa Stankovic", University of Belgrade Bulevar Despota Stefana 142, 11060 Belgrade, Serbia.
authors.forename: Tijana
authors.initials: T
authors.lastname: Stankovic
authors.affiliation: Institute for Oncology and Radiology of Serbia, University of Belgrade Pasterova 14, 11000 Belgrade, Serbia.
authors.forename: Marko
authors.initials: M
authors.lastname: Buta
authors.affiliation: Institute for Neurology, Clinical Center of Serbia, University of Belgrade Dr Subotica 6, 11000 Belgrade, Serbia ; School of Medicine, University of Belgrade Dr Subotica 8, 11000 Belgrade, Serbia.
authors.forename: Dragana
authors.initials: D
authors.lastname: Lavrnic
authors.affiliation: Institute for Oncology and Radiology of Serbia, University of Belgrade Pasterova 14, 11000 Belgrade, Serbia.
authors.forename: Zorka
authors.initials: Z
authors.lastname: Milovanovic
authors.affiliation: Institute for Oncology and Radiology of Serbia, University of Belgrade Pasterova 14, 11000 Belgrade, Serbia.
authors.forename: Gordana
authors.initials: G
authors.lastname: Pupic
authors.affiliation: Institute for Biological Research "Sinisa Stankovic", University of Belgrade Bulevar Despota Stefana 142, 11060 Belgrade, Serbia.
authors.forename: Sonja
authors.initials: S
authors.lastname: Stojkovic
authors.affiliation: Institute for Biological Research "Sinisa Stankovic", University of Belgrade Bulevar Despota Stefana 142, 11060 Belgrade, Serbia.
authors.forename: Vedrana
authors.initials: V
authors.lastname: Milinkovic
authors.affiliation: Department of Surgery, Kuma Hospital 8-2-35, Shimoyamate-dori, Chuo-ku, Kobe, 650-0011, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Institute for Oncology and Radiology of Serbia, University of Belgrade Pasterova 14, 11000 Belgrade, Serbia ; School of Medicine, University of Belgrade Dr Subotica 8, 11000 Belgrade, Serbia.
authors.forename: Radan
authors.initials: R
authors.lastname: Dzodic
mesh_terms: D000328:Adult; D001379:Azathioprine / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000235:genetics* / Q000628:therapy; D001943:Breast Neoplasms / Q000235:genetics* / Q000628:therapy; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000628:therapy; D018276:Carcinoma, Medullary / Q000235:genetics / Q000628:therapy; D002291:Carcinoma, Papillary / Q000235:genetics / Q000628:therapy; D003131:Combined Modality Therapy; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008545:Melanoma / Q000235:genetics / Q000628:therapy; D009103:Multiple Sclerosis / Q000150:complications* / Q000188:drug therapy*; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000628:therapy; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D007166:Immunosuppressive Agents; C117307:KRAS protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D001379:Azathioprine
keywords: HRAS; PTEN; Quadruple cancers; multiple sclerosis; p53