Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer

Yurgelun, Matthew B.; Chittenden, Anu; Morales-Oyarvide, Vicente; Rubinson, Douglas A.; Dunne, Richard F.; Kozak, Margaret M.; Qian, Zhi Rong; Welch, Marisa W.; Brais, Lauren K.; Silva, Annacarolina da; Bui, Justin; Yuan, Chen; Li, Tingting; Li, Wanwan; Masuda, Atsuhiro; Gu, Mancang; Bullock, Andrea J.; Chang, Daniel T.; Clancy, Thomas E.; Linehan, David C.; Findeis‐Hosey, Jennifer J.; Doyle, Leona A.; Thorner, Aaron R.; Ducar, Matthew D.; Wollison, Bruce M.; Khalaf, Natalia; Perez, Kimberly; Syngal, Sapna; Aguirre, Andrew J.; Hahn, William C.; Meyerson, Matthew; Fuchs, Charles S.; Ogino, Shuji; Hornick, Jason L.; Hezel, Aram F.; Koong, Albert C.; Nowak, Jonathan A.; Wolpin, Brian M.

doi:10.1038/s41436-018-0009-5

Cited by 172 publications

(168 citation statements)

References 38 publications

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“…5,6,8,9,11,25,[47][48][49][50][51][52][53][54][55][56][57]. Importantly, in one study that showed that nearly 10% of PDAC patients carried a germline ATM mutation, in 44% of these patients a somatic second hit was identified (58). Although this loss-of-heterozygosity (LOH) seems to occur frequently in tumors arising from patients with germline ATM mutations (e.g., as seen in breast and pancreatic cancers; refs.…”

Section: Inactivating Atm Variants In Pancreatic Cancermentioning

confidence: 99%

ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications

Armstrong

Schultz

Azimi-Sadjadi

et al. 2019

Molecular Cancer Therapeutics

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Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid malignancies with very few therapeutic options to treat advanced or metastatic disease. The utilization of genomic sequencing has identified therapeutically relevant alterations in approximately 25% of PDAC patients, most notably in the DNA damage response and repair (DDR) genes, rendering cancer cells more sensitive to DNA-damaging agents and to DNA damage response inhibitors, such as PARP inhibitors. ATM is one of the most commonly mutated DDR genes, with somatic mutations identified in 2% to 18% of PDACs and germline mutations identified in 1% to 34% of PDACs. ATM plays a complex role as a cell-cycle checkpoint kinase, regulator of a wide array of downstream proteins, and responder to DNA damage for genome stability. The disruption of ATM signaling leads to downstream reliance on ATR and CHK1, among other DNA-repair mechanisms, which may enable exploiting the inhibition of downstream proteins as therapeutic targets in ATM-mutated PDACs. In this review, we detail the function of ATM, review the current data on ATM deficiency in PDAC, examine the therapeutic implications of ATM alterations, and explore the current clinical trials surrounding the ATM pathway.

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Section: Inactivating Atm Variants In Pancreatic Cancermentioning

confidence: 99%

ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications

Armstrong

Schultz

Azimi-Sadjadi

et al. 2019

Molecular Cancer Therapeutics

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“…In these familial PDAC cases, germline mutations in, among others, BRCA1 , BRCA2 , ATM , BRIP1 , CHEK2 , NBN , PALB2 , RAD50 , RAD51C and MLH1 are frequently detected [19,20,21,22,23]. Intriguingly, these genes encode proteins involved in different DNA repair pathways, including homologous recombination-mediated DNA double-strand break (DSB) repair and mismatch repair.…”

Section: Inherited Pancreatic Cancer Riskmentioning

confidence: 99%

“…This is particularly important for ATM aberrations in CLL, as these are subclonal to a large extend [93]. Nevertheless, given that a relatively large proportion of PDAC patients carries germline aberrations in known HR genes, including BRCA1 , BRCA2 , PALB2 , and ATM [19,20,21,22,23], PDAC may represent an entity in which PARP and/or DNA-PKcs inhibitors may be effective as single agents or as part of combination regimens. …”

Section: Targeting Defective Dna Repair Pathways In Familial and Spormentioning

confidence: 99%

“…While direct targeting of oncogenically mutated KRAS is still in its infancy [54,55], several approaches to indirectly target oncogenic KRAS, including combined CHK1/MAPKAP-K2 inhibition, CHK1 inhibition in combination with genotoxic chemotherapy, combined MEK/PI3K or combined MEK/SHP2 inhibition, have recently emerged and await clinical validation [60,61,62,64,65,66,68,71]. Second, a sizable fraction of PDAC cases harbor germline mutations in a number of DNA repair genes, particularly those involved in DSB repair [13,14,15,16,17,18,19,20,21,22,23]. Recent data derived from different in vitro systems and numerous in vivo models, including PDAC models, led to the characterization of various molecular vulnerabilities that are associated with defective HR-mediated DSB repair.…”

Section: Clinical Perspectivementioning

confidence: 99%

“…At present, this field is still in flux and it remains to be seen which tools and technologies will eventually prevail in the molecular diagnostic workup of PDAC patients. Since a number of HR genes are frequently mutated in sporadic and familial PDAC [13,14,15,16,17,18,19,20,21,22,23], PARP inhibitors including olaparib, talazoparib and rucaparib have been evaluated in the context of clinical trials (comprehensively reviewed in [83]). Particularly olaparib was evaluated in the context of a prospective, open-label, non-comparative multicenter phase II trial that enrolled individuals harboring germline BRCA1/2 mutations suffering from recurrent cancer [76].…”

Section: Targeting Defective Dna Repair Pathways In Familial and Spormentioning

confidence: 99%

See 2 more Smart Citations

Targeting Defects in the Cellular DNA Damage Response for the Treatment of Pancreatic Ductal Adenocarcinoma

Schmitt¹,

Feldmann²,

Zander³

et al. 2018

Oncol Res Treat

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Pancreatic cancer is one of the most common causes of cancer-related mortality in the Western world and pancreatic ductal adenocarcinoma (PDAC) is by far the most common pancreatic cancer entity. Locally advanced or metastatic PDAC remains a major clinical challenge, and the prognosis of affected patients is dismal despite substantial research efforts in this area. Recent large-scale genomic analyses of PDAC revealed that KRAS is the most frequently mutated driver gene in this entity. In addition, a relatively large proportion of PDAC patients displays germline variants in genes involved in DNA repair, particularly DNA double-strand repair. Similarly, a sizable fraction of sporadic PDAC cases harbor mutations in genome maintenance genes, such as BRCA1, BRCA2, and ATM. While direct targeting of oncogenic KRAS is currently not possible in the clinical setting, these defects in DNA repair may open new therapeutic avenues. Here, we discuss the potential use of compounds that interfere with DNA repair and genome maintenance mechanisms for the treatment of PDAC. We particularly focus on the genotype-tailored use of compounds, such as PARP inhibitors, as well as ATR- and DNA-protein kinase catalytic subunit (PKcs) inhibitors.

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An Emerging Paradigm for Germline Testing in Pancreatic Ductal Adenocarcinoma and Immediate Implications for Clinical Practice

et al. 2020

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adenocarcinoma (PDAC) is a malignant neoplasm with a rising incidence and is a leading public health challenge. Pancreatic ductal adenocarcinoma has been well characterized genomically, with findings of therapeutic actionability that have substantive implications for clinical practice based on recent high-level evidence.OBSERVATIONS Pathogenic germline alterations (PGAs) are relatively common in individuals with PDAC, as evidenced in multiple recent data sets, with a frequency of approximately 10%. The most common PGAs are in BRCA1, BRCA2, and ATM and more rarely in PALB2, MLH1, MSH2, MSH6, PMS2, CDKN2A, and TP53, among others, with an aggregate frequency of 3.8% to 9.7%. These PGAs are of key interest owing to therapeutic actionability and the downstream identification of at-risk family members and possible hereditary cancer syndromes. Approximately 3% to 7% of individuals with PDAC harbor a BRCA1 or BRCA2 mutation, which are among the most frequently mutated genes in PDAC. Recent updates to the American Society of Clinical Oncology and the National Comprehensive Cancer Network guidelines recommend risk assessment for all individuals with PDAC irrespective of personal or family history or ethnicity. Treatment implications include the use of checkpoint inhibitor therapy for mismatch repair-deficient PDAC and the validation of poly-ADP (adenosine diphosphate)-ribose polymerase inhibitor (PARPi) therapy as a maintenance strategy in platinum-sensitive PDAC. CONCLUSIONS AND RELEVANCEWith increasing evidence and slow improvement of outcomes, PDAC has entered the era of precision medicine. Germline mutations have been identified in key genes with an aggregate frequency of 3.8% to 9.7%, several of which are therapeutically actionable with platinum, PARPi, and checkpoint inhibitor therapy. Potential therapeutic targets need to be actively sought and identified.

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Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer

Abstract: Nearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.

Cited by 172 publications

References 38 publications

ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications

ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications

Targeting Defects in the Cellular DNA Damage Response for the Treatment of Pancreatic Ductal Adenocarcinoma

An Emerging Paradigm for Germline Testing in Pancreatic Ductal Adenocarcinoma and Immediate Implications for Clinical Practice

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