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Frequency of RAS Mutations (KRAS, NRAS, HRAS) in Human Solid Cancer

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Frequency of RAS Mutations (KRAS, NRAS, HRAS) in Human Solid Cancer DOI: 10.14744/ejmo.2017.22931 EJMO 2017;1(1):1–7 Review Frequency of RAS Mutations (KRAS, NRAS, HRAS) in Human Solid Cancer Hilmi Kodaz,1 Osman Kostek,2 Muhammet Bekir Hacioglu,2 Bulent Erdogan,2 Cagnur Elpen Kodaz,3 Ilhan Hacibekiroglu,4 Esma Turkmen,2 Sernaz Uzunoglu,2 Irfan Cicin2 1Department of Medical Oncology, Acibadem Eskisehir Hospital, Eskisehir, Turkey 2Department of Medical Oncology, Trakya University Faculty of Medicine, Edirne, Turkey 3Department of Health, Acibadem Eskisehir Hospital, Eskisehir, Turkey 4Department of Medical Oncology, Sakarya University Faculty of Medicine, Sakarya, Turkey Abstract RAS oncogene affects numerous cellular functions including growth, proliferation, apoptosis, migration, division and differentiation of the cells. It has 3 known isoforms as Harvey- RAS (HRAS), Kirsten - RAS (KRAS) and Neuroblastoma- RAS (NRAS). RAS has an intrinsic GTPase activity. It encodes proteins binding the guanine nucleotides. KRAS and HRAS were discovered in studies carried out on viruses leading to cancer. Retroviral oncogenes related to murine sarcoma virus genes (Kristen Rat Sarcoma Virus and Murine Sarcoma Virus) were discovered in 1982. These two oncogenes are similar to human KRAS. Approximately 30% of all human cancers have ras genes. Mutations in KRAS account for about 85% for all RAS mutations in human tumors, NRAS is about 11–15%, and HRAS is about 1%. Keywords: KRAS, NRAS, HRAS, cancer Cite This Article: Kodaz H, Kostek O, Hacioglu M, Erdogan B, Elpen Kodaz C, Hacibekiroglu I, Turkmen E, Uzunoglu S, Cicin I. Frequency of Ras Mutations (Kras, Nras, Hras) in Human Solid Cancer. EJMO. 2017; 1(1): 1-7 he RAS oncogene affects numerous cellular functions, in- Frequency of RAS mutation Tcluding growth, proliferation, apoptosis, migration, divi- in intracranial tumors sion, and differentiation of the cells. It has 3 known isoforms: Harvey-RAS (HRAS), Kirsten-RAS (KRAS), and neuroblasto- Gliomas constitute 80% of malignant brain tumors. RAS ma-RAS (NRAS). RAS has an intrinsic GTPase activity; it en- mutations are very rare in malignant gliomas; no RAS mu- codes proteins binding the guanine nucleotides. KRAS and tation was found in a study in which 30 glioblastoma mul- HRAS were discovered in studies conducted on cancer-caus- tiforme (GBM) patients were evaluated. The frequency of ing viruses. Retroviral oncogenes related to murine sarcoma NRAS mutation was 2.1% in another study, although KRAS virus genes (Kristen rat sarcoma virus and Harvey rat sarco- and HRAS mutations were not detected. It was reported ma virus) were discovered in 1982. These 2 oncogenes are that RAS mutation frequency was 12% in a study of isoc- similar to human KRAS. Approximately 30% of all human itrate-dehydrogenase 1-mutant malignant glioma. RAS cancers have RAS gene involvement. Mutations in KRAS ac- genes were studied in 21 cases of glioblastoma multiforme, count for about 85% of all RAS mutations in human tumors, 4 cases of fibrillary astrocytoma, 4 cases of anaplastic astro- NRAS for about 11% to 15%, and HRAS for about 1%.[1–6] cytoma, and 15 normal specimens. RAS mutation was de- Address for correspondence: Hilmi Kodaz, MD. Acibadem Eskisehir Hastanesi, Tibbi Onkoloji Klinigi, Eskisehir, Turkey Phone: +90 507 931 42 86 E-mail: [email protected] Submitted Date: May 21, 2017 Accepted Date: July 03, 2017 Available Online Date: July 26, 2017 ©Copyright 2017 by Eurasian Journal of Medicine and Oncology - Available online at www.ejmo.org 2 Kodaz et al., Frequency of RAS Mutations / doi: 14744/ejmo.2017.22931 tected in 1 normal and 1 pathological sample. It was con- Table 1. Frequency of RAS mutations according to cancer type cluded that brain tumor development was found to involve Cancer KRAS NRAS HRAS KRAS and HRAS mutations, while NRAS mutation may play % % % a lesser role. The frequency of RAS mutation in GBM is 2% in Glioblastoma multiforme 0–2 2.1 0 the atlas of the human genome. KRAS mutation was found Pilocytic astrocytoma 4.7 0 0 in 4.7% of pilocytic astrocytomas, while there was no NRAS Oligodendroglioma LD LD LD and HRAS mutation. RAS mutations in oligodendrogliomas Oral cavity tumor 0–18 <1 35 [7–15] have not yet been sufficiently researched. Larynx cancer 4.8–11.5 0 0 Nasopharynx cancer 0 4 <1 Frequency of RAS mutation Colorectal cancer 27–56 1–7 <1 in head and neck cancers Stomach cancer 2.8–9.4 1,9 <1 Pancreatic cancer 90 <1 <1 Many head and neck cancers are squamous cell carcino- Hepatocellular cancer 0–5 15 29 mas. More than half a million people are affected every Cholangiocarcinoma 16–38 LD <1 year. The prevalence has continued to gradually increase in Small cell lung cancer 1–16 <1 <1 [16] recent years. Overall survival in patients with KRAS mu- Squamous cell lung cancer 3 <1 <1 tation head and neck tumor is worse. KRAS mutations also Lung adenocarcinoma 12–36 <1 <1 demonstrate social differences in head and neck tumors, Large cell lung cancer 14 <1 <1 like many cancers. Though the mutation frequency is 5% in Large cell lung cancer <1 <1 <1 oral cavity tumors in Western societies, it can be seen in up Serous ovarian carcinoma 6 8 <1 to 18% of cases in Eastern societies. The frequency of KRAS Ovarian clear cell carcinoma 14 0 mutation in malignant larynx lesions was 4.8% in one study IMSC 68 performed, while there were no HRAS and NRAS mutations. Low-grade serous tumour 29,5 In Eastern societies, the frequency of HRAS mutation in oral High-grade serous carcinoma 12 cavity tumors can be as much as 35%. KRAS mutation was Mucinous borderline tumor 33–78 not detected at all in mouth and hypopharynx cancers in Serous borderline tumor 60 another study conducted. There is KRAS mutation in 11.5% Mucinous carcinoma 46–75 and 3.3% of patients with laryngeal cancer and oropharynx LGOEC 33 cancer, respectively. NRAS mutation in nasopharynx cancer Endometrial cancer 11–35 LGEEC 18 is reported as 4%, while HRAS mutation is <1% and KRAS NEEC 0–5 mutation is very rare.[17–21] Cervical cancer 5–14 <1 <1 Frequency of RAS mutation Cervical squamous cell carcinoma <1 Cervical adenocarcinoma 10 in gastrointestinal cancer Prostate adenocarcinoma 7–9 Colorectal cancers are one of the leading causes of can- Vulvar cancer 1 9 cer-related death, though incidence and mortality have Germ cell testicular tumor 6 6 LD decreased in recent years. This is probably due to early di- Seminoma 6–18 <1 LD agnosis and screening methods. RAS mutation testing is Non-seminoma 0–9 <1 LD frequently used in everyday practice in cases of metastatic Bladder cancer 0–4 0–80 0–84 colorectal cancer. RAS mutations are significant in the selec- Renal cell carcinoma 0–16 <1 <1 Clear cell renal cell carcinoma 0–100 <1 <1 tion of targeted treatment. There is no marker for the use of Soft tissue sarcoma 0–44 <1 0–16 bevacizumab; however, KRAS wild tumors are a marker for Cutaneous malignant melanoma <1 15–30 <1 the use of cetuximab, and KRAS and NRAS wild colorectal Breast cancer 7–12 5 <1 tumors are a marker for the use of panitumumab. The fre- Luminal A 2 quency of KRAS mutations in colorectal cancers varies from Luminal B 20 27% to 56% from community to community. The frequency HER2 overexpression 17 of NRAS mutations in colorectal cancers is between 1% and Triple negative 0–8 7%. NRAS mutation frequency is 5.3%, 4.1%, and 2.2% in KRAS: Kirsten - RAS; NRAS: Neuroblastoma- RAS; HRAS: Harvey- RAS: IMSC: Romanian, Italian, and Chinese patients, respectively. There Invasive micropapillary serous carcinoma; LGOEC: Low-grade ovarian is almost no HRAS mutation seen in colorectal cancers. endometrioid carcinomas; LGEEC: Low-grade endometrial endometrioid carcinoma; NEEC: Non- endometrioid endometrial cancer; LD: Limited data KRAS mutations do not seem to be prognostic in colorectal EJMO 3 cancers, but are predictive. NRAS mutations also show geo- Frequency of RAS mutation graphical and ethnic differences in colorectal cancers, like in genitourinary cancer KRAS mutations. The frequency of KRAS mutations in the right and left colon is different. Exposure to embryogen- RAS mutation frequency in cancer overall is 27%. Ovarian esis and/or carcinogens may play a role in this difference. clear cell carcinoma constitutes 15% of all ovarian can- The left colon is subject to carbonaceous substances for a cers. KRAS mutation frequency is 14% in ovarian clear cell greater period of time. It is interesting that there are fewer carcinoma, and there is no NRAS mutation. The frequency KRAS mutations in the left colon than in the right colon. of NRAS mutation in epithelial ovarian cancer is 8%. KRAS The first column shadow subject to carcinogenic substanc- mutation prevalence is 68%, 29.5%, 12%, 33%–78%, 60%, es is the right colon. The right colon may be more sensitive 46%–75%, 6%, and 33% in invasive micropapillary serous to carcinogenic substances. carcinoma, low-grade serous tumor, high-grade serous carcinoma, mucinous borderline tumor, serous borderline Stomach cancers are observed more often in Third World tumor, mucinous carcinoma, serous ovarian carcinoma, countries and Eastern societies. KRAS mutation frequency and low-grade ovarian endometrioid carcinoma, respec- in gastric cancer has ranged from 2.8% to 9.4% in studies. tively. In ovarian cancer, the frequency of KRAS mutation NRAS mutation in gastric cancer can be found in 1.9%. varies greatly according to the histological subtype. The HRAS mutation is very rare in gastric cancer. KRAS muta- data regarding KRAS mutation are limited. The frequency tion is present in over 90% of pancreatic cancers. There are of KRAS mutation in endometrial cancer ranges from 11% almost no NRAS and HRAS mutations in pancreatic cancers.
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