Genetics & Genomics

Management of Individuals With a Mutation in the Ataxia Telangiectasia Mutated Gene

genetics, genetic testing, hereditary cancer syndromes, breast cancer, colon cancer, ataxia telangiectasia
ONF 2016, 43(1), 114-117. DOI: 10.1188/16.ONF.114-117

Advances in genetic testing have led to the identification of multiple genes associated with a hereditary risk for developing breast and other cancers. One such gene is the ataxia telangiectasia mutated (ATM) gene, which is available on many genetic panels offered to individuals with suspected hereditary risk. Genetic testing can often lead to improved understanding and clarification of risk for developing cancer, as well as allow affected individuals to make informed choices about management, including the adoption of primary prevention strategies and more aggressive screening than typically recommended in the general population. This article provides an overview of the role of mutations in the ATM gene in developing malignancies, along with emerging research on treatment implications based on genetic testing results.

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    Advances in genetic testing have led to the identification of multiple genes associated with a hereditary risk for developing breast and other cancers. One such gene is the ataxia telangiectasia mutated (ATM) gene, which is available on many genetic panels offered to individuals with suspected hereditary risk. Genetic testing can often lead to improved understanding and clarification of risk for developing cancer, as well as allow affected individuals to make informed choices about management, including the adoption of primary prevention strategies and more aggressive screening than typically recommended in the general population. This article provides an overview of the role of mutations in the ATM gene in developing malignancies, along with emerging research on treatment implications based on genetic testing results.

    Physiologic Function

    The ATM gene is located on the long (q) arm of chromosome 11 between positions 22 and 23, spanning from base pair 108,222,499 to base pair 108,369,101 (Genetics Home Reference, 2015). The ATM gene is large; with 63 exons containing about 150 kb of genomic DNA, analyzing the gene is technologically difficult (Graña et al., 2011; Mitui et al., 2009). In addition, the ATM gene provides the code to produce a protein that functions in the nucleus of the cell (Genetics Home Reference, 2015).

    The function of the ATM protein is to regulate the rate at which cells grow and divide, as well as to promote the normal development and activity of the nervous and immune systems. This protein also plays an important role in recognizing damaged or broken DNA strands and facilitating DNA repair by activating enzymes to repair the damaged DNA strands. The ATM gene is considered to be a major guardian of genomic stability (Shiloh, 2014).

    The impact of mutations in the ATM gene depends on the number of alleles affected. When an individual is homozygous (both alleles are affected) for a mutation in the ATM gene, the person will develop ataxia telangiectasia (AT), a rare autosomal recessive disorder (Lindor, McMaster, Lindor, & Greene, 2008). Individuals who are heterozygous (one copy is affected) are at increased risk for developing several malignancies, including breast, colon, stomach, bladder, pancreatic, lung, and ovarian cancers (Gatti, 2010).

    Clinical Manifestations

    Homozygous: AT occurs because of a germline biallelic (both copies affected) mutation in 1 out of every 40,000 to 100,000 live births (Gatti, 2010). In individuals with suspected AT, germline sequence analysis of the ATM coding region detects about 90% of ATM sequence variants (Gatti, 2010). More than 600 different germline mutations have been reported (Chessa et al., 2009). In individuals with AT, about 90% have no detectable ATM protein, and less than 10% have only trace amounts of ATM protein (Gatti, 2010). In about 1% of individuals with AT, a normal amount of ATM protein is present, but the protein is not functional because it lacks ATM serine/threonine kinase activity (Gatti, 2010; Lindor et al., 2008).

    The primary clinical sign of biallelic AT is progressive cerebellar ataxia, which is usually first seen from ages 1–4 years (Gatti, 2010). Other clinical manifestations include oculomotor apraxia, telangiectasias of the conjunctivae, immunodeficiency, and frequent infections (Lindor et al., 2008). Individuals with AT are also at increased risk for developing malignancies, particularly leukemia and lymphoma.

    Because individuals with AT are unusually sensitive to ionizing radiation, special consideration should be given to limiting exposure to repeated computed tomography scans or other x-rays (Genetics Home Reference, 2015). Increased risks exist when anesthesia is administered, requiring more attention because of impaired swallowing, reduced respiratory capacity, and higher infection risks (Gatti, 2010). Classic AT is treated with IV immunoglobulin replacement therapy to manage the frequent and severe infections and to replace low immunoglobulin G levels. Many individuals with chronic bronchiectasis will require ongoing aggressive pulmonary hygiene (Gatti, 2010). Most affected individuals will require supportive therapy for drooling and physical therapy to help maintain mobility (Gatti, 2010).

    Heterozygous: Next-generation sequencing panels for germline mutations associated with hereditary risk for developing breast and colon cancers typically include sequencing of the ATM gene. With the increased use of next-generation panels, many more individuals with a heterozygous mutation (one allele affected) in the ATM gene have been identified (Aloraifi et al., 2015). Heterozygous germline mutations in the ATM gene are considered to be moderate penetrance mutations associated with a 30%–60% lifetime risk of developing breast cancer (Tavtigian et al., 2009). Epidemiologic evidence suggests that one mutation (p.V2424G) has even been estimated to confer a breast cancer risk as high as 52%–69% (Kapoor et al., 2015). Ionizing radiation is a known mutagen associated with increased breast cancer risk. Because the ATM gene is a key regulator of cellular responses to the DNA damage induced by ionizing radiation, women with breast cancer treated with radiation may be at increased risk for developing a second breast cancer (Bernstein et al., 2010; Hammond & Muschel, 2014).

    Heterozygous mutations in the ATM gene may account for about 5%–15% of hereditary breast cancer (Aloraifi et al., 2015; Kapoor et al., 2015). The risk of breast cancer is at least twice as high in ATM carriers than in the general population (Economopoulou, Dimitriadis, & Psyrri, 2015). Epidemiologic evidence suggests that the risk of breast cancer in heterozygotes with ATM mutations is higher in women younger than age 50 years and may be as high as five times the risk in the general population (Ahmed & Rahman, 2006; Economopoulou et al., 2015). Whether some mutations are associated with different risks of developing breast and other cancers is unclear (Ahmed & Rahman, 2006). Breast cancers diagnosed in women who are heterozygous for the ATM mutation may be more aggressive than those in noncarriers (Economopoulou et al., 2015).

    The risk of gastric cancer may be increased in individuals with a germline ATM mutation (Kim, Choi, Min, Kim, & Kim, 2013). Gastric cancer in ATM carriers typically is associated with older age, larger tumor size, distal location in the stomach, more extensive invasion, and lower recurrence rate. Risk for ovarian cancer in ATM germline mutation carriers is also possibly increased, but the exact increase in risk is not clear (Pennington et al., 2014). A three-fold increased risk for developing colon cancer has been reported, as have small increased risks for developing bladder, lung, prostate, gallbladder, and esophageal cancers (Thompson et al., 2005) The risk of pancreatic cancer is also increased (Roberts et al., 2012).

    Emerging Research in Somatic Mutations

    Somatic mutations, or acquired mutations that occur after conception, in the ATM gene have been detected in cancer biopsy specimens from a small fine-needle aspiration (Beltran et al., 2013; Kanagal-Shamanna et al., 2014). Early research suggests that somatic mutations in the ATM gene may be sensitive to inhibition of poly(adenosine diphosphate-ribose) polymerase (PARP), playing an important role in base excision DNA repair. Somatic ATM mutations have been found in breast, lung, prostate, and colorectal cancers, as well as in hematologic malignancies (Ouillette et al., 2012; Skowronska et al., 2012; Weber & Ryan, 2015). Identifying loss of ATM function in somatic tumor mutations may allow for the identification of a patient subset that could receive increased benefit from targeted PARP inhibitor therapy.

    Management of a Heterozygous Germline Mutation

    Because of the size of the ATM gene and the relatively new ability to perform germline mutation genetic testing, variants of unknown significance (VUS) are detected frequently (Kapoor et al., 2015). This potential outcome of testing should be addressed in pretest genetic counseling. The detection of a VUS can be confusing, is largely uninformative, and may increase anxiety and stress levels (Mahon, 2015). Oncology nurses need to be prepared to address these concerns.

    No specific recommendations exist for screening and early detection in heterozygous ATM carriers. Given that the risk of breast cancer is at least 20% and perhaps as high as 60% in ATM germline mutation carriers, the National Comprehensive Cancer Network ([NCCN], 2015) recommends considering adding breast magnetic resonance imaging to screening. The NCCN (2015) has stated that inadequate evidence exists to support prophylactic mastectomies in ATM germline mutation carriers. Because the risks of developing colon, gastric, pancreatic, and ovarian cancers may also be increased in germline mutation carriers, consideration should be given to the modification of screening recommendations. Family and personal history of cancer is an important consideration when developing recommendations for prevention and early detection. Oncology nurses should ensure that patients and families understand the importance of complying with these recommendations.

    Knowing if a patient carries a germline ATM mutation may help to guide treatment decisions (Stagni et al., 2014). Those with a germline ATM mutation being treated for ovarian cancer may have a better response to platinum-based therapy or PARP inhibitors, according to a few small retrospective reviews (Gilardini Montani et al., 2013; Pennington et al., 2014). Oncology nurses should anticipate more research in this area and be willing to provide basic information to patients and families about how knowing whether an individual carries a mutation may aid in the selection of the best treatment plan.

    Conclusion

    Although routine testing for germline and somatic mutations in the ATM gene is relatively new, knowledge is quickly emerging about the gene’s role as one of the primary caretakers of genomic stability and its part in DNA damage response and repair. A heterozygous mutation in the ATM gene can lead to cancer initiation and progression. More widespread identification of this gene should lead to the development of more effective therapeutic choices for those diagnosed with malignancy. Oncology nurses should anticipate that recommendations for the management of individuals with an ATM mutation will be refined and updated, as well as ensure that those who have an ATM mutation are provided with this information.

    References

    Ahmed, M., & Rahman, N. (2006). ATM and breast cancer susceptibility. Oncogene, 25, 5906–5911. doi:10.1038/sj.onc.1209873

    Aloraifi, F., McDevitt, T., Martiniano, R., McGreevy, J., McLaughlin, R., Egan, C.M., . . . Bracken, A.P. (2015). Detection of novel germline mutations for breast cancer in non-BRCA1/2 families. FEBS Journal, 282, 3424–3437. doi:10.1111/febs.13352

    Beltran, H., Yelensky, R., Frampton, G.M., Park, K., Downing, S.R., MacDonald, T.Y.,. . . Rubin, M.A. (2013). Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity. European Urology, 63, 920–926. doi:10.1016/j.eururo.2012.08.053

    Bernstein, J.L., Haile, R.W., Stovall, M., Boice, J.D., Jr., Shore, R.E., Langholz, B., . . . Concannon, P. (2010). Radiation exposure, the ATM gene, and contralateral breast cancer in the women’s environmental cancer and radiation epidemiology study. Journal of the National Cancer Institute, 102, 475–483. doi:10.1093/jnci/djq055

    Chessa, L., Piane, M., Magliozzi, M., Torrente, I., Savio, C., Lulli, P., . . . Dallapiccola, B. (2009). Founder effects for ATM gene mutations in Italian ataxia telangiectasia families. Annals of Human Genetics, 73, 532–539. doi:10.1111/j.1469-1809.2009.00535.x

    Economopoulou, P., Dimitriadis, G., & Psyrri, A. (2015). Beyond BRCA: New hereditary breast cancer susceptibility genes. Cancer Treatment Reviews, 41, 1–8. doi:10.1016/j.ctrv.2014.10.008

    Gatti, R. (2010). Ataxia-telangectasia. In R.A. Pagon, M.P. Adam, H.H. Ardinger, S.E. Wallace, A. Amemiya, L.J.H. Bean, . . . K. Stephens (Eds.), GeneReviews®. Seattle, WA: University of Washington, Seattle. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK26468/?report=reader

    Genetics Home Reference. (2015). ATM. Retrieved from http://ghr.nlm.nih.gov/gene/ATM

    Gilardini Montani, M.S., Prodosmo, A., Stagni, V., Merli, D., Monteonofrio, L., Gatti, V., . . . Soddu, S. (2013). ATM-depletion in breast cancer cells confers sensitivity to PARP inhibition. Journal of Experimental and Clinical Cancer Research, 32, 95. doi:10.1186/1756-9966-32-95

    Graña, B., Fachal, L., Darder, E., Balmaña, J., Ramón Y Cajal, T., Blanco, I., . . . Brunet, J. (2011). Germline ATM mutational analysis in BRCA1/BRCA2 negative hereditary breast cancer families by MALDI-TOF mass spectrometry. Breast Cancer Research and Treatment, 128, 573–579. doi:10.1007/s10549-011-1462-x

    Hammond, E.M., & Muschel, R.J. (2014). Radiation and ATM inhibition: The heart of the matter. Journal of Clinical Investigation, 124, 3289–3291. doi:10.1172/JCI77195

    Kanagal-Shamanna, R., Portier, B.P., Singh, R.R., Routbort, M.J., Aldape, K.D., Handal, B.A., . . . Patel, K.P. (2014). Next-generation sequencing-based multi-gene mutation profiling of solid tumors using fine needle aspiration samples: Promises and challenges for routine clinical diagnostics. Modern Pathology, 27, 314–327. doi:10.1038/modpathol.2013.122

    Kapoor, N.S., Curcio, L.D., Blakemore, C.A., Bremner, A.K., McFarland, R.E., West, J.G., & Banks, K.C. (2015). Multigene panel testing detects equal rates of pathogenic BRCA1/2 mutations and has a higher diagnostic yield compared to limited BRCA1/2 analysis alone in patients at risk for hereditary breast cancer. Annals of Surgical Oncology, 22, 3282–3288. doi:10.1245/s10434-015-4754-2

    Kim, H.S., Choi, S.I., Min, H.L., Kim, M.A., & Kim, W.H. (2013). Mutation at intronic repeats of the ataxia-telangiectasia mutated (ATM) gene and ATM protein loss in primary gastric cancer with microsatellite instability. PLOS ONE, 8, e82769. doi:10.1371/journal.pone.0082769

    Lindor, N.M., McMaster, M.L., Lindor, C.J., & Greene, M.H. (2008). Concise handbook of familial cancer susceptibility syndromes—Second edition. Journal of the National Cancer Institute. Monographs, 2008, 1–93. doi:10.1093/jncimonographs/lgn001

    Mahon, S.M. (2015). Management of patients with a genetic variant of unknown significance. Oncology Nursing Forum, 42, 316–318. doi:10.1188/15.ONF.316-318

    Mitui, M., Nahas, S.A., Du, L.T., Yang, Z., Lai, C.H., Nakamura, K., . . . Gatti, R.A. (2009). Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: Mutations with increased cancer risk. Human Mutation, 30, 12–21. doi:10.1002/humu.20805

    National Comprehensive Cancer Network. (2015). NCCN Clinical Practice Guidelines in Oncology: Genetic/familial high-risk assessment: Breast and ovarian [v.2.2015]. Retrieved from http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening…

    Ouillette, P., Li, J., Shaknovich, R., Li, Y., Melnick, A., Shedden, K., & Malek, S.N. (2012). Incidence and clinical implications of ATM aberrations in chronic lymphocytic leukemia. Genes, Chromosomes and Cancer, 51, 1125–1132. doi:10.1002/gcc.21997

    Pennington, K.P., Walsh, T., Harrell, M.I., Lee, M.K., Pennil, C.C., Rendi, M.H., . . . Swisher, E.M. (2014). Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clinical Cancer Research, 20, 764–775. doi:10.1158/1078-0432.CCR-13-2287

    Roberts, N.J., Jiao, Y., Yu, J., Kopelovich, L., Petersen, G.M., Bondy, M.L., . . . Klein, A.P. (2012). ATM mutations in patients with hereditary pancreatic cancer. Cancer Discovery, 2, 41–46. doi:10.1158/2159-8290.CD-11-0194

    Shiloh, Y. (2014). ATM: Expanding roles as a chief guardian of genome stability. Experimental Cell Research, 329, 154–161. doi:10.1016/j.yexcr.2014.09.002

    Skowronska, A., Austen, B., Powell, J.E., Weston, V., Oscier, D.G., Dyer, M.J.,. . . Stankovic, T. (2012). ATM germline heterozygosity does not play a role in chronic lymphocytic leukemia initiation but influences rapid disease progression through loss of the remaining ATM allele. Haematologica, 97, 142–146. doi:10.3324/haematol.2011.048827

    Stagni, V., Oropallo, V., Fianco, G., Antonelli, M., Cinà, I., & Barilà, D. (2014). Tug of war between survival and death: Exploring ATM function in cancer. International Journal of Molecular Sciences, 15, 5388–5409. doi:10.3390/ijms15045388

    Tavtigian, S.V., Oefner, P.J., Babikyan, D., Hartmann, A., Healey, S., Le Calvez-Kelm, F., . . . Chenevix-Trench, G. (2009). Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. American Journal of Human Genetics, 85, 427–446. doi:10.1016/j.ajhg.2009.08.018

    Thompson, D., Duedal, S., Kirner, J., McGuffog, L., Last, J., Reiman, A., . . . Easton, D.F. (2005). Cancer risks and mortality in heterozygous ATM mutation carriers. Journal of the National Cancer Institute, 97, 813–822. doi:10.1093/jnci/dji141

    Weber, A.M., & Ryan, A.J. (2015). ATM and ATR as therapeutic targets in cancer. Pharmacology and Therapeutics, 149, 124–138. doi:10.1016/j.pharmthera.2014.12.001

    About the Author(s)

    Mahon is a professor in the Division of Hematology and Oncology and a professor of adult nursing in the School of Nursing at Saint Louis University in Missouri. No financial relationships to disclose. Mahon can be reached at mahonsm@slu.edu, with copy to editor at ONFEditor@ons.org.

     

    References

    Ahmed, M., & Rahman, N. (2006). ATM and breast cancer susceptibility. Oncogene, 25, 5906–5911. doi:10.1038/sj.onc.1209873
    Aloraifi, F., McDevitt, T., Martiniano, R., McGreevy, J., McLaughlin, R., Egan, C.M., . . . Bracken, A.P. (2015). Detection of novel germline mutations for breast cancer in non-BRCA1/2 families. FEBS Journal, 282, 3424–3437. doi:10.1111/febs.13352
    Beltran, H., Yelensky, R., Frampton, G.M., Park, K., Downing, S.R., MacDonald, T.Y.,. . . Rubin, M.A. (2013). Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity. European Urology, 63, 920–926. doi:10.1016/j.eururo.2012.08.053
    Bernstein, J.L., Haile, R.W., Stovall, M., Boice, J.D., Jr., Shore, R.E., Langholz, B., . . . Concannon, P. (2010). Radiation exposure, the ATM gene, and contralateral breast cancer in the women’s environmental cancer and radiation epidemiology study. Journal of the National Cancer Institute, 102, 475–483. doi:10.1093/jnci/djq055
    Chessa, L., Piane, M., Magliozzi, M., Torrente, I., Savio, C., Lulli, P., . . . Dallapiccola, B. (2009). Founder effects for ATM gene mutations in Italian ataxia telangiectasia families. Annals of Human Genetics, 73, 532–539. doi:10.1111/j.1469-1809.2009.00535.x
    Economopoulou, P., Dimitriadis, G., & Psyrri, A. (2015). Beyond BRCA: New hereditary breast cancer susceptibility genes. Cancer Treatment Reviews, 41, 1–8. doi:10.1016/j.ctrv.2014.10.008
    Gatti, R. (2010). Ataxia-telangectasia. In R.A. Pagon, M.P. Adam, H.H. Ardinger, S.E. Wallace, A. Amemiya, L.J.H. Bean, . . . K. Stephens (Eds.), GeneReviews®. Seattle, WA: University of Washington, Seattle. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK26468/?report=reader
    Genetics Home Reference. (2015). ATM. Retrieved from http://ghr.nlm.nih.gov/gene/ATM
    Gilardini Montani, M.S., Prodosmo, A., Stagni, V., Merli, D., Monteonofrio, L., Gatti, V., . . . Soddu, S. (2013). ATM-depletion in breast cancer cells confers sensitivity to PARP inhibition. Journal of Experimental and Clinical Cancer Research, 32, 95. doi:10.1186/1756-9966-32-95
    Graña, B., Fachal, L., Darder, E., Balmaña, J., Ramón Y Cajal, T., Blanco, I., . . . Brunet, J. (2011). Germline ATM mutational analysis in BRCA1/BRCA2 negative hereditary breast cancer families by MALDI-TOF mass spectrometry. Breast Cancer Research and Treatment, 128, 573–579. doi:10.1007/s10549-011-1462-x
    Hammond, E.M., & Muschel, R.J. (2014). Radiation and ATM inhibition: The heart of the matter. Journal of Clinical Investigation, 124, 3289–3291. doi:10.1172/JCI77195
    Kanagal-Shamanna, R., Portier, B.P., Singh, R.R., Routbort, M.J., Aldape, K.D., Handal, B.A., . . . Patel, K.P. (2014). Next-generation sequencing-based multi-gene mutation profiling of solid tumors using fine needle aspiration samples: Promises and challenges for routine clinical diagnostics. Modern Pathology, 27, 314–327. doi:10.1038/modpathol.2013.122
    Kapoor, N.S., Curcio, L.D., Blakemore, C.A., Bremner, A.K., McFarland, R.E., West, J.G., & Banks, K.C. (2015). Multigene panel testing detects equal rates of pathogenic BRCA1/2 mutations and has a higher diagnostic yield compared to limited BRCA1/2 analysis alone in patients at risk for hereditary breast cancer. Annals of Surgical Oncology, 22, 3282–3288. doi:10.1245/s10434-015-4754-2
    Kim, H.S., Choi, S.I., Min, H.L., Kim, M.A., & Kim, W.H. (2013). Mutation at intronic repeats of the ataxia-telangiectasia mutated (ATM) gene and ATM protein loss in primary gastric cancer with microsatellite instability. PLOS ONE, 8, e82769. doi:10.1371/journal.pone.0082769
    Lindor, N.M., McMaster, M.L., Lindor, C.J., & Greene, M.H. (2008). Concise handbook of familial cancer susceptibility syndromes—Second edition. Journal of the National Cancer Institute. Monographs, 2008, 1–93. doi:10.1093/jncimonographs/lgn001
    Mahon, S.M. (2015). Management of patients with a genetic variant of unknown significance. Oncology Nursing Forum, 42, 316–318. doi:10.1188/15.ONF.316-318
    Mitui, M., Nahas, S.A., Du, L.T., Yang, Z., Lai, C.H., Nakamura, K., . . . Gatti, R.A. (2009). Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: Mutations with increased cancer risk. Human Mutation, 30, 12–21. doi:10.1002/humu.20805
    National Comprehensive Cancer Network. (2015). NCCN Clinical Practice Guidelines in Oncology: Genetic/familial high-risk assessment: Breast and ovarian [v.2.2015]. Retrieved from http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening…
    Ouillette, P., Li, J., Shaknovich, R., Li, Y., Melnick, A., Shedden, K., & Malek, S.N. (2012). Incidence and clinical implications of ATM aberrations in chronic lymphocytic leukemia. Genes, Chromosomes and Cancer, 51, 1125–1132. doi:10.1002/gcc.21997
    Pennington, K.P., Walsh, T., Harrell, M.I., Lee, M.K., Pennil, C.C., Rendi, M.H., . . . Swisher, E.M. (2014). Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clinical Cancer Research, 20, 764–775. doi:10.1158/1078-0432.CCR-13-2287
    Roberts, N.J., Jiao, Y., Yu, J., Kopelovich, L., Petersen, G.M., Bondy, M.L., . . . Klein, A.P. (2012). ATM mutations in patients with hereditary pancreatic cancer. Cancer Discovery, 2, 41–46. doi:10.1158/2159-8290.CD-11-0194
    Shiloh, Y. (2014). ATM: Expanding roles as a chief guardian of genome stability. Experimental Cell Research, 329, 154–161. doi:10.1016/j.yexcr.2014.09.002
    Skowronska, A., Austen, B., Powell, J.E., Weston, V., Oscier, D.G., Dyer, M.J.,. . . Stankovic, T. (2012). ATM germline heterozygosity does not play a role in chronic lymphocytic leukemia initiation but influences rapid disease progression through loss of the remaining ATM allele. Haematologica, 97, 142–146. doi:10.3324/haematol.2011.048827
    Stagni, V., Oropallo, V., Fianco, G., Antonelli, M., Cinà, I., & Barilà, D. (2014). Tug of war between survival and death: Exploring ATM function in cancer. International Journal of Molecular Sciences, 15, 5388–5409. doi:10.3390/ijms15045388
    Tavtigian, S.V., Oefner, P.J., Babikyan, D., Hartmann, A., Healey, S., Le Calvez-Kelm, F., . . . Chenevix-Trench, G. (2009). Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. American Journal of Human Genetics, 85, 427–446. doi:10.1016/j.ajhg.2009.08.018
    Thompson, D., Duedal, S., Kirner, J., McGuffog, L., Last, J., Reiman, A., . . . Easton, D.F. (2005). Cancer risks and mortality in heterozygous ATM mutation carriers. Journal of the National Cancer Institute, 97, 813–822. doi:10.1093/jnci/dji141
    Weber, A.M., & Ryan, A.J. (2015). ATM and ATR as therapeutic targets in cancer. Pharmacology and Therapeutics, 149, 124–138. doi:10.1016/j.pharmthera.2014.12.001