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ATM Mutations in Patients with Hereditary Pancreatic Cancer
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Abstract
Pancreatic cancers are the fourth most-common cause of cancer-related deaths in the Western world, with >200,000 cases reported in 2010. Although up to 10% of these cases occur in familial patterns, the hereditary basis for predisposition in the vast majority of affected families is unknown. We used next-generation sequencing, including whole-genome and whole-exome analyses, and identified heterozygous, constitutional, ataxia telangiectasia mutated (ATM) gene mutations in 2 kindreds with familial pancreatic cancer. Mutations segregated with disease in both kindreds and tumor analysis demonstrated LOH of the wild-type allele. By using sequence analysis of an additional 166 familial pancreatic cancer probands, we identified 4 additional patients with deleterious mutations in the ATM gene, whereas we identified no deleterious mutations in 190 spouse controls (P = 0.046). When we considered only the mostly severely affected families with 3 or more pancreatic cancer cases, 4 deleterious mutations were found in 87 families (P = 0.009). Our results indicate that inherited ATM mutations play an important role in familial pancreatic cancer predisposition. Significance: The genes responsible for the majority of cases of familial pancreatic ductal adenocarcinoma are unknown. We here identify ATM as a predisposition gene for pancreatic ductal adenocarcinoma. Our results have important implications for the management of patients in affected families and illustrate the power of genome-wide sequencing to identify the basis of familial cancer syndromes. Cancer Discovery; 2(1): 41–6. ©2011 AACR. Read the Commentary on this article by Bakker and de Winter, p. 14 This article is highlighted in the In This Issue feature, p. 1
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“Pancreatic surveillance is recommended for carriers of germline deleterious variants in cancer susceptibility gene,22–26: BRCA2, ATM, BRCA1, PALB2, CDKN2A, STK11, MLH1 and MSH2.”
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Andersen, D. K., Andrén‐Sandberg, Å., Duell, E. J., Goggins, M., Korc, M., Petersen, G. M., Smith, J. P., & Whitcomb, D. C. (2013) · Pancreas · doi:10.1097/mpa.0b013e3182a9ad9d · Cited by 132
Self-citationSurgical and molecular pathology of pancreatic neoplasms
Hackeng, W. M., Hruban, R. H., Offerhaus, G. J. A., & Brosens, L. A. A. (2016) · Diagnostic Pathology · doi:10.1186/s13000-016-0497-z · Cited by 133
Self-citationLoss of ATM accelerates pancreatic cancer formation and epithelial–mesenchymal transition
Russell, R., Perkhofer, L., Liebau, S., Lin, Q., Lechel, A., Feld, F. M., Heßmann, E., Gaedcke, J., Güthle, M., Zenke, M., et al. (2015) · Nature Communications · doi:10.1038/ncomms8677 · Cited by 125
Inherited pancreatic cancer syndromes
Solomon, S., Das, S., Brand, R., & Whitcomb, D. C. (2012) · The Cancer Journal · doi:10.1097/ppo.0b013e318278c4a6 · Cited by 120
“4%were identified as ATM mutation arriers.(31) Furthermore, 4.”
BackgroundFamilial pancreatic cancer: Concept, management and issues
Matsubayashi, H., Takaori, K., Morizane, C., Maguchi, H., Mizuma, M., Takahashi, H., Wada, K., Hosoi, H., Yachida, S., Suzuki, M., et al. (2017) · World Journal of Gastroenterology · doi:10.3748/wjg.v23.i6.935 · Cited by 109
ATM-Deficient Cancers Provide New Opportunities for Precision Oncology
Jette, N., Kumar, M., Radhamani, S., Arthur, G., Goutam, S., Yip, S., Kolinsky, M. P., Williams, G. J., Bose, P., & Lees‐Miller, S. P. (2020) · Cancers · doi:10.3390/cancers12030687 · Cited by 112
“ATM is frequently mutated in prostate cancer [68], as well as somatic and hereditary forms of pancreatic cancers [69,70], suggesting that patients with these cancers might also benefit from treatment with a PARP inhibitor.”
BackgroundBRCA Mutations in Pancreas Cancer: Spectrum, Current Management, Challenges and Future Prospects
Wong, W., Raufi, A. G., Safyan, R. A., Bates, S. E., & Manji, G. A. (2020) · Cancer Management and Research · doi:10.2147/cmar.s211151 · Cited by 114
Mekonnen, N., Yang, H., & Shin, Y. K. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.880643 · Cited by 117
The Role of BRCA Testing in Hereditary Pancreatic and Prostate Cancer Families
Pilarski, R. (2019) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_238977 · Cited by 115
State of the art and future directions of pancreatic ductal adenocarcinoma therapy
Neuzillet, C., Tijeras‐Raballand, A., Bourget, P., Cros, J. F., Couvelard, A., Sauvanet, A., Vullierme, M., Tournigand, C., & Hammel, P. R. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.08.006 · Cited by 114
Abe, T., Blackford, A. L., Tamura, K., Ford, M., McCormick, P., Chuidian, M., Almario, J. A., Borges, M., Lennon, A. M., Shin, E. J., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.18.01512 · Cited by 102
Self-citationGenetic predisposition to pancreatic cancer
Ghiorzo, P. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i31.10778 · Cited by 109
Familial pancreatic cancer: genetic advancesPreprint
Rustgi, A. K. (2014) · Genes & Development · doi:10.1101/gad.228452.113 · Cited by 101
“In a genome-wide sequencing analysis of nearly 170 families with familial pancreatic cancer, two families were identified as having germline heterozygous ATM mutations, and four families had deleterious homozygous ATM mutations (Roberts et al. 2012).”
BackgroundAmundadottir, L. T. (2016) · International Journal of Biological Sciences · doi:10.7150/ijbs.15001 · Cited by 98
“3) have also been found mutated in pancreatic cancer families [13, 29, 45-48].”
BackgroundRisk of Pancreatic Cancer in Breast Cancer Families from the Breast Cancer Family Registry
Mocci, E., Milne, R. L., Méndez-Villamil, E. Y., Hopper, J. L., John, E. M., Andrulis, I. L., Chung, W. K., Daly, M. B., Buys, S. S., Malats, N., et al. (2013) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-12-0195 · Cited by 97
“17% of FPC cases are found to carry germline mutations in BRCA2 (6–8), approximately 3% have PALB2 mutations (9–11) and 2% carry deleterious ATM mutations (12).”
BackgroundMutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer
Tamura, K., Yu, J., Hata, T., Suenaga, M., Shindo, K., Abe, T., MacGregor-Das, A., Borges, M., Wolfgang, C. L., Weiss, M. J., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1720588115 · Cited by 95
Self-citationGraffeo, R., Rana, H. Q., Conforti, F., Bonanni, B., Cardoso, M. J., Paluch–Shimon, S., Pagani, O., Goldhirsch, A., Partridge, A. H., Lambertini, M., et al. (2022) · The Breast · doi:10.1016/j.breast.2022.06.003 · Cited by 104
The ATM Gene in Breast Cancer: Its Relevance in Clinical Practice
Stucci, L. S., Internò, V., Tucci, M., Perrone, M., Mannavola, F., Palmirotta, R., & Porta, C. (2021) · Genes · doi:10.3390/genes12050727 · Cited by 99
“In addition to conventional BC subtypes, ATM heterozygous mutations were recently associated to the predisposition of familial ductal pancreatic adenocarcinoma [34].”
BackgroundGenetics of familial and sporadic pancreatic cancer
Wood, L. D., Yurgelun, M. B., & Goggins, M. G. (2019) · Gastroenterology · doi:10.1053/j.gastro.2018.12.039 · Cited by 91
Self-citationRisk of Pancreatic Cancer Among Individuals With Pathogenic Variants in the ATM Gene
Hsu, F.-C., Roberts, N. J., Childs, E., Porter, N., Rabe, K. G., Borgida, A., Ukaegbu, C., Goggins, M. G., Hruban, R. H., Zogopoulos, G., et al. (2021) · JAMA Oncology · doi:10.1001/jamaoncol.2021.3701 · Cited by 91
Self-citationParikh, A. R., He, Y., Hong, T. S., Corcoran, R. B., Clark, J. W., Ryan, D. P., Zou, L., Ting, D. T., Catenacci, D. V. T., Chao, J., et al. (2019) · The Oncologist · doi:10.1634/theoncologist.2019-0034 · Cited by 92
Self-citationPersonalized Sequencing and the Future of Medicine: Discovery, Diagnosis and Defeat of Disease
Esplin, E. D., Oei, L., & Snyder, M. P. (2014) · Pharmacogenomics · doi:10.2217/pgs.14.117 · Cited by 91
Kim, H., Saka, B., Knight, S., Borges, M. W., Childs, E. J., Klein, A. P., Wolfgang, C. L., Herman, J. M., Adsay, V. N., Hruban, R. H., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-1239 · Cited by 88
“from a patient known to have a germline mutation in ATM and loss of the wild-type ATM allele in their cancer (14).”
BackgroundInfluentialSelf-citationEmerging concepts in pancreatic cancer medicine: targeting the tumor stroma
Neeße, A., Gress, T. M., Tuveson, D. A., Michl, P., & Krug, S. (2013) · OncoTargets and Therapy · doi:10.2147/ott.s38111 · Cited by 87
Genetic Predisposition to Colorectal Cancer: How Many and Which Genes to Test?
Rebuzzi, F., Ulivi, P., & Tedaldi, G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032137 · Cited by 84
Slater, E. P., Strauch, K., Rospleszcz, S., Ramaswamy, A., Esposito, I., Klöppel, G., Matthäi, E., Heeger, K., Fendrich, V., Langer, P., et al. (2014) · Translational Oncology · doi:10.1016/j.tranon.2014.05.007 · Cited by 83
“The major underlying gene defect(s) of FPChas not yet been identified, but causative BRCA2,PALB2,CDKN2a, andATM germlinemutationswere identified in about 10% to 15% of the FPC families [4–9].”
BackgroundHirotsu, Y., Nakagomi, H., Sakamoto, I., Amemiya, K., Oyama, T., Mochizuki, H., & Omata, M. (2015) · Molecular Genetics & Genomic Medicine · doi:10.1002/mgg3.157 · Cited by 83
“ATM is a predisposing gene for breast and pancreatic cancer (Broeks et al. 2000; Roberts et al. 2012).”
BackgroundGenetic Progression of Pancreatic Cancer
Cowan, R. W., & Maitra, A. (2014) · The Cancer Journal · doi:10.1097/ppo.0000000000000011 · Cited by 76
Имянитов, Е. Н., Kuligina, E. S., Соколенко, А. П., Suspitsin, E. N., Yanus, G. A., Iyevleva, A. G., Ivantsov, A. O., & Алексахина, С. Н. (2023) · World Journal of Clinical Oncology · doi:10.5306/wjco.v14.i2.40 · Cited by 82
ATM and ATR signaling at a glance
Awasthi, P., Foiani, M., & Kumar, A. (2016) · Journal of Cell Science · doi:10.1242/jcs.188631 · Cited by 78
ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications
Armstrong, S. A., Schultz, C. W., Azimi-Sadjadi, A., Brody, J. R., & Pishvaian, M. J. (2019) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-19-0208 · Cited by 78
“Additionally, a study of familial PDAC patients showed that deleterious ATM mutations were significantly higher than the control group, suggesting ATM's role in malignancy (25).”
BackgroundGermline mutations in Japanese familial pancreatic cancer patients
Takai, E., Yachida, S., Shimizu, K., Furuse, J., Kubo, E., Ohmoto, A., Suzuki, M., Hruban, R. H., Okusaka, T., Morizane, C., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.12490 · Cited by 73
“%) of the 54 FPC patients with available germline DNA carried deleterious mutations in BRCA2, PALB2, ATM, or MLH1.”
BackgroundInfluentialSelf-citationPancreatic adenocarcinoma pathology: changing "landscape".
Brosens, L. A. A., Hackeng, W. M., Offerhaus, G. J. A., Hruban, R. H., & Wood, L. D. (2015) · Europe PMC (PubMed Central) · doi:10.3978/j.issn.2078-6891.2015.032 · Cited by 73
“pancreatic cancer and less frequently in sporadic PDAC (14-16).”
BackgroundSelf-citationUpdate on Hereditary Colorectal Cancer: Improving the Clinical Utility of Multigene Panel Testing
Lorans, M., Dow, E., Macrae, F., Winship, I., & Buchanan, D. D. (2018) · Clinical Colorectal Cancer · doi:10.1016/j.clcc.2018.01.001 · Cited by 72
Type-3c Diabetes Mellitus, Diabetes of Exocrine Pancreas - An Update
Bhattamisra, S. K., Siang, T. C., Rong, C. Y., Annan, N. C., Sean, E. H. Y., Xi, L. W., Lyn, O. S., Liew, H. S., Choudhury, H., Pandey, M., et al. (2019) · Current Diabetes Reviews · doi:10.2174/1573399815666190115145702 · Cited by 73
Genetics and Genetic Testing in Pancreatic Cancer
Whitcomb, D. C., Shelton, C. A., & Brand, R. E. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.07.057 · Cited by 69
Metadata
- Authors
- Roberts, N. J., Jiao, Y., Yu, J., Kopelovich, L., Petersen, G. M., Bondy, M. L., Gallinger, S., Schwartz, A. G., Syngal, S., Cote, M. L., Axilbund, J., Schulick, R., Ali, S. Z., Eshleman, J. R., Velculescu, V. E., Goggins, M., Vogelstein, B., Papadopoulos, N., Hruban, R. H., Kinzler, K. W., & Klein, A. P.
- Affiliations
- Brigham and Women's Hospital (US)
- Authors' Affiliations: 1Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center; Departments of 2Medicine, 3Pathology, 4Surgery, and 5Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions; 6Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland; 7Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland; 8Division of Epidemiology, Mayo Clinic, Rochester, Minnesota; 9Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas; 10Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; 11Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan; 12Population Sciences Division, Dana-Farber Cancer Institute, and Gastroenterology Division, Brigham and Women's Hospital, Boston, Massachusetts
- Mayo Clinic (US)
- Corresponding author
- Hruban, Ralph H.
- Kinzler, Kenneth W.
- Klein, Alison P.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2012-01-01
- Volume
- 2
- Issue
- 1
- Pages
- 41-46
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC3676748
- OpenAlex
- W2146542392
- Cited by
- 491
- References
- 30
- Citations by year
- 2026: 13 · 2025: 11 · 2024: 22 · 2023: 27 · 2022: 30 · 2021: 49 · 2020: 36 · 2019: 43 · 2018: 42 · 2017: 38 · 2016: 49 · 2015: 41 · 2014: 38 · 2013: 31 · 2012: 20
- FWCI
- 14.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (n01pc35145-19-0-7, n01cn43302-6-0-1, 5r01ca121113-15)
- National Cancer Institute (N01 CN043302, R01CA-97075, CA123483, R01CA123483, R01-CA121113, N01 PC035145, CA-121113, N01 PC 35145, CA057345, P50CA102701, R01CA057345, R01CA097075, N01-CN 43302, P50CA062924, R37CA057345, CA 62924)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- ATM gene, hereditary pancreatic cancer, pancreatic ductal adenocarcinoma, hereditary cancer predisposition, loss of heterozygosity, constitutional mutation, cancer susceptibility genes, hereditary cancer
- MeSH terms
- Ataxia Telangiectasia, DNA-Binding Proteins, Humans, Mutation, Pancreatic Neoplasms, Pedigree, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Genetic Predisposition to Disease, Carcinoma, Pancreatic Ductal, Tumor Suppressor Proteins, Genome-Wide Association Study, Exome, Ataxia Telangiectasia Mutated Proteins
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