BARD1 Expression Predicts Outcome in Colon Cancer

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2011 Jun 23

PMID 21693656

Citations 31

Authors

Judith C Sporn

Torsten Hothorn

Barbara Jung

Affiliations

Soon will be listed here.

Abstract

Purpose: BARD1 is a BRCA1-binding partner with tumor suppressive properties. Aberrant splice variants of BARD1 have been detected in various cancers, and it has been postulated that the presence of some splice variants is cancer specific. This is the first study assessing BARD1 expression patterns and correlation with clinical outcome in colon cancer.

Experimental Design: We analyzed colon cancer samples for the occurrence of BARD1 splice variants, characterized novel BARD1 splice variants, and quantified the mRNA expression levels of these isoforms in primary colon cancers and their corresponding normal tissue. We tested the correlation of full-length BARD1 protein expression and clinical outcome in primary colon cancer samples.

Results: In addition to the full-length BARD1 mRNA, we now find 19 distinct BARD1 splice variants in colon cancer. Contrary to previous assumptions, these splice variants also occur in the adjacent normal colon tissue. Although BARD1 splice variants account for a considerable amount of BARD1 mRNA in both cancer and normal colon samples, distinct variants show a cancer-specific regulation pattern. Consistent with its role as tumor suppressor, we further find that the expression of the full-length BARD1 protein predicts outcome in colon cancer and that loss of full-length BARD1 protein is associated with a poor prognosis (P = 0.0002).

Conclusion: Taken together, this is the first report to suggest that BARD1 regulation is an important pathway in colon cancer and that the BARD1 full-length protein may be a useful marker to improve risk stratification in colon cancer patients.

Citing Articles

BARD1 deletion in a patient with suspected hereditary colorectal cancer.

Takaiso N, Imoto I, Yoshimura A, Ouchi A, Komori K, Iwata H Hum Genome Var. 2024; 11(1):11.

PMID: 38485918 PMC: 10940602. DOI: 10.1038/s41439-024-00267-y.

Isoform alterations in the ubiquitination machinery impacting gastrointestinal malignancies.

Kasturirangan S, Nancarrow D, Shah A, Lagisetty K, Lawrence T, Beer D Cell Death Dis. 2024; 15(3):194.

PMID: 38453895 PMC: 10920915. DOI: 10.1038/s41419-024-06575-z.

Zooming into the structure-function of RING finger proteins for anti-cancer therapeutic applications.

George M, Masamba P, Iwalokun B, Kappo A Am J Cancer Res. 2023; 13(7):2773-2789.

PMID: 37559981 PMC: 10408477.

Germline heterozygous exons 8-11 pathogenic BARD1 gene deletion reported for the first time in a family with suspicion of a hereditary colorectal cancer syndrome: more than an incidental finding?.

Carrera S, Rodriguez-Martinez A, Garin I, Sarasola E, Martinez C, Maortua H Hered Cancer Clin Pract. 2023; 21(1):2.

PMID: 36709314 PMC: 9883939. DOI: 10.1186/s13053-023-00246-4.

BARD1 mystery: tumor suppressors are cancer susceptibility genes.

Hawsawi Y, Shams A, Theyab A, Abdali W, Hussien N, Alatwi H BMC Cancer. 2022; 22(1):599.

PMID: 35650591 PMC: 9161512. DOI: 10.1186/s12885-022-09567-4.

References

Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A . Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002; 3(7):RESEARCH0034. PMC: 126239. DOI: 10.1186/gb-2002-3-7-research0034. View

Rozen S, Skaletsky H . Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol. 1999; 132:365-86. DOI: 10.1385/1-59259-192-2:365. View

Owzar K . Alternate statistical tools and limitations in genetic marker association studies in single-arm drug cancer trials. J Clin Oncol. 2008; 26(9):1400-1. DOI: 10.1200/JCO.2007.14.7306. View

Feki A, Jefford C, Berardi P, Wu J, Cartier L, Krause K . BARD1 induces apoptosis by catalysing phosphorylation of p53 by DNA-damage response kinase. Oncogene. 2005; 24(23):3726-36. DOI: 10.1038/sj.onc.1208491. View

Carethers J, Smith E, Behling C, Nguyen L, Tajima A, Doctolero R . Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology. 2004; 126(2):394-401. DOI: 10.1053/j.gastro.2003.12.023. View

Tsuzuki M, Wu W, Nishikawa H, Hayami R, Oyake D, Yabuki Y . A truncated splice variant of human BARD1 that lacks the RING finger and ankyrin repeats. Cancer Lett. 2005; 233(1):108-16. DOI: 10.1016/j.canlet.2005.03.012. View

Venables J . Aberrant and alternative splicing in cancer. Cancer Res. 2004; 64(21):7647-54. DOI: 10.1158/0008-5472.CAN-04-1910. View

Hothorn T, Bretz F, Westfall P . Simultaneous inference in general parametric models. Biom J. 2008; 50(3):346-63. DOI: 10.1002/bimj.200810425. View

Jemal A, Siegel R, Xu J, Ward E . Cancer statistics, 2010. CA Cancer J Clin. 2010; 60(5):277-300. DOI: 10.3322/caac.20073. View

10.

Kadouri L, Hubert A, Rotenberg Y, Hamburger T, Sagi M, Nechushtan C . Cancer risks in carriers of the BRCA1/2 Ashkenazi founder mutations. J Med Genet. 2007; 44(7):467-71. PMC: 2598014. DOI: 10.1136/jmg.2006.048173. View

11.

De Brakeleer S, De Greve J, Loris R, Janin N, Lissens W, Sermijn E . Cancer predisposing missense and protein truncating BARD1 mutations in non-BRCA1 or BRCA2 breast cancer families. Hum Mutat. 2010; 31(3):E1175-85. DOI: 10.1002/humu.21200. View

12.

Erickson H, Albert P, Gillespie J, Wallis B, Rodriguez-Canales J, Linehan W . Assessment of normalization strategies for quantitative RT-PCR using microdissected tissue samples. Lab Invest. 2007; 87(9):951-62. DOI: 10.1038/labinvest.3700659. View

13.

Brinkman B . Splice variants as cancer biomarkers. Clin Biochem. 2004; 37(7):584-94. DOI: 10.1016/j.clinbiochem.2004.05.015. View

14.

Feki A, Jefford C, Jefford C, Durand P, Harb J, Lucas H . BARD1 expression during spermatogenesis is associated with apoptosis and hormonally regulated. Biol Reprod. 2004; 71(5):1614-24. DOI: 10.1095/biolreprod.104.029678. View

15.

Li L, Cohen M, Wu J, Sow M, Nikolic B, Bischof P . Identification of BARD1 splice-isoforms involved in human trophoblast invasion. Int J Biochem Cell Biol. 2007; 39(9):1659-72. DOI: 10.1016/j.biocel.2007.04.018. View

16.

Li L, Ryser S, Dizin E, Pils D, Krainer M, Jefford C . Oncogenic BARD1 isoforms expressed in gynecological cancers. Cancer Res. 2007; 67(24):11876-85. DOI: 10.1158/0008-5472.CAN-07-2370. View

17.

Wu L, Wang Z, Tsan J, Spillman M, Phung A, Xu X . Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat Genet. 1996; 14(4):430-40. DOI: 10.1038/ng1296-430. View

18.

Thai T, DU F, Tsan J, Jin Y, Phung A, Spillman M . Mutations in the BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian and uterine cancers. Hum Mol Genet. 1998; 7(2):195-202. DOI: 10.1093/hmg/7.2.195. View

19.

Sauer M, Andrulis I . Identification and characterization of missense alterations in the BRCA1 associated RING domain (BARD1) gene in breast and ovarian cancer. J Med Genet. 2005; 42(8):633-8. PMC: 1736120. DOI: 10.1136/jmg.2004.030049. View

20.

Lombardi G, Falaschi E, Di Cristofano C, Naccarato A, Sensi E, Aretini P . Identification of novel alternatively spliced BRCA1-associated RING domain (BARD1) messenger RNAs in human peripheral blood lymphocytes and in sporadic breast cancer tissues. Genes Chromosomes Cancer. 2007; 46(9):791-5. DOI: 10.1002/gcc.20460. View