BRAF and PIK3CA Genes Are Somatically Mutated in Hepatocellular Carcinoma Among Patients from South Italy

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2012 Jan 20

PMID 22258409

Citations 45

Authors

M Colombino

P Sperlongano

F Izzo

F Tatangelo

G Botti

A Lombardi

M Accardo

L Tarantino

I Sordelli

M Agresti

A Abbruzzese

M Caraglia

G Palmieri

Affiliations

Soon will be listed here.

Abstract

Poor data have been previously reported about the mutation rates in K-RAS, BRAF, and PIK3CA genes among patients with hepatocellular carcinoma (HCC). Here we further elucidated the role of these genes in pathogenesis of primary hepatic malignancies. Archival tumour tissue from 65 HCC patients originating from South Italy were screened for mutations in these candidate genes by direct sequencing. Overall, oncogenic mutations were detected in 15 (23%) patients for BRAF gene, 18 (28%) for PIK3CA gene, and 1 (2%) for K-RAS gene. Using statistical analysis, BRAF mutations were significantly correlated with the presence of either multiple HCC nodules (P=0.021) or higher proliferation rates (P=0.034). Although further extensive screenings are awaited in HCC patients among different populations, our findings clearly indicated that mutational activation of both BRAF and PIK3CA genes does contribute to hepatocellular tumorigenesis at somatic level in Southern Italian population.

Citing Articles

The Complexity of the Tumor Microenvironment in Hepatocellular Carcinoma and Emerging Therapeutic Developments.

Argentiero A, Delvecchio A, Fasano R, Andriano A, Caradonna I, Memeo R J Clin Med. 2023; 12(23).

PMID: 38068521 PMC: 10706931. DOI: 10.3390/jcm12237469.

Comprehensive analysis of immunogenic cell death associated genes expression, tumor microenvironment, and prognosis in hepatocellular carcinoma.

Xiang J, Liu C, He Q, He P, Dong W Front Pharmacol. 2023; 14:1122011.

PMID: 36998605 PMC: 10045985. DOI: 10.3389/fphar.2023.1122011.

Tumor Promoting Effects of Sulforaphane on Diethylnitrosamine-Induced Murine Hepatocarcinogenesis.

Zheng J, Kim D, Fang X, Kim S, Saeidi S, Kim S Int J Mol Sci. 2022; 23(10).

PMID: 35628208 PMC: 9141104. DOI: 10.3390/ijms23105397.

AK2 is an AMP-sensing negative regulator of BRAF in tumorigenesis.

Kim H, Jeong M, Na D, Ryu S, Jeong E, Jung K Cell Death Dis. 2022; 13(5):469.

PMID: 35585049 PMC: 9117275. DOI: 10.1038/s41419-022-04921-7.

Mutations in TP53 and PIK3CA genes in hepatocellular carcinoma patients are associated with chronic Schistosomiasis.

AlGabbani Q Saudi J Biol Sci. 2022; 29(2):848-853.

PMID: 35197752 PMC: 8847977. DOI: 10.1016/j.sjbs.2021.10.022.

References

Llovet J, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J . Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008; 359(4):378-90. DOI: 10.1056/NEJMoa0708857. View

Flaherty K, Puzanov I, Kim K, Ribas A, McArthur G, Sosman J . Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010; 363(9):809-19. PMC: 3724529. DOI: 10.1056/NEJMoa1002011. View

Tanaka Y, Kanai F, Tada M, Asaoka Y, Guleng B, Jazag A . Absence of PIK3CA hotspot mutations in hepatocellular carcinoma in Japanese patients. Oncogene. 2005; 25(20):2950-2. DOI: 10.1038/sj.onc.1209311. View

Garcia-Echeverria C, Sellers W . Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene. 2008; 27(41):5511-26. DOI: 10.1038/onc.2008.246. View

Chapman P, Hauschild A, Robert C, Haanen J, Ascierto P, Larkin J . Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011; 364(26):2507-16. PMC: 3549296. DOI: 10.1056/NEJMoa1103782. View

Davies H, Bignell G, Cox C, Stephens P, Edkins S, Clegg S . Mutations of the BRAF gene in human cancer. Nature. 2002; 417(6892):949-54. DOI: 10.1038/nature00766. View

Tannapfel A, Sommerer F, Benicke M, Katalinic A, Uhlmann D, Witzigmann H . Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut. 2003; 52(5):706-12. PMC: 1773624. DOI: 10.1136/gut.52.5.706. View

Prete S, Montella L, Caraglia M, Maiorino L, Cennamo G, Montesarchio V . Sorafenib plus octreotide is an effective and safe treatment in advanced hepatocellular carcinoma: multicenter phase II So.LAR. study. Cancer Chemother Pharmacol. 2009; 66(5):837-44. DOI: 10.1007/s00280-009-1226-z. View

Parkin D, Bray F, Ferlay J, Pisani P . Global cancer statistics, 2002. CA Cancer J Clin. 2005; 55(2):74-108. DOI: 10.3322/canjclin.55.2.74. View

10.

Yau T, Chan P, Epstein R, Poon R . Management of advanced hepatocellular carcinoma in the era of targeted therapy. Liver Int. 2009; 29(1):10-7. DOI: 10.1111/j.1478-3231.2008.01916.x. View

11.

Teufel A, Staib F, Kanzler S, Weinmann A, Schulze-Bergkamen H, Galle P . Genetics of hepatocellular carcinoma. World J Gastroenterol. 2007; 13(16):2271-82. PMC: 4147134. DOI: 10.3748/wjg.v13.i16.2271. View

12.

Arcaro A, Guerreiro A . The phosphoinositide 3-kinase pathway in human cancer: genetic alterations and therapeutic implications. Curr Genomics. 2009; 8(5):271-306. PMC: 2652403. DOI: 10.2174/138920207782446160. View

13.

Gray-Schopfer V, Wellbrock C, Marais R . Melanoma biology and new targeted therapy. Nature. 2007; 445(7130):851-7. DOI: 10.1038/nature05661. View

14.

Sensi M, Nicolini G, Petti C, Bersani I, Lozupone F, Molla A . Mutually exclusive NRASQ61R and BRAFV600E mutations at the single-cell level in the same human melanoma. Oncogene. 2006; 25(24):3357-64. DOI: 10.1038/sj.onc.1209379. View

15.

Boyault S, Rickman D, De Reynies A, Balabaud C, Rebouissou S, Jeannot E . Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 2006; 45(1):42-52. DOI: 10.1002/hep.21467. View

16.

Bose S, Sakhuja P, Bezawada L, Agarwal A, Kazim S, Khan L . Hepatocellular carcinoma with persistent hepatitis B virus infection shows unusual downregulation of Ras expression and differential response to Ras mediated signaling. J Gastroenterol Hepatol. 2010; 26(1):135-44. DOI: 10.1111/j.1440-1746.2010.06305.x. View

17.

Lee J, Soung Y, Kim S, Lee H, Park W, Nam S . PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene. 2004; 24(8):1477-80. DOI: 10.1038/sj.onc.1208304. View

18.

Bai F, Nakanishi Y, Takayama K, Pei X, Inoue K, Harada T . Codon 64 of K-ras gene mutation pattern in hepatocellular carcinomas induced by bleomycin and 1-nitropyrene in A/J mice. Teratog Carcinog Mutagen. 2003; Suppl 1:161-70. DOI: 10.1002/tcm.10071. View

19.

Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim P, Cho H . Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010; 467(7315):596-9. PMC: 2948082. DOI: 10.1038/nature09454. View

20.

Caraglia M, Giuberti G, Marra M, Addeo R, Montella L, Murolo M . Oxidative stress and ERK1/2 phosphorylation as predictors of outcome in hepatocellular carcinoma patients treated with sorafenib plus octreotide LAR. Cell Death Dis. 2011; 2:e150. PMC: 3122065. DOI: 10.1038/cddis.2011.34. View