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

Published on Jan 1, 2019in Genetics in Medicine8.904
· DOI :10.1038/S41436-018-0009-5
Matthew B. Yurgelun23
Estimated H-index: 23
(Harvard University),
Anu Chittenden10
Estimated H-index: 10
(Harvard University)
+ 35 AuthorsBrian M. Wolpin64
Estimated H-index: 64
(Harvard University)
Sources
Abstract
Germline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses. Using a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression. We found that 28/289 (9.7%; 95% confidence interval [CI] 6.5–13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30–0.99; P = 0.05). Nearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.
📖 Papers frequently viewed together
175 Citations
20185.74Cancer
27 Authors (Randall E. Brand, ..., Nadine Tung)
28 Citations
199 Citations
References38
Newest
#1Alyssa L. SmithH-Index: 7
#2Cavin WongH-Index: 2
Last. George ZogopoulosH-Index: 2
view all 28 authors...
PurposeWe investigated the translational value of reflex testing for germline mutations in four homology-directed DNA repair predisposition genes (BRCA1, BRCA2, PALB2, and ATM) in consecutive patients with pancreatic adenocarcinoma.MethodsOne hundred fifty patients with French-Canadian (FC) ancestry were evaluated for founder mutations, and 114 patients were subsequently assessed by full gene sequencing and multiplex ligation-dependent probe amplification for nonfounder mutations. Two hundred th...
10 CitationsSource
3 CitationsSource
#1Kim A. Reiss (UPenn: University of Pennsylvania)H-Index: 13
#2Shun Yu (UPenn: University of Pennsylvania)H-Index: 5
Last. Susan M. Domchek (UPenn: University of Pennsylvania)H-Index: 90
view all 6 authors...
PurposeGermline mutations in the homologous recombination (HR) genes BRCA1, BRCA2, and PALB2 confer an increased risk for pancreatic ductal adenocarcinoma (PDAC). Tumors associated with mutations in HR genes are sensitive to DNA-damaging agents, such as platinum chemotherapies. We hypothesized that patients with PDAC with germline BRCA1, BRCA2, or PALB2 mutations may benefit preferentially from platinum-based chemotherapy.Materials and MethodsTwenty-nine individuals with deleterious germline mut...
19 CitationsSource
#1Safi ShahdaH-Index: 17
#1Safi ShahdaH-Index: 3
Last. Bert H. O'NeilH-Index: 2
view all 9 authors...
PurposeMutations or copy number abnormalities of genes involved in homologous recombination (HR) occur in pancreatic ductal adenocarcinoma (PDAC). DNA-based measures of HR deficiency (HRD) have been developed and may help identify tumors with better response to DNA-damaging agents. This study aimed to describe the HR pathway mutations and HRD status and determine their association with treatment response and outcome in patients with PDAC.Patients and MethodsWe performed a retrospective analysis ...
9 CitationsSource
#1Zhi Rong Qian (Harvard University)H-Index: 56
#2Douglas A. Rubinson (Harvard University)H-Index: 25
Last. Brian M. Wolpin (Harvard University)H-Index: 64
view all 43 authors...
Importance Although patients with resected pancreatic adenocarcinoma are at high risk for disease recurrence, few biomarkers are available to inform patient outcomes. Objective To evaluate the alterations of the 4 main driver genes in pancreatic adenocarcinoma and patient outcomes after cancer resection. Design, Setting, and Participants This study analyzed protein expression and DNA alterations for the KRAS , CDKN2A , SMAD4 , and TP53 genes by immunohistochemistry and next-generation sequencing...
52 CitationsSource
#1Diana Mandelker (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 20
#2Liying Zhang (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 26
Last. Kenneth Offit (Kettering University)H-Index: 134
view all 51 authors...
Importance Guidelines for cancer genetic testing based on family history may miss clinically actionable genetic changes with established implications for cancer screening or prevention. Objective To determine the proportion and potential clinical implications of inherited variants detected using simultaneous sequencing of the tumor and normal tissue (“tumor-normal sequencing”) compared with genetic test results based on current guidelines. Design, Setting, and Participants From January 2014 unti...
197 CitationsSource
9 CitationsSource
#1Benjamin J. RaphaelH-Index: 54
#2Ralph H. HrubanH-Index: 208
Last. Jean C. ZenklusenH-Index: 34
view all 266 authors...
Summary We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS , TP5 3, CDKN2A , SMAD4 , RNF43 , ARID1A , TGFβR2 , GNAS , RREB1 , and PBRM1 . KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS , BRAF , CTNNB1 , and additional RAS pathway genes. A sub...
731 CitationsSource
#1Koji Shindo (Johns Hopkins University)H-Index: 17
#2Jun Yu (Johns Hopkins University)H-Index: 154
Last. Michael Goggins (Johns Hopkins University)H-Index: 118
view all 22 authors...
PurposeDeleterious germline mutations contribute to pancreatic cancer susceptibility and are well documented in families in which multiple members have had pancreatic cancer.MethodsTo define the prevalence of these germline mutations in patients with apparently sporadic pancreatic cancer, we sequenced 32 genes, including known pancreatic cancer susceptibility genes, in DNA prepared from normal tissue obtained from 854 patients with pancreatic ductal adenocarcinoma, 288 patients with other pancre...
165 CitationsSource
#1Dung T. Le (Johns Hopkins University)H-Index: 53
#2Jennifer N. Durham (Johns Hopkins University)H-Index: 11
Last. Luis A. Diaz (Johns Hopkins University)H-Index: 120
view all 46 authors...
The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor–1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair–deficient cancers across 12 different tumor types. Objective radiogra...
2,633 CitationsSource
Cited By67
Newest
#1Lukas PerkhoferH-Index: 14
#2Talia GolanH-Index: 20
Last. Johann GoutH-Index: 12
view all 0 authors...
Impaired DNA damage repair (DDR) is increasingly recognised as a hallmark in pancreatic ductal adenocarcinoma (PDAC). It is estimated that around 14% of human PDACs harbour mutations in genes involved in DDR, including, amongst others, BRCA1/2, PALB2, ATM, MSH2, MSH6 and MLH1. Recently, DDR intervention by PARP inhibitor therapy has demonstrated effectiveness in germline BRCA1/2-mutated PDAC. Extending this outcome to the significant proportion of human PDACs with somatic or germline mutations i...
Source
#1Fionnuala Crowley (Mount Sinai Hospital)
#2Wungki ParkH-Index: 14
Last. Eileen M. O'Reilly (Cornell University)H-Index: 73
view all 3 authors...
Pancreas ductal adenocarcinoma (PDAC) is the third most common cause of cancer death in the USA. While other cancers with historically poor prognoses have benefited from new immunotherapies and targeted agents, the 5-year survival rate for PDAC patients has remained static. The accessibility to genomic testing has improved in recent years, and it is now clear that PDAC is a heterogenous disease, with a subset of patients harboring actionable mutations. There are several targeted therapies approv...
1 CitationsSource
#2Tanya Dwarte (Garvan Institute of Medical Research)H-Index: 1
Last. Amber L. Johns (Garvan Institute of Medical Research)H-Index: 27
view all 0 authors...
Background null The Australian Pancreatic Cancer Screening Program (APCSP) offers endoscopic ultrasound surveillance for individuals at increased risk of pancreatic ductal adenocarcinoma (PDAC) with all participants requiring assessment by a Familial Cancer Service before or after study enrolment. null Methods null Individuals aged 40-80 years (or 10 years younger than the earliest PDAC diagnosis) were eligible for APCSP study entry if they had 1) ≥ two blood relatives with PDAC (at least one of...
Source
#2Gillian GreshamH-Index: 4
Last. Andrew Eugene HendifarH-Index: 28
view all 8 authors...
Source
#1Eleonora Lai (University of Cagliari)H-Index: 5
#2Pina Ziranu (University of Cagliari)H-Index: 8
Last. Mara Persano (University of Cagliari)H-Index: 4
view all 16 authors...
Despite continued research, pancreatic ductal adenocarcinoma (PDAC) remains one of the main causes of cancer death. Interest is growing in the role of the tumour suppressors breast cancer 1 (BRCA1) and BRCA2-typically associated with breast and ovarian cancer-in the pathogenesis of PDAC. Indeed, both germline and sporadic mutations in BRCA1/2 have been found to play a role in the development of PDAC. However, data regarding BRCA1/2-mutant PDAC are lacking. In this review, we aim to outline the s...
Source
#1Esteban Astiazaran-Symonds (NIH: National Institutes of Health)H-Index: 1
#2Alisa M. Goldstein (NIH: National Institutes of Health)H-Index: 86
The genetics of pancreatic ductal adenocarcinoma (PDAC) is complex with patients reported to harbor germline pathogenic variants (PVs) in many different genes. PDAC patients with familial pancreatic cancer (FPC) are more likely to carry germline PVs but there is no consensus main gene involved in FPC. We performed a systematic review of publications from PubMed and Scopus reporting PVs in patients with FPC, sporadic pancreatic cancer (SPC) and unselected cohorts of PDAC patients undergoing genet...
Source
#1Lin Shui (Sichuan University)H-Index: 2
#2Xiaofen Li (Sichuan University)H-Index: 1
Last. Heli Gao (Fudan University)
view all 13 authors...
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with molecular heterogeneity, inducing differences in biological behavior, and therapeutic strategy. NGS profiles of pathogenic alterations in the Chinese PDAC population are limited. We conducted a retrospective study to investigate the predictive role of DNA damage repair (DDR) mutations in precision medicine. METHODS The NGS profiles were performed on resected tissues from 195 Chinese PDAC patients. Baseline clinical or gen...
Source
#1Raffaella Casolino (Glas.: University of Glasgow)H-Index: 2
#2Salvatore PaiellaH-Index: 23
Last. Fieke E.M. Froeling (Glas.: University of Glasgow)H-Index: 15
view all 18 authors...
PURPOSETo analyze the prevalence of homologous recombination deficiency (HRD) in patients with pancreatic ductal adenocarcinoma (PDAC).MATERIALS AND METHODSWe conducted a systematic review and meta...
Source
#1Akhil ChawlaH-Index: 4
#2Andrew J. AguirreH-Index: 26
Source
#1Annie WangH-Index: 1
#2Jessica EverettH-Index: 16
Last. Freya SchnabelH-Index: 27
view all 6 authors...
Changing practice guidelines and recommendations have important implications for cancer survivors. This study investigated genetic testing patterns and outcomes and reported family history of pancreatic cancer (FHPC) in a large registry population of breast cancer (BC) patients. Variables including clinical and demographic characteristics, FHPC in a first or second-degree relative, and genetic testing outcomes were analyzed for BC patients diagnosed between 2010 and 2018 in the NYU Langone Healt...
Source