Ataxia-Telangiectasia-Mutated (<b>
                     <i>ATM</i>
                  </b>) Gene in Head and Neck Squamous Cell Carcinoma

Ai, Lingbao; Vo, Quynh N; Zuo, Chunlai; Liu, Liwen; Ling, Wenhua; Suen, James Y.; Hanna, Ehab Y.; Brown, Kevin D.; Fan, Chun Yang

doi:10.1158/1055-9965.epi-082-3

Cited by 98 publications

(77 citation statements)

References 16 publications

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“…More recently, we determined that aberrant methylation of the ATM promoter occurs in a subset of head and neck tumors (Ai et al, 2004). Further, several reports showed that reduced ATM expression, as judged by immunohistochemical staining, occurs in a significant portion of breast tumors (Kairouz et al, 1999;Angele et al, 2000).…”

Section: Published Online 1 November 2004mentioning

confidence: 96%

The ATM gene is a target for epigenetic silencing in locally advanced breast cancer

Kim

Cvitanovic

et al. 2004

Oncogene

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Several epidemiological studies on ataxia-telangiectasia families indicate that obligate ATM heterozygotes display an elevated risk for developing breast cancer. However, a molecular basis for a potential link between diminished ATM function and sporadic breast malignancy remains elusive. Here, we show that 78% (18 out of a panel of 23) of surgically removed breast tumors (stage II or greater) displayed aberrant methylation of the ATM proximal promoter region as judged by methylation-specific PCR. Aberrant methylation of the ATM promoter was independently confirmed in several tumors by bisulfite sequencing. Moreover, bisulfite sequencing indicated that this region of the genome is subject to dense methylation. Further, we found a highly significant correlation (P ¼ 0.0006) between reduced ATM mRNA abundance, as measured by realtime RT-PCR, and aberrant methylation of the ATM gene promoter. These findings indicate that epigenetic silencing of ATM expression occurs in locally advanced breast tumors, and establish a link at the molecular level between reduced ATM function and sporadic breast malignancy. Oncogene (2004Oncogene ( ) 23, 9432-9437. doi:10.1038 Published online 1 November 2004Keywords: ATM; epigenetics; promoter hypermethylation; breast cancer Germline mutation of the ATM gene is the underlying cause of the cancer-prone disorder ataxia-telangiectasia (A-T) (Rotman and Shiloh, 1998). As outlined in the seminal work of Swift et al. (1987), and validated in subsequent studies (Easton, 1994;Athma et al., 1996), obligate ATM heterozygotes display an approximate fourfold elevated risk for developing breast cancer. Following the cloning of the ATM gene, several groups (FitzGerald et al., 1997;Bebb et al., 1999;Shafman et al., 2000) studied large cohorts of sporadic breast cancer patients and age-matched controls for nonsense or frame-shift mutations within the ATM gene. Neither group found evidence for a higher incidence of defective ATM alleles in the cancer patient cohort. Furthermore, the correlation between breast cancer and dominantnegative forms of ATM arising from defined missense or intronic mutations within the ATM gene remains controversial (Chenevix-Trench et al., 2002;Bernstein et al., 2003). Thus, a potential role for diminished ATM function in sporadic breast cancer remains unresolved.We have reported that, in cultured tumor cells, the ATM gene is subject to epigenetic silencing attributable to aberrant methylation of its proximal promoter region (Kim et al., 2002). More recently, we determined that aberrant methylation of the ATM promoter occurs in a subset of head and neck tumors (Ai et al., 2004). Further, several reports showed that reduced ATM expression, as judged by immunohistochemical staining, occurs in a significant portion of breast tumors (Kairouz et al., 1999;Angele et al., 2000). Collectively, these findings led us to hypothesize that epigenetic events, rather than somatic mutation of the ATM gene itself, link reduced ATM function to sporadic breast cancer.The putative proximal pro...

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Section: Published Online 1 November 2004mentioning

confidence: 96%

The ATM gene is a target for epigenetic silencing in locally advanced breast cancer

Kim

Cvitanovic

et al. 2004

Oncogene

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“…Recent genomic analyses of a variety of human cancers found that somatic mutations in ATM are relatively common and appear to be a driving force in tumorigenesis (Davies et al, 2005;Greenman et al, 2007). Silencing of ATM gene expression by promoter hypermethylation has also been shown to frequently occur in several human cancers (Ai et al, 2004;Vo et al, 2004;Safar et al, 2005). Kinzler and Vogelstein (Kinzler and Vogelstein, 1997) originally classified tumor suppressors into two main categories: gatekeepers and caretakers.…”

Section: Discussionmentioning

confidence: 99%

Transgenic expression of E2F3a causes DNA damage leading to ATM-dependent apoptosis

et al. 2008

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Many early stage human tumors display markers of a DNA-damage response (DDR), including ataxia telangiectasia mutated (ATM) kinase activation. This suggests that DNA damage accumulates during the process of carcinogenesis and that the ATM-dependent response to this damage may function to suppress cancer progression. The E2F3a transcription factor plays an important role in regulating cell proliferation and is amplified in a subset of human cancers. Similar to human premalignant lesions, we find activated ATM and other markers of the DDR in the hyperplastic epidermis of transgenic mice expressing E2F3a through a keratin 5 (K5) promoter. Primary keratinocytes from K5 E2F3a transgenic mice contain increased levels of DNA breaks compared to wild-type cells. E2F3a overexpression also induced DNA damage in primary human fibroblasts that was inhibited by blocking DNA replication. The absence of ATM impaired apoptosis induced by E2F3a and treating K5 E2F3a transgenic mice with caffeine, an inhibitor of ATM and Rad3-related (ATR), promoted skin tumor development. These findings demonstrate that the deregulated expression of E2F3a causes DNA damage under physiological conditions and indicate that the ATM-dependent response to this damage is important for the induction of apoptosis and tumor suppression.

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“…Since methylation of a tumor suppressor gene does not mean that each CpG site is methylated and that methylation is 100% at each site, primer design has a big impact on the results. 44 However, the ATM gene is a target for epigenetic silencing in advanced breast cancer, 45 head and neck cancer 46 and colorectal cancer. 47 Future studies will have to clarify whether promoter methylation, which was shown in four of the five cell lines for the first time, induces relevant inactivation of ATM in patients with MCL and CLL and whether it is associated with the clinical outcome.…”

Section: Discussionmentioning

confidence: 99%

Promoter methylation of PARG1, a novel candidate tumor suppressor gene in mantle cell lymphomas

Ripperger¹,

Neuhoff²,

Kamphues³

et al. 2007

Haematologica

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Ataxia-Telangiectasia-Mutated ( ATM ) Gene in Head and Neck Squamous Cell Carcinoma

Cited by 98 publications

References 16 publications

The ATM gene is a target for epigenetic silencing in locally advanced breast cancer

The ATM gene is a target for epigenetic silencing in locally advanced breast cancer

Transgenic expression of E2F3a causes DNA damage leading to ATM-dependent apoptosis

Promoter methylation of PARG1, a novel candidate tumor suppressor gene in mantle cell lymphomas

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