Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer

Roberts, Nicholas J.; Norris, Alexis L.; Petersen, Gloria M.; Bondy, Melissa L.; Brand, Randall E.; Gallinger, Steven; Kurtz, Robert C.; Olson, Sara H.; Rustgi, Anil K.; Schwartz, Ann G.; Stoffel, Elena M.; Syngal, Sapna; Zogopoulos, George; Ali, Syed Z.; Axilbund, Jennifer E.; Chaffee, Kari G.; Chen, Yunching; Coté, Michele L.; Childs, Erica J.; Douville, Christopher; Goes, Fernando S.; Herman, Joseph M.; Iacobuzio‐Donahue, Christine A.; Kramer, Melissa; Makohon-Moore, Alvin; McCombie, Richard W.; McMahon, K. Wyatt; Niknafs, Noushin; Parla, Jennifer; Pirooznia, Mehdi; Potash, James B.; Rhim, Andrew D.; Smith, Alyssa L.; Wang, Yuxuan; Wolfgang, Christopher L.; Wood, Laura D.; Zandi, Peter P.; Goggins, Michael; Karchin, Rachel; Eshleman, James R.; Papadopoulos, Nickolas; Kinzler, Kenneth W.; Vogelstein, Bert; Hruban, Ralph H.; Klein, Alison P.

doi:10.1158/2159-8290.cd-15-0402

Cited by 314 publications

(334 citation statements)

References 46 publications

Supporting

Mentioning

304

Contrasting

Unclassified

Order By: Relevance

“…Importantly, several novel FPC susceptibility genes were identified and are involved in DNA damage repair or chromosomal stability processes. Newly identified mutations in BUB1B, CPA1, FANCC and FANCG may thus predispose these patients to sensitivity for chemotherapeutics targeting the DNA damage repair pathway (22). This study illustrated the challenges in identifying and defining low prevalence PDAC susceptibility mutations and further work to delineate these associations and their therapeutic implications is encouraged.…”

Section: Transcriptomementioning

confidence: 91%

“…They described two sets of gene programs that define either an activated or normal stroma (20). The activated stroma was associated with a worse prognosis and enriched for genes previously associated with poor survival including patients with familial pancreatic cancer (FPC) and reaffirmed known PDAC susceptibility genes such as ATM, BRCA2, CDKN2A and PALB2, but also revealed rare germline variants that likely play a role in the disease (22,23). Importantly, several novel FPC susceptibility genes were identified and are involved in DNA damage repair or chromosomal stability processes.…”

Section: Transcriptomementioning

confidence: 96%

See 1 more Smart Citation

Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development

Dreyer

Chang

Bailey

et al. 2017

Clinical Cancer Research

146

114

View full text Add to dashboard Cite

Pancreatic cancer has become the 3 rd leading cause of cancer death, with little improvement in outcomes despite decades of research. Surgery remains the only chance of cure, yet, only 20% will be alive at 5 years after pancreatic resection. Few chemotherapeutics provide any improvement in outcome, and even then, for approved therapies, the survival benefits are marginal. Genomic sequencing studies of pancreatic cancer have revealed a small set of consistent mutations found in most pancreatic cancers, and beyond that a low prevalence for targetable mutations. This may explain the failure of conventional clinical trial designs to show any meaningful survival benefit, except in small and undefined patient sub-groups. With the development of next generation sequencing technology, genomic sequencing and analysis can be performed in a clinically meaningful turnaround time. This can identify therapeutic targets in individual patients and personalize treatment selection.Incorporating pre-clinical discovery and molecularly guided therapy into clinical trial design has the potential to significantly improve outcomes in this lethal malignancy. In this review, we discuss the findings of recent large scale genomic sequencing projects in pancreatic cancer and the potential relevance of these data to therapeutic development.3

show abstract

Section: Transcriptomementioning

confidence: 91%

Section: Transcriptomementioning

confidence: 96%

Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development

Dreyer

Chang

Bailey

et al. 2017

Clinical Cancer Research

146

114

View full text Add to dashboard Cite

show abstract

“…When 638 patients with familial pancreatic cancer without known germline mutations were subjected to whole genome sequencing, truncating mutations in a wide range of DNA damage repair genes were identified at low frequencies, including ATM, Polymerase (DNA Directed) Nu (POLN), Polymerase (DNA Directed) Theta (POLQ), Fanconi Anemia, Complementation Group C (FANCC), FANCM, et cetera (49).…”

Section: Germline Mutations In Other Members Of Homologous Recombinatmentioning

confidence: 99%

Is it time to split strategies to treat homologous recombinant deficiency in pancreas cancer?

Teo¹,

O'Reilly²

2016

J. Gastrointest. Oncol.

View full text Add to dashboard Cite

Pancreatic cancer is a highly lethal malignancy which tends to present with late stage disease.To date, identification of oncogenic drivers and aberrations has not led to effective targeted therapy.Approximately 5-15% of pancreatic cancer has an inheritable component. In fact, pancreatic adenocarcinoma is now recognized as a BRCA1/2-related cancer. Germline BRCA1/2 mutations can be found in up to 3.6-7% of unselected pancreatic cancer patients although the rates are significantly higher amongst patients with Ashkenazi Jewish ancestry. Germline mutations of other components of DNA repair and homologous recombination have also been identified although at much lower frequency. Large sequencing efforts have further identified somatic mutations in these genes in a small subset of pancreatic cancers. Small series and case reports have suggested that pancreatic cancers harboring BRCA1/2 or other homologous repair gene mutations demonstrate enhanced response to platinum-based chemotherapy although this has not been prospectively validated. Clinical trials with poly (ADP-ribose) polymerase (PARP) inhibitors as monotherapy or in combination with chemotherapy in different clinical settings are currently on-going. A subtype of pancreatic adenocarcinoma as characterized by deficiency in homologous recombination exists although the optimal management strategy remains to be fully elucidated.

show abstract

“…Germline mutations have been described in BRCA2, BRCA1,p16/CDKN2A,PALB2,PRSS1,STK11,TP53, ATM and Lynch syndrome-associated genes (Klein 2012, Salo-Mullen et al 2015, Zhen et al 2015, Hu et al 2016, Roberts et al 2016. However, no germline mutations have been identified in up to 80-85% of cases of familial PDAC.…”

Section: Introductionmentioning

confidence: 99%

Pancreatic ductal adenocarcinoma in BRCA2 mutation carriers

Mestier

Danset

Neuzillet

et al. 2016

Endocrine-Related Cancer

View full text Add to dashboard Cite

Germline BRCA2 mutations are the first known cause of inherited (familial) pancreatic ductal adenocarcinoma (PDAC). This tumor is the third most frequent cancer in carriers of germline BRCA2 mutations, as it occurs in around 10% of BRCA2 families. PDAC is known as one of the most highly lethal cancers, mainly because of its chemoresistance and frequently late diagnosis. Based on recent developments in molecular biology, a subgroup of BRCA2-associated PDAC has been created, allowing screening, early surgical treatment and personalized systemic treatment. BRCA2 germline mutation carriers who have ≥1 first-degree relative, or ≥2 blood relatives with PDAC, should undergo screening and regular follow-up based on magnetic resonance imaging and endoscopic ultrasound. The goal of screening is to detect early invasive PDAC and advanced precancerous lesions suitable for a stepwise surgical complete (R0) resection. Increasing evidence on the molecular role of the BRCA2 protein in the homologous recombination of DNA damages suggest that BRCA2-related PDAC are sensitive to agents causing DNA cross-linking damage, such as platinum salts, and treatments targeting rescue DNA repair pathways, such as poly(ADP-ribose) polymerase inhibitors that are currently under investigation.

show abstract

Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer

Cited by 314 publications

References 46 publications

Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development

Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development

Is it time to split strategies to treat homologous recombinant deficiency in pancreas cancer?

Pancreatic ductal adenocarcinoma in BRCA2 mutation carriers

Contact Info

Product

Resources

About