scholarly journals PancPRO: Risk Assessment for Individuals With a Family History of Pancreatic Cancer

2007 ◽  
Vol 25 (11) ◽  
pp. 1417-1422 ◽  
Author(s):  
Wenyi Wang ◽  
Sining Chen ◽  
Kieran A. Brune ◽  
Ralph H. Hruban ◽  
Giovanni Parmigiani ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Pancreatic Cancer ◽  
Family History ◽  
High Risk ◽  
Cancer Risk ◽  
Risk Prediction ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Familial Pancreatic Cancer ◽  
Cancer Susceptibility Gene

Purpose The rapid fatality of pancreatic cancer is, in large part, the result of an advanced stage of diagnosis for the majority of patients. Identification of individuals at high risk of developing pancreatic cancer is a first step towards the early detection of this disease. Individuals who may harbor a major pancreatic cancer susceptibility gene are one such high-risk group. The goal of this study was to develop and validate PancPRO, a Mendelian model for pancreatic cancer risk prediction in individuals with familial pancreatic cancer, to identify high-risk individuals. Methods PancPRO was built by extending the Bayesian modeling framework developed for BRCAPRO, trained using published data, and validated using independent prospective data on 961 families enrolled onto the National Familial Pancreas Tumor Registry, including 26 individuals who developed incident pancreatic cancer during follow-up. Results We developed a risk prediction model, PancPRO, and free software for the estimation of pancreatic cancer susceptibility gene carrier probabilities and absolute pancreatic cancer risk. Model validation demonstrated an observed to predicted pancreatic cancer ratio of 0.83 (95% CI, 0.52 to 1.20) and high discriminatory ability, with an area under the receiver operating characteristic curve of 0.75 (95% CI, 0.68 to 0.81) for PancPRO. Conclusion PancPRO is the first risk prediction model for pancreatic cancer. When we validated our model using the largest registry of familial pancreatic cancer, our model provided accurate risk assessment. Our findings highlight the importance of detailed family history for clinical cancer risk assessment and demonstrate that accurate genetic risk assessment is possible even when the causative genes are not known.

scholarly journals Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance

2019 ◽  
Vol 37 (13) ◽  
pp. 1070-1080 ◽  
Author(s):  
Toshiya Abe ◽  
Amanda L. Blackford ◽  
Koji Tamura ◽  
Madeline Ford ◽  
Patrick McCormick ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Family History ◽  
Germline Mutation ◽  
Cancer Susceptibility ◽  
Risk Group ◽  
Susceptibility Gene ◽  
Familial Risk ◽  
Germline Mutations ◽  
Neoplastic Progression ◽  
Cancer Susceptibility Gene

PURPOSE To compare the risk of neoplastic progression by germline mutation status versus family history without a known germline mutation (familial risk) among individuals with an increased risk for pancreatic cancer who are undergoing surveillance. METHODS Of 464 high-risk individuals in the Cancer of the Pancreas Screening program at Johns Hopkins Hospital who were undergoing pancreatic surveillance, 119 had a known deleterious germline mutation in a pancreatic cancer susceptibility gene; 345 met family history criteria for pancreatic surveillance but were not known to harbor a germline mutation. We used next-generation sequencing to identify previously unrecognized germline mutations among these 345 individuals. We compared the development of pancreatic cancer, high-grade dysplasia, or clinically worrisome features, adjusting for competing mortality, among all germline mutation carriers with the risk of progression in a cohort without a known germline mutation. RESULTS Fifteen (4.3%) of 345 individuals classified as having familial risk had a previously unrecognized pancreatic cancer susceptibility gene mutation (nine that involved ATM, two BRCA2, one BRCA1, one PALB2, one TP53, and one CPA1). The cumulative incidence of pancreatic cancer, high-grade dysplasia, or worrisome features on pancreatic imaging was significantly higher in the germline mutation risk group (n = 134) than in the familial risk group (n = 330 [for pancreatic cancer, hazard ratio, 2.85; 95% CI, 1.0 to 8.18; P = .05]). CONCLUSION The cumulative incidence of pancreatic cancer is significantly higher among individuals with an identifiable deleterious germline mutation in a pancreatic cancer susceptibility gene than it is among individuals with a strong family history but no identified mutation. Gene testing of individuals who meet criteria for pancreatic surveillance on the basis of their family history may better define those most at risk for neoplastic progression.

Abstract 2628: Genome-wide sequencing identifiesATMas a pancreatic cancer susceptibility gene

2012 ◽  
Author(s):  
Nicholas J. Roberts ◽  
Yuchen Jiao ◽  
Jun Yu ◽  
Levy Kopelovich ◽  
Gloria M. Petersen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Genome Wide ◽  
Cancer Susceptibility Gene

S1996 Attitudes Toward Genetic Testing for Pancreatic Cancer Risk Assessment in High-Risk Families

2010 ◽  
Vol 138 (5) ◽  
pp. S-297
Author(s):  
Caroline Hwang ◽  
Elana B. Mitchel ◽  
Reem Z. Sharaiha ◽  
Wendy Chung ◽  
Harold Frucht
Keyword(s):  
Risk Assessment ◽  
Pancreatic Cancer ◽  
Genetic Testing ◽  
High Risk ◽  
Cancer Risk ◽  
Cancer Risk Assessment ◽  
Pancreatic Cancer Risk ◽  
High Risk Families

scholarly journals Long-term yield of pancreatic cancer surveillance in high-risk individuals

Gut ◽  
2021 ◽  
pp. gutjnl-2020-323611
Author(s):  
Kasper A Overbeek ◽  
Iris J M Levink ◽  
Brechtje D M Koopmann ◽  
Femme Harinck ◽  
Ingrid C A W Konings ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
High Risk ◽  
Diagnostic Yield ◽  
Susceptibility Gene ◽  
Cancer Surveillance ◽  
Ductal Adenocarcinoma ◽  
Familial Pancreatic Cancer ◽  
Low Grade ◽  
Mutation Carriers

ObjectiveWe aimed to determine the long-term yield of pancreatic cancer surveillance in hereditary predisposed high-risk individuals.DesignFrom 2006 to 2019, we prospectively enrolled asymptomatic individuals with an estimated 10% or greater lifetime risk of pancreatic ductal adenocarcinoma (PDAC) after obligatory evaluation by a clinical geneticist and genetic testing, and subjected them to annual surveillance with both endoscopic ultrasonography (EUS) and MRI/cholangiopancreatography (MRI/MRCP) at each visit.Results366 individuals (201 mutation-negative familial pancreatic cancer (FPC) kindreds and 165 PDAC susceptibility gene mutation carriers; mean age 54 years, SD 9.9) were followed for 63 months on average (SD 43.2). Ten individuals developed PDAC, of which four presented with a symptomatic interval carcinoma and six underwent resection. The cumulative PDAC incidence was 9.3% in the mutation carriers and 0% in the FPC kindreds (p<0.001). Median PDAC survival was 18 months (range 1–32). Surgery was performed in 17 individuals (4.6%), whose pathology revealed 6 PDACs (3 T1N0M0), 7 low-grade precursor lesions, 2 neuroendocrine tumours <2 cm, 1 autoimmune pancreatitis and in 1 individual no abnormality. There was no surgery-related mortality. EUS detected more solid lesions than MRI/MRCP (100% vs 22%, p<0.001), but less cystic lesions (42% vs 83%, p<0.001).ConclusionThe diagnostic yield of PDAC was substantial in established high-risk mutation carriers, but non-existent in the mutation-negative proven FPC kindreds. Nevertheless, timely identification of resectable lesions proved challenging despite the concurrent use of two imaging modalities, with EUS outperforming MRI/MRCP. Overall, surveillance by imaging yields suboptimal results with a clear need for more sensitive diagnostic markers, including biomarkers.

scholarly journals Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer

2017 ◽  
Vol 35 (10) ◽  
pp. 1086-1095 ◽  
Author(s):  
Matthew B. Yurgelun ◽  
Matthew H. Kulke ◽  
Charles S. Fuchs ◽  
Brian A. Allen ◽  
Hajime Uno ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Family History ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Gene Mutations ◽  
Age At Diagnosis ◽  
Pathogenic Mutations ◽  
High Penetrance ◽  
History Of ◽  
Cancer Susceptibility Gene

Purpose Hereditary factors play an important role in colorectal cancer (CRC) risk, yet the prevalence of germline cancer susceptibility gene mutations in patients with CRC unselected for high-risk features (eg, early age at diagnosis, personal/family history of cancer or polyps, tumor microsatellite instability [MSI], mismatch repair [MMR] deficiency) is unknown. Patients and Methods We recruited 1,058 participants who received CRC care in a clinic-based setting without preselection for age at diagnosis, personal/family history, or MSI/MMR results. All participants underwent germline testing for mutations in 25 genes associated with inherited cancer risk. Each gene was categorized as high penetrance or moderate penetrance on the basis of published estimates of the lifetime cancer risks conferred by pathogenic germline mutations in that gene. Results One hundred five (9.9%; 95% CI, 8.2% to 11.9%) of 1,058 participants carried one or more pathogenic mutations, including 33 (3.1%) with Lynch syndrome (LS). Twenty-eight (96.6%) of 29 available LS CRCs demonstrated abnormal MSI/MMR results. Seventy-four (7.0%) of 1,058 participants carried non-LS gene mutations, including 23 (2.2%) with mutations in high-penetrance genes (five APC, three biallelic MUTYH, 11 BRCA1/2, two PALB2, one CDKN2A, and one TP53), 15 of whom lacked clinical histories suggestive of their underlying mutation. Thirty-eight (3.6%) participants had moderate-penetrance CRC risk gene mutations (19 monoallelic MUTYH, 17 APC*I1307K, two CHEK2). Neither proband age at CRC diagnosis, family history of CRC, nor personal history of other cancers significantly predicted the presence of pathogenic mutations in non-LS genes. Conclusion Germline cancer susceptibility gene mutations are carried by 9.9% of patients with CRC. MSI/MMR testing reliably identifies LS probands, although 7.0% of patients with CRC carry non-LS mutations, including 1.0% with BRCA1/2 mutations.

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