Copy number variant in the candidate tumor suppressor gene MTUS1 and familial breast cancer risk

Abstract

Copy number variants (CNVs), insertions, deletions and duplications, contribute considerably to human genetic variation and disease development. A recent study has characterized 100 CNVs including a deletion in the mitochondrial tumor suppressor gene 1 (MTUS1) lacking the coding exon 4. MTUS1 maps to chromosome 8p, a region frequently deleted and associated with disease progression in human cancers, including breast cancer (BC). To investigate the effect of the MTUS1 CNV on familial BC risk, we analyzed 593 BC patients and 732 control individuals using a case-control study design. We found a significant association of the deletion variant with a decreased risk for both familial and high-risk familial BC (odds ratio (OR) = 0.58, 95% confidence interval (CI) = 0.37-0.90, P = 0.01 and OR = 0.41, 95% CI = 0.23-0.74, P = 0.003), supporting its role in human cancer. To our knowledge, the present study is the first to determine the impact of a CNV in a tumor suppressor gene on cancer risk.

Down-regulation of MTUS1 in human colon tumors

“…Since it already has been reported that CpNpG methylation can occur in vivo and that methylation of these islands is suspected to stabilize the DNA (28), the hypomethylation of CpNpG islands could be a mechanism for the MTUS1 inactivation. Nevertheless, some published investigations have found deletion and some small mutations in the exon region of MTUS1, so that further analyses are needed to understand the mechanism of down-regulation in this gene (19,21).…”

“…Previously, the inhibitory effect of MTUS1 on cell proliferation was linked to the growth inhibitory signaling cascade by trans-inactivation of receptor tyrosine kinases in insulin, bFGF, PDGF and EGF-induced ERK2 activation (17). A previously published investigation demonstrated a significant down-regulation of MTUS1 in ovarian carcinoma tissues, implicating a possible role of MTUS1 on the development of ovarian carcinoma (18 (19)(20)(21). The gene responsible for tumor progression in colon cancer, located at chromosome 8p21.3-22 near marker D8S254, would be expected to be down-regulated in colon cancer (1,10).…”

Implications of gene copy-number variation in health and diseases

“…When studied in the German population, the deletion of exon 4 of MTUS1 was found to be associated with the slower progression of disease in both familial and high-risk breast cancer patients. 68 There are many large structural variations, which might predispose to cancer but it has been less appreciated as the deletions and duplication breakpoints are not well characterized in many cases and the PCR method to detect these large structural variation is not reliable. Therefore, to characterize these structural variations involved in cancer syndromes newer methods such as multiplex ligationdependent probe amplification and others needs to be used, which allow the detection of copy number changes in a single gene or exon.…”

8p deletion is strongly linked to poor prognosis in breast cancer

“…8p deletion typically involves extended areas or even the entire 8p arm, with several putative tumor suppressor genes which are located in this region. [17][18][19][20][21][22][23][24] Some breast cancer studies found associations between 8p deletions and advanced tumor stage, [25][26][27] highgrade, 28 metastatic growth, 25,27,29 familial breast cancer risk, 30 and poor prognosis, 25,27,29,31 but these associations could not be confirmed by others. 14,[32][33][34][35][36][37][38][39] To better understand the clinical relevance of 8p deletions in breast cancer, including association to tumor grade, pathological tumor stage, patient survival, hormone receptor status, and amplifications of HER2, MYC and CCND1, we analyzed more than 2,100 breast cancers with clinical follow-up data.…”