Pancreatic cancer as a sentinel for hereditary cancer predisposition

Abstract

BackgroundGenes associated with hereditary breast and ovarian cancer (HBOC) and colorectal cancer (CRC) predisposition have been shown to play a role in pancreatic cancer susceptibility. Growing evidence suggests that pancreatic cancer may be useful as a sentinel cancer to identify families that could benefit from HBOC or CRC surveillance, but to date pancreatic cancer is only considered an indication for genetic testing in the context of additional family history.MethodsPreliminary data generated at the Huntsman Cancer Hospital (HCH) included variants identified on a custom 34-gene panel or 59-gene panel including both known HBOC and CRC genes for respective sets of 66 and 147 pancreatic cancer cases, unselected for family history. Given the strength of preliminary data and corresponding literature, 61 sequential pancreatic cancer cases underwent a custom 14-gene clinical panel. Sequencing data from HCH pancreatic cancer cases, pancreatic cancer cases of the Cancer Genome Atlas (TCGA), and an unselected pancreatic cancer screen from the Mayo Clinic were combined in a meta-analysis to estimate the proportion of carriers with pathogenic and high probability of pathogenic variants of uncertain significance (HiP-VUS).ResultsApproximately 8.6% of unselected pancreatic cancer cases at the HCH carried a variant with potential HBOC or CRC screening recommendations. A meta-analysis of unselected pancreatic cancer cases revealed that approximately 11.5% carry a pathogenic variant or HiP-VUS.ConclusionWith the inclusion of both HBOC and CRC susceptibility genes in a panel test, unselected pancreatic cancer cases act as a useful sentinel cancer to identify asymptomatic at-risk relatives who could benefit from relevant HBOC and CRC surveillance measures.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4573-5) contains supplementary material, which is available to authorized users.

Genetic testing for hereditary breast and ovarian cancer and the USPSTF recommendations

“…There are also important implications of the expanded spectrum of BRCA‐associated cancers, which have been recognized over time. While the most common cancers continue to be breast and ovarian cancers, additional cancers have been found to be significantly associated with BRCA gene mutations, specifically prostate and pancreatic cancer, each associated with mutations in several genes, with BRCA2 mutations being the most prevalent . Given this new information, we believe that recommendations for “BRCA‐related Cancer, Genetic Counseling, and Genetic Testing” should consider individuals affected with breast, ovarian, pancreatic, and prostate cancer.…”

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

“…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.…”

“…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. …”

“…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.…”

“…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].…”