Germline Mutation in ATR in Autosomal- Dominant Oropharyngeal Cancer Syndrome

Abstract

ATR (ataxia telangiectasia and Rad3 related) is an essential regulator of genome integrity. It controls and coordinates DNA-replication origin firing, replication-fork stability, cell-cycle checkpoints, and DNA repair. Previously, autosomal-recessive loss-of-function mutations in ATR have been demonstrated in Seckel syndrome, a developmental disorder. Here, however, we report on a different kind of genetic disorder that is due to functionally compromised ATR activity, which translates into an autosomal-dominant inherited disease. The condition affects 24 individuals in a five-generation pedigree and comprises oropharyngeal cancer, skin telangiectases, and mild developmental anomalies of the hair, teeth, and nails. We mapped the disorder to a ∼16.8 cM interval in chromosomal region 3q22-24, and by sequencing candidate genes, we found that ATR contained a heterozygous missense mutation (c.6431A>G [p.Gln2144Arg]) that segregated with the disease. The mutation occurs within the FAT (FRAP, ATM, and TRRAP) domain-which can activate p53-of ATR. The mutation did not lead to a reduction in ATR expression, but cultured fibroblasts showed lower p53 levels after activation of ATR with hydroxyurea than did normal control fibroblasts. Moreover, loss of heterozygosity for the ATR locus was noted in oropharyngeal-tumor tissue. Collectively, the clinicopathological and molecular findings point to a cancer syndrome and provide evidence implicating a germline mutation in ATR and susceptibility to malignancy in humans.

ATM and ATR signaling at a glance

“…In pre-cancerous lesions, both the ATM and ATR pathways are activated, thereby helping the cell to mount a resistance to tumor development (Gorgoulis et al, 2005;Negrini et al, 2010). In addition, loss-of-function mutations or deletions of ATM or ATR, as well as their reduced kinase activity or expression levels, or deletions of components of their downstream pathways, all promote cell survival and result in a multi-fold increase in the propensity of a cell to become cancerous, and in an acceleration of tumor progression (Nevanlinna and Bartek, 2006;Spring et al, 2002;Vahteristo et al, 2002;Bertoni et al, 1999;Greenman et al, 2007;Guarini et al, 2012;Hollestelle et al, 2010;Menoyo et al, 2001;Reiman et al, 2011;Renwick et al, 2006;Roberts et al, 2012;Squatrito et al, 2010;Tanaka et al, 2012;Zighelboim et al, 2015Zighelboim et al, , 2009) (see poster). In particular, in ATM, distinct mutations have been found that cause different human malignancies, including lung cancer, breast cancer, colon cancer, lymphocytic leukemia, pancreatic cancer, and head and neck cancer, among others (Ding et al, 2008;Goldgar et al, 2011;Guarini et al, 2012;Roberts et al, 2012;Seshagiri et al, 2012) (see poster).…”

Is activation of the intra-S checkpoint in human fibroblasts an important factor in protection against UV-induced mutagenesis?

“…However, some insight can be derived from research describing germline or somatic mutations that are presumed to affect this pathway, or by examining data from animal models targeting ATR/CHK1. A germline mutation in the FAT domain of ATR in an autosomal-dominant oropharyngeal cancer syndrome, 36 or a mutation in the checkpoint mediator CLSPN in the germline of a familial breast cancer case, 37 did not impair intra-S checkpoint activation as measured by CHK1 phosphorylation. Somatic mutations in ATR and CHK1 have also been reported in endometrial, colorectal, and stomach cancers, particularly in mismatch repair-deficient cells with microsatellite instability (MSI).…”

Diseases Associated with Defective Responses to DNA Damage

“…Tanaka and colleagues recently described an unusual disorder comprising oropharyngeal cancer, pronounced dermal telangiectasias, and dental caries in 24 individuals from a large five-generation Caucasian pedigree originating from Indiana, United States (Tanaka et al 2012). Homozygosity mapping identified the causal gene, unexpectedly, as ATR.…”

“…Interestingly, loss of heterozygosity for the ATR locus was observed in the oropharyngeal tumor tissue. This syndrome represents the first example of germline mutation in ATR associated with a cancer syndrome representing a novel clinical outcome of impaired ATR function (Tanaka et al 2012).…”