Functional consequences of <i>ATM</i> sequence variants for chromosomal radiosensitivity

Gutiérrez‐Enríquez, Sara; Fernet, Marie; Dörk, Thilo; Bremer, Michael; Laugé, Anthony; Stoppa‐Lyonnet, Dominique; Moullan, Norman; Angèle, Sandra; Hall, Janet

doi:10.1002/gcc.20025

Cited by 78 publications

(45 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, the LCL established from a homozygous carrier of the 3161G allele shows a cell cycle progression profile with time after exposure to ionising radiation that is intermediate between that seen for LCLs carrying a wild-type or a mutant ATM gene. In addition, this line and five other LCLs established from breast cancer patients carrying the linked 2572T4C and 3161 C4G variants in the heterozygous state had higher levels of micronuclei induction after exposure to ionising radiation compared with LCLs with a wild-type ATM gene (Gutiérrez-Enríquez et al, 2004) T 48 h Figure 1 Cell cycle analysis at 0, 24 and 48 h after exposure to 5 Gy ionising radiation in LCLs carrying either a wild-type ATM (IARC 1104) or a mutated ATM (AT11) or the linked 3161G and 2572C ATM variants in the homozygote state (HA220).…”

Section: Discussionmentioning

confidence: 85%

ATM polymorphisms as risk factors for prostate cancer development

et al. 2004

View full text Add to dashboard Cite

The risk of prostate cancer is known to be elevated in carriers of germline mutations in BRCA2, and possibly also in carriers of BRCA1 and CHEK2 mutations. These genes are components of the ATM-dependent DNA damage signalling pathways. To evaluate the hypothesis that variants in ATM itself might be associated with prostate cancer risk, we genotyped five ATM variants in DNA from 637 prostate cancer patients and 445 controls with no family history of cancer. No significant differences in the frequency of the variant alleles at 5557G4A (D1853N), 5558A4T (D1853V), ivs38-8t4c and ivs38-15g4c were found between the cases and controls. The 3161G (P1054R) variant allele was, however, significantly associated with an increased risk of developing prostate cancer (any G vs CC OR 2.13, 95% CI 1.17 -3.87, P ¼ 0.016). A lymphoblastoid cell line carrying both the 3161G and the 2572C (858L) variant in the homozygote state shows a cell cycle progression profile after exposure to ionising radiation that is significantly different to that seen in cell lines carrying a wild-type ATM gene. These results provide evidence that the presence of common variants in the ATM gene, may confer an altered cellular phenotype, and that the ATM 3161C4G variant might be associated with prostate cancer risk. Prostate cancer is the second most common malignancy and the second commonest cause of cancer deaths in men in the European Union, with 143 000 new cases and 60 000 deaths year À1 (GLOB-CAN 2000, www-dep.iarc.fr). The aetiology of prostate cancer is poorly understood. Prostate cancer is known to aggregate in families, indicating that genetic susceptibility may be important, but the genes involved are largely unknown. Linkage studies in multiple case families have suggested susceptibility loci on chromosomes 1q24, 1q42, 1p36, 8p22 -23, 17p, 20q13 and Xq (see recent reviews by DeMarzo et al, 2003;Gronberg, 2003) but none have been definitively replicated. As a consequence of these linkage studies, variants in prostate cancer families have been identified in several genes including Macrophage Scavenger Receptor 1(MSR1), 2 0 -5 0 -oligoadenylate-dependent ribonuclease L (RNASEL) and ELAC2 (chromosome 17p11/HPC2 region) (reviewed in Simard et al, 2003), but again none have been reliably associated with risk.Several independent studies have demonstrated that individuals with germline mutations in BRCA2 are at increased risk of prostate cancer (The Breast Cancer Linkage Consortium, 1999;Edwards et al, 2003;Giusti et al, 2003). There is also some evidence for an increased risk in carriers of BRCA1 mutations (Thompson et al, 2002). More recently, Seppala et al (2003) have found that the CHEK2 variant 1100delC, known to be associated with an increased risk of breast cancer, is also associated with an increased risk of prostate cancer, and Dong et al (2003) found that this and other missense variants in CHEK2 occurred at increased frequency in prostate cancer cases. The proteins encoded by the BRCA1 and BRCA2 genes participate in the maintenance of geno...

show abstract

Section: Discussionmentioning

confidence: 85%

ATM polymorphisms as risk factors for prostate cancer development

et al. 2004

View full text Add to dashboard Cite

show abstract

“…However, it remains unclear whether cells from ATM heterozygotes exhibit clinically relevant radiosensitivity in vivo. It has also been hypothesized that ATM heterozygotes may be over-represented in the proportion of breast cancer cases that exhibit exaggerated acute or late reaction of normal tissues following radiotherapy (Angele et al, 2003;Gutierrez-Enriquez et al, 2004;Meyer et al, 2004). Given the increased risk of breast cancer in ATM heterozygotes the response to radiation therapy is of potential clinical importance and requires further investigation.…”

Section: Other Phenotypic Features In Atm Heterozygotesmentioning

confidence: 99%

ATM and breast cancer susceptibility

2006

View full text Add to dashboard Cite

ATM was originally identified by positional cloning as the gene that underlies the autosomal recessive condition ataxia-telangiectasia. The encoded protein plays a central role in the complex processes that repair DNA doublestrand breaks. Nearly 20 years ago, epidemiological surveys of relatives of ataxia-telangiectasia cases suggested that female relatives were at modestly increased risk of breast cancer. Subsequently, many studies have tried to clarify the role of ATM in breast cancer susceptibility, but have produced inconclusive and/or inconsistent results. Recently, large epidemiological and molecular studies have finally provided conclusive evidence that ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles.

show abstract

“…Although current literature is conflicting, given that ATM carriers may have an increased sensitivity to radiation, we recommended that mammography and X-rays should only be considered if no alternative method could be considered for a particular therapy, treatment, or management option. 15,16 Evidence suggests that specific mutations within the ATM gene may increase the risks for other cancers; we recommended family history to be used to guide screening and management recommendations for these other cancers. 17 Finally, given that homozygous ATM mutations can cause ataxia telangiectasia, preconception/prenatal genetic counseling was recommended for any ATM carrier of reproductive age.…”

Section: Discussionmentioning

confidence: 99%