Citations 6
Thibodeau, Stephen N. , Liu, Wanguo
The Japanese Journal of Urology | April 6, 2017 | Volume: 91 | Issue: 3 | Pages: 308
Frequent Truncating Mutation of TFAM Induces Mitochondrial DNA Depletion and Apoptotic Resistance in Microsatellite-Unstable Colorectal Cancer
Guo, Jianhui, Wang, Zemin , Wang, Zehua , French, Amy J. , Kang, Dongchon, Chen, Lin, Thibodeau, Stephen N., Li, Zheng , Liu, Wenyong , Liu, Wanguo
Cancer Research | April 5, 2011 | Volume: 71 | Issue: 8 | Pages: 2978-2987
Abstract The mitochondrial transcription factor A (TFAM) is required for mitochondrial DNA (mtDNA) replication and transcription. Disruption of TFAM results in heart failure and premature aging in mice. But very little is known about the role of TFAM in cancer development. Here, we report the identification of frequent frameshift mutations in the coding mononucleotide repeat of TFAM in sporadic colorectal cancer (CRC) cell lines and in primary tumors with microsatellite instability (MSI), but not in microsatellite stable (MSS) CRC cell lines and tumors. The presence of the TFAM truncating mutation, in CRC cells with MSI, reduced the TFAM protein level in vivo and in vitro and correlated with mtDNA depletion. Furthermore, forced overexpression of wild-type TFAM in RKO cells carrying a TFAM truncating mutation suppressed cell proliferation and inhibited RKO cell-induced xenograft tumor growth. Moreover, these cells showed more susceptibility to cisplatin-induced apoptosis due to an increase of cytochrome b (Cyt b) expression and its release from mitochondria. An interaction assay between TFAM and the heavy-strand promoter (HSP) of mitochondria revealed that mutant TFAM exhibited reduced binding to HSP, leading to reduction in Cyt b transcription. Collectively, these data provide evidence that a high incidence of TFAM truncating mutations leads to mitochondrial copy number reduction and mitochondrial instability, distinguishing most CRC with MSI from MSS CRC. These mutations may play an important role in tumorigenesis and cisplatin-induced apoptotic resistance of most microsatellite-unstable CRCs. Cancer Res; 71(8); 2978–87. ©2011 AACR.
Mutational Analysis of Thirty-two Double-Strand DNA Break Repair Genes in Breast and Pancreatic Cancers
Qian, Chiping , Amadio, Peter G., Thibodeau, Stephen N. , Cerhan, James R. , Petersen, Gloria M. , Wang, Xianshu , Szabo, Csilla I. , Liu, Wanguo , Couch, Fergus J. , Cerhan, James R
Cancer Research | February 15, 2008 | Volume: 68 | Issue: 4 | Pages: 971-975
Abstract Inactivating mutations in several genes that encode components of the DNA repair machinery have been associated with an increased risk of breast cancer. To assess whether alterations in other DNA repair genes contribute to breast cancer and to further determine the relevance of these genes to pancreatic cancer, we performed mutational analysis of 32 DNA double-strand break repair genes in genomic DNA from 38 breast tumors, 48 pancreatic tumors, and 10 non-BRCA1/BRCA2 hereditary breast cancer patients. A total of 494 coding exons were screened by denatured high-performance liquid chromatography and direct DNA sequencing. Two inactivating mutations were identified in breast tumor samples, a germline single-nucleotide deletion in POLQ (c.3605delT) and a somatic nonsense change in PRKDC (c.2408C>A, p.Ser803X). Two germline-inactivating mutations in RAD50 (c.1875C>G, p.Tyr625X and IVS14+1G>A) were also detected in separate pancreatic tumor samples. In addition, 35 novel nonsynonymous amino acid substitutions, resulting from two in-frame deletions and 33 single nucleotide alterations, were identified. Seven of these were predicted to influence protein function. A separate analysis of the CLSPN c.3839C>T (rs35490896) variant that was observed more frequently in breast tumors than in pancreatic tumors or normal controls failed to detect a significant association with breast cancer risk in a Mayo Clinic breast cancer case-control study. In conclusion, this screen of DNA repair genes implicates PRKDC and POLQ as candidate tumor suppressor genes involved in breast cancer and suggests that inactivating mutations in RAD50 predispose to pancreatic cancer as well as breast cancer. [Cancer Res 2008;68(4):971–5]
Truncating Variants in p53AIP1 Disrupting DNA Damage–Induced Apoptosis Are Associated with Prostate Cancer Risk
Wang, Fengwei , Taniguchi, Ken, Seelan, Ratnam S. , Zarfas, Katherine E., McDonnell, Shannon K. , Qian, Chiping , Lu, Youyong , Shridhar, Viji , Tindall, Donald J., Beebe‐Dimmer, Jennifer , Cooney, Kathleen A. , Isaacs, William B., Jacobsen, Steven J. , Schaid, Daniel J. , Thibodeau, Stephen N. , Wang, Xianshu , Wang, Liang , Pan, Kai‐Feng , Couch, Fergus J. , Liu, Wanguo , McDonnell, Shannon K
Cancer Research | November 2, 2006 | Volume: 66 | Issue: 21 | Pages: 10302-10307
Abstract Germ line mutations in several genes (BRCA1, BRCA2, and CHEK2) whose products are involved in the DNA damage–signaling pathway have been implicated in prostate cancer risk. To identify additional genes in this pathway that might confer susceptibility to this cancer, we analyzed a recently identified DNA damage–response gene, p53AIP1 (a gene encoding for p53-regulated apoptosis-inducing protein 1), for genetic variants in prostate cancer. Five novel germ line variants were identified. The two truncating variants (Ser32Stop and Arg21insG) were found in 3% (4 of 132) of unselected prostate tumor samples. Genotyping of the two variants in an additional 393 men with sporadic prostate cancer showed a frequency of 3.1% (12 of 393) in contrast to 0.6% (2 of 327) in 327 unaffected men (Fisher's exact test, P = 0.018), with an odds ratio (OR) of 5.1 [95% confidence interval (95% CI), 1.1-23.0]. In addition, two of six tumors carrying the truncating variants were associated with loss of heterozygosity of the wild-type alleles, suggesting that p53AIP1 may act as a tumor suppressor. We also showed that the truncated p53AIP1 was unable to induce apoptosis and suppress cell growth in HeLa and COS-7 cells. These results suggest that loss-of-function variants in p53AIP1 associated with the risk of sporadic prostate cancer and further support the concept that the genetic defects in the DNA damage–response genes play an important role in the development of prostate cancer. (Cancer Res 2006; 66(21): 10302-7)
Papillary Renal Cell Carcinoma: Analysis of Germline Mutations in the MET Proto-Oncogene in a Clinic-Based Population
Lindor, Noralane M. , Dechet, Christopher , Greene, Mark H. , Jenkins, Robert B. , Zincke, M. Tanja, Weaver, Amy L. , Wilson, Marcia, Zincke, Horst, Liu, Wanguo
Genetic Testing | July 26, 2002 | Volume: 5 | Issue: 2 | Pages: 101-106
Centrosome amplification drives chromosomal instability in breast tumor development
Lingle, Wilma L., Barrett, Susan L., Negron, Vivian , D’Assoro, Antonino B. , Boeneman, Kelly, Whitehead, Clark M., Reynolds, Carol, Salisbury, Jeffrey L., Liu, Wanguo
Proceedings of the National Academy of Sciences | July 26, 2002 | Volume: 99 | Issue: 4 | Pages: 1978-1983
Earlier studies of invasive breast tumors have shown that 60–80% are aneuploid and ≈80% exhibit amplified centrosomes. In this study, we investigated the relationship of centrosome amplification with aneuploidy, chromosomal instability, p53 mutation, and loss of differentiation in human breast tumors. Twenty invasive breast tumors and seven normal breast tissues were analyzed by fluorescence in situ hybridization with centromeric probes to chromosomes 3, 7, and 17. We analyzed these tumors for both aneuploidy and unstable karyotypes as determined by chromosomal instability. The results were then tested for correlation with three measures of centrosome amplification: centrosome size, centrosome number, and centrosome microtubule nucleation capacity. Centrosome size and centrosome number both showed a positive, significant, linear correlation with aneuploidy and chromosomal instability. Microtubule nucleation capacity showed no such correlation, but did correlate significantly with loss of tissue differentiation. Centrosome amplification was detected in in situ ductal carcinomas, suggesting that centrosome amplification is an early event in these lesions. Centrosome amplification and chromosomal instability occurred independently of p53 mutation, whereas p53 mutation was associated with a significant increase in centrosome microtubule nucleation capacity. Together, these results demonstrate that independent aspects of centrosome amplification correlate with chromosomal instability and loss of tissue differentiation and may be involved in tumor development and progression. These results further suggest that aspects of centrosome amplification may have clinical diagnostic and/or prognostic value and that the centrosome may be a potential target for cancer therapy.