<i>ATM</i> Mutations in Patients with Hereditary Pancreatic Cancer

Roberts, Nicholas J.; Jiao, Yuchen; Yu, Jun; Kopelovich, Levy; Petersen, Gloria M.; Bondy, Melissa L.; Gallinger, Steven; Schwartz, Ann G.; Syngal, Sapna; Coté, Michele L.; Axilbund, Jennifer E.; Schulick, Richard; Ali, Syed Z.; Eshleman, James R.; Velculescu, Victor E.; Goggins, Michael; Vogelstein, Bert; Papadopoulos, Nickolas; Hruban, Ralph H.; Kinzler, Kenneth W.; Klein, Alison P.

doi:10.1158/2159-8290.cd-11-0194

Cited by 439 publications

(307 citation statements)

References 25 publications

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“…Finally, inherited ATM mutations are also felt to play a role in familial pancreatic ductal adenocarcinoma (32)(33)(34). Radiosensitivity and chemosensitivity and ATM Radiosensitivity is also a hallmark of the A-T syndrome (35,36).…”

Section: Germ-line Atm Heterozygosity and Cancer Susceptibilitymentioning

confidence: 99%

ATM Mutations in Cancer: Therapeutic Implications

Choi¹,

Kipps²,

Kurzrock³

2016

Molecular Cancer Therapeutics

361

306

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Activation of checkpoint arrest and homologous DNA repair are necessary for maintenance of genomic integrity during DNA replication. Germ-line mutations of the ataxia telangiectasia mutated (ATM) gene result in the well-characterized ataxia telangiectasia syndrome, which manifests with an increased cancer predisposition, including a 20% to 30% lifetime risk of lymphoid, gastric, breast, central nervous system, skin, and other cancers. Somatic ATM mutations or deletions are commonly found in lymphoid malignancies, as well as a variety of solid tumors. Such mutations may result in chemotherapy resistance and adverse prognosis, but may also be exploited by existing or emerging targeted therapies that produce synthetic lethal states.

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Section: Germ-line Atm Heterozygosity and Cancer Susceptibilitymentioning

confidence: 99%

ATM Mutations in Cancer: Therapeutic Implications

Choi¹,

Kipps²,

Kurzrock³

2016

Molecular Cancer Therapeutics

361

306

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“…Germline mutations in ATM are associated with an increased risk for breast cancer and pancreatic cancer (Roberts et al. 2012). …”

Section: Introductionmentioning

confidence: 99%

Panel testing reveals nonsense and missense CDH1 mutations in families without hereditary diffuse gastric cancer

Huynh

Laukaitis

2016

Molec Gen & Gen Med

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BackgroundThe reported penetrance of germline CDH1 mutations is high in families with hereditary diffuse gastric cancer (HDGC). Men and women have a 70% and 56%, respectively, cumulative risk of developing diffuse gastric cancer by age 80. Women additionally have a 42% cumulative risk of developing breast cancer. Due to the high penetrance of these mutations, prophylactic total gastrectomy is currently recommended for CDH1 mutation carriers. However, whether everyone with a CDH1 gene mutation is at risk for HDGC is not clear.MethodsMutation identification was performed by next‐generation sequencing. Mutations and variant status was confirmed by Sanger sequencing in 11 family members.ResultsWe present two families with pathogenic CDH1 mutations. The first family carries a novel truncating, nonsense CDH1 mutation that we were able to trace for three generations, but reports no family history of diffuse gastric cancer. The occurrence of cancer in this family deviates significantly from the expectation for HDGC. The proband from the second family presents with breast cancer and carries a previously reported pathogenic CDH1 mutation, but also reports no family history of diffuse gastric cancer.ConclusionsOur study demonstrates the need for further analysis of CDH1 mutation penetrance in order to better counsel asymptomatic CDH1 mutation carriers on preventative measures and general care.

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“…These include germline mutations in BRCA2, BRCA1, PALB2, p16/CDKN2A, STK11, ATM, PRSS1, and the DNA repair genes (such as MSH2). [25][26][27] The challenge of the next decade, as outlined below, will be to translate these genetic discoveries to improving patient care.…”

Section: Genetic Sequencingmentioning

confidence: 99%

“…Germline mutations in one of the Fanconi anemia pathway genes, including BRCA1, BRCA2, and PALB2 (also known as FANCN), increase the risk of pancreatic cancer. [25][26][27] Fanconi anemia pathway genes code for proteins that help repair DNA cross-linking damage. Therefore, pancreatic cancers in which one of these genes is genetically inactivated should be exquisitely sensitive to treatments that induce DNA cross-linking damage or which further impede DNA repair.…”

Section: Applying Advances To Tumor Treatmentmentioning

confidence: 99%

“…39,40 Similarly, germline mutations in the ATM gene predispose to pancreatic cancer, and the ataxia telangiectasia-mutated (ATM) pathway is also potentially therapeutically targetable with existing agents. 24,25 PARP inhibitors, external beam radiation therapy and DNA-PKcs (protein kinase DNA-activated catalytic polypeptide) inhibitors may all be selectively effective in these patients. 41,42 The take-home message of all of this is that soon pathologists will be asked not only about cancer morphology, but also about the genetic background in which the cancer has arisen.…”

Section: Applying Advances To Tumor Treatmentmentioning

confidence: 99%

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Adenocarcinoma of the Pancreas

Encyclopedia of Diagnostic Imaging

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Infiltrating ductal adenocarcinoma of the pancreas is a real enigma. On one hand, it is one of the most deadly of all of the solid malignancies. On the other hand, the neoplastic glands can be remarkably well-differentiated, and it can be difficult to distinguish between a reactive nonneoplastic gland and a gland of invasive adenocarcinoma. In this review, we will present diagnostic criteria that one can "hang your hat on" when establishing the diagnosis of infiltrating ductal adenocarcinoma of the pancreas. We will also review clinically important features of the disease, and, with the impending incorporation of molecular genetics into everyday practice, we will emphasize clinical applications of cancer genetics.

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ATM Mutations in Patients with Hereditary Pancreatic Cancer

Cited by 439 publications

References 25 publications

ATM Mutations in Cancer: Therapeutic Implications

ATM Mutations in Cancer: Therapeutic Implications

Panel testing reveals nonsense and missense CDH1 mutations in families without hereditary diffuse gastric cancer

Adenocarcinoma of the Pancreas

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