Abstract
Complex rearrangement patterns and mitotic errors are hallmarks of most pancreatic
ductal adenocarcinomas (PDAC), a disease with dismal prognosis despite some therapeutic
advances in recent years. DNA double-strand breaks (DSB) bear the greatest risk of
provoking genomic instability, and DNA damage repair (DDR) pathways are crucial in
preserving genomic integrity following a plethora of damage types. Two major repair
pathways dominate DSB repair for safeguarding the genome integrity: non-homologous end
joining and homologous recombination (HR). Defective HR, but also alterations in other
DDR pathways, such as BRCA1,
BRCA2, ATM and
PALB2, occur frequently in both inherited and sporadic
PDAC. Personalised treatment of pancreatic cancer is still in its infancy and predictive
biomarkers are lacking. DDR deficiency might render a PDAC vulnerable to a potential new
therapeutic intervention that increases the DNA damage load beyond a tolerable
threshold, as for example, induced by poly (ADP-ribose) polymerase inhibitors. The
Pancreas Cancer Olaparib Ongoing (POLO) trial, in which olaparib as a maintenance
treatment improved progression-free survival compared with placebo after platinum-based
induction chemotherapy in patients with PDAC and germline
BRCA1/2 mutations, raised great hopes of a substantially
improved outcome for this patient subgroup. This review summarises the relationship
between DDR and PDAC, the prevalence and characteristics of DNA repair mutations and
options for the clinical management of patients with PDAC and DNA repair
deficiency.
Funder
Deutsche
Forschungsgemeinschaft
Else
Kröner-Fresenius-Stiftung
Agence Nationale de la
Recherche
Baden-Württemberg Stiftung
Boehringer Ingelheim Fonds
Universität Ulm
NDIMED-Verbund
PancChip
Deutsche Krebshilfe
Cited by
123 articles.
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