Germline Variants in DNA Damage Repair Genes: An Emerging Role in the Era of Precision Medicine in Pancreatic Adenocarcinoma

Abstract

Pancreatic adenocarcinoma is a lethal disease that is projected to become the second most common cause of cancer deaths by 2030. The role of adjuvant therapy after surgical resection has been established by several clinical trials to prolong survival and improve outcomes. Multiagent chemotherapy seems to be the most promising approach to counteract early recurrence and improve survival; however, in the era of precision medicine, patient selection and individualized therapy seems to hold the key to desirable superior outcomes. Several cancer susceptibility genes have been proven to be associated with an increased risk of pancreatic cancer, both familial and sporadic cases. The role of genomic profiling for germline variants has been extensive and of limited clinical value, considering their low prevalence in pancreatic ductal adenocarcinoma (PDAC). However, an accumulating body of evidence from several studies in the past decade have successfully shown a recognizable value of germline variants in risk assessment and patient stratification. Recently, anti‐PD‐1 therapy (pembrolizumab) has been FDA‐approved for use in solid malignancies with a Mismatch repair deficiency or high Microsatellite instability. Several trials have evaluated the role of poly (ADP‐ribose) polymerase (PARP) inhibitors in patients harboring germline BRCA1/2 mutations. Finally, germline variants in DNA damage response genes and particularly deleterious ones have the potential to guide therapy after surgical resection and serve as biomarkers to predict survival. The dire need to address challenges for applying precision medicine in real‐life clinical settings for PDAC patients lies in further characterizing the genetic and molecular processes through translational research.

Association between a single nucleotide polymorphism in the R3HCC1 gene and irinotecan toxicity

“…WES is a high-throughput technology that allows the sequencing of almost all protein-coding genes of the human genome. 43,44 Our results showed that an SNP in R3HCC1 (c.919G > A, rs2272761) was useful as a biomarker of hematotoxicity, such as severe neutropenia, in patients who received irinotecan-containing doublet chemotherapy (i.e., FOLFIRI) for mCRC. R3HCC1 may be a useful biomarker for irinotecan-related toxicity in addition to UGT1A polymorphisms (Table 4).…”

Targeted therapy for pancreatic ductal adenocarcinoma: Mechanisms and clinical study

“…PARPi prevents repair of SSB by trapping PARP enzymes on DNA, creating a stall in the replication fork and converting the SSB into a DSB. 282 , 289 While normal cells without HDR mutations are able to repair the induced DSB via HDR, HDR‐deficient cells are unable to repair the DSB in an error‐free way, leading to accumulation of DNA errors and eventual tumor cell death. 291 Several different PARPi (Olaparib, Velaparib, and Rucaparib) have been developed and tested over the past few years with promising results.…”

“…These genes encode for key proteins in homology‐directed repair (HDR), which is an error‐free repair system for DNA double strand breaks (DSB) 280,281 . When loss of function mutations occur in one or more of these genes, HDR is impaired, and cells become more reliant on nonhomologous end joining and other DSB repair systems, which are more error prone 282 . Previous studies have reported that HDR‐mutated ovarian and breast cancers are more susceptible to drugs that induce DSB, such as platinum‐based chemotherapy 283–285 .…”

“…PARP enzymes play a role in repairing DNA single strand breaks (SSB) through base excision repair. PARPi prevents repair of SSB by trapping PARP enzymes on DNA, creating a stall in the replication fork and converting the SSB into a DSB 282,289 . While normal cells without HDR mutations are able to repair the induced DSB via HDR, HDR‐deficient cells are unable to repair the DSB in an error‐free way, leading to accumulation of DNA errors and eventual tumor cell death 291 .…”

“…280,281 When loss of function mutations occur in one or more of these genes, HDR is impaired, and cells become more reliant on nonhomologous end joining and other DSB repair systems, which are more error prone. 282 Previous studies have reported that HDR-mutated ovarian and breast cancers are more susceptible to drugs that induce DSB, such as platinumbased chemotherapy. [283][284][285] In 2018, Blair et al 286 reported that within a group of BRCA1/2-mutated PDAC patients, platinum-based adjuvant chemotherapy was associated with better outcomes compared with nonplatinum-based adjuvant chemotherapy and no adjuvant chemotherapy (31.0 vs. 17.8 vs. 9.3 mo, p < 0.001).…”