Germline genetic testing in unselected pancreatic ductal adenocarcinoma (PDAC) patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1501-1501 ◽  
Author(s):  
Mary Linton Bounetheau Peters ◽  
Randall Brand ◽  
Erkut Hasan Borazanci ◽  
Lindsey Stobie ◽  
Beth Dudley ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Germline Mutations ◽  
Ductal Adenocarcinoma ◽  
Familial Pancreatic Cancer ◽  
Cancer Risks ◽  
Mutation Status ◽  
Mutation Carriers ◽  
History Of ◽  
Brca1 Brca2 ◽  
Current Guidelines

1501 Background: The aim of this study is to assess the prevalence of known heritable germline mutations in unselected PDAC patients and to determine how well current guidelines for genetic testing identify mutation carriers. Methods: Consecutive, unselected patients with recently diagnosed PDAC from three centers were enrolled from May to December 2016 in an ongoing prospective study. A three-generation pedigree was obtained. Germline mutations in 12 genes associated with PDAC risk ( APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, PALB2, PMS2, STK11, TP53) and in 19 genes related to other cancer risks were screened for by NGS. American College of Gastroenterology and NCCN criteria for genetic testing for BRCA1/2, Lynch syndrome, and Familial Pancreatic Cancer (FPC) were assessed. Results: Among 183 patients, 46% are female, 79% are Caucasian and 10% are Ashkenazi Jewish, with median (IQR) age 68 (62,75) years at diagnosis. 41% of patients met ³1 criteria for genetic testing (35.5% BRCA1/2, 2.7% Lynch, 9.3% FPC). Twenty patients (11%) were found to have a total of 21 pathogenic mutations (table). Mutation status was not associated with age at diagnosis, sex, or personal history of cancer (all p > 0.05). Six mutation carriers (30% of positives) did not meet current criteria for genetic testing. Conclusions: Preliminary results show that 6.6% of unselected PDAC patients carry a germline mutation in a gene known to increase PDAC risk and 4.3% have a mutation in genes not previously linked to PDAC. Existing testing criteria did not identify 30% of carriers. Continued refinement of guidelines is necessary to align genetic testing with inherited PDAC risk. Clinical trial information: NCT02790944. [Table: see text]

scholarly journals Novel and Recurrent BRCA1/BRCA2 Germline Mutations in Patients with Breast /Ovarian Cancer: A Series from the South of Tunisia

2020 ◽  
Author(s):  
Dorra Ben Ayed-Guerfali ◽  
Wala Ben Kridis-Rejab ◽  
Nihel Ammous-Boukhris ◽  
Wajdi Ayadi ◽  
Slim Charfi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
High Risk ◽  
Germline Mutations ◽  
Brca Mutations ◽  
Mutation Carriers ◽  
Counseling And Testing ◽  
Recurrent Mutations ◽  
Tunisian Patients ◽  
History Of ◽  
Brca1 Brca2

Abstract Background: The incidence of breast/ovarian cancer is increasing in Tunisia especially in young women and mostly those with family history. However, the spectrum of BRCA mutations remains little explored in Tunisian patients in particular in the southern region. Methods: We sequenced the entire coding regions of BRCA1and BRCA2 genes using Next Generation Sequencing (NGS) in 134 selected patients with breast/ovarian cancer. Results: Among the 134 patients, 19 (14.17%) carried pathogenic mutations (10 are BRCA1 mutation carriers and 9 are BRCA2 mutation carriers) that are mainly frameshisft indel (76.9%). Interestingly, 5 out of the 13 variants (38.46%) were found at least twice in unrelated patients, as the c.1310-1313 delAAGA in BRCA2 and the c.5030_5033 delCTAA that has been identified in 4/98 BC patients and in 3/15 OC patients from unrelated families with strong history of cancer. Besides recurrent mutations, 6 variant (4 in BRCA1 and 2 in BRCA2) were not reported previously. Furthermore, 3 unrelated patients carried the VUS c.9976A>T, (K3326*) in BRCA2 exon 27. BRCA carriers correlated significantly with tumor site (p=0.029) and TNBC cases (p=0.008). In the groups of patients (31-40 y and 41-50 y), BRCA1 mutations occurred more frequently in patients with OC than those with BC, and conversely BRCA2 carriers are mostly affected with BC (p=0.001 and p=0.044 respectively).Conclusions: The overall frequency of the BRCA germline mutations was 14.17% in patients with high risk of breast /ovarian cancer. We identified recurrent mutations as the c.1310_1313 delAAGA in BRCA2 gene and the c.5030_5033 delCTAA in BRCA1 gene that were found in 4% and 20% of familial BC and OC respectively. Our data will contribute in the implementation of genetic counseling and testing for families with high-risk of breast/ovarian cancer.

scholarly journals Novel and recurrent BRCA1/BRCA2 germline mutations in patients with breast/ovarian cancer: a series from the south of Tunisia

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Dorra Ben Ayed-Guerfali ◽  
Wala Ben Kridis-Rejab ◽  
Nihel Ammous-Boukhris ◽  
Wajdi Ayadi ◽  
Slim Charfi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
High Risk ◽  
Germline Mutations ◽  
Mutation Carriers ◽  
Counseling And Testing ◽  
Recurrent Mutations ◽  
Tunisian Patients ◽  
History Of ◽  
Brca1 Brca2 ◽  
Next Generation Sequencing Ngs

AbstractBackgroundThe incidence of breast cancer (BC) and/or ovarian cancer (OC) is increasing in Tunisia especially in young women and mostly those with family history. However, the spectrum ofBRCAmutations remains little explored in Tunisian patients in particular in the southern region.MethodsWe sequenced the entire coding regions ofBRCA1andBRCA2genes using next generation sequencing (NGS) in 134 selected patients with BC and/or OC.ResultsAmong the 134 patients, 19 (14.17%) carried pathogenic mutations (10 areBRCA1mutation carriers and 9 areBRCA2mutation carriers) that are mainly frameshift index (76.9%). Interestingly, 5 out of the 13 variants (38.46%) were found at least twice in unrelated patients, as the c.1310-1313 delAAGA inBRCA2and the c.5030_5033 delCTAA that has been identified in 4/98 BC patients and in 3/15 OC patients from unrelated families with strong history of cancer. Besides recurrent mutations, 6 variant (4 inBRCA1and 2 inBRCA2) were not reported previously. Furthermore, 3 unrelated patients carried the VUS c.9976A > T, (K3326*) inBRCA2exon 27.BRCAcarriers correlated significantly with tumor site (p = 0.029) and TNBC cases (p = 0.008). In the groups of patients aged between 31 and 40, and 41–50 years,BRCA1mutations occurred more frequently in patients with OC than those with BC, and converselyBRCA2carriers are mostly affected with BC (p = 0.001, and p = 0.044 respectively).ConclusionsThe overall frequency of the BRCA germline mutations was 14.17% in patients with high risk of breast/ovarian cancer. We identified recurrent mutations as the c.1310_1313 delAAGA inBRCA2gene and the c.5030_5033 delCTAA inBRCA1gene that were found in 4% and 20% of familial BC and OC respectively. Our data will contribute in the implementation of genetic counseling and testing for families with high-risk of BC and/or OC.

scholarly journals Risk-adapted approach to prostate cancer screening

2018 ◽  
Vol 14 (2) ◽  
pp. 109-121 ◽  
Author(s):  
A. A. Kirichek ◽  
L. N. Lyubchenko ◽  
V. B. Matveev
Keyword(s):  
Prostate Cancer ◽  
Early Detection ◽  
Germline Mutation ◽  
Prostate Cancer Screening ◽  
Germline Mutations ◽  
Polygenic Inheritance ◽  
Psa Screening ◽  
Psa Testing ◽  
Mutation Carriers ◽  
Brca1 Brca2

Mass prostatic specific antigen (PSA) testing (population-based PSA screening) has remained controversial, nevertheless there are men cohorts likely to benefit from PSA screening. Heritable factors contribute to 60 % risk for developing familial prostate cancer. Despite the fact that its clinical application is challenging due to polygenic inheritance, advances in new generation sequencing technologies permit identifying highly penetrant germline mutations in genes BRCA1, BRCA2, CHEK2, HOXB13 and MMR associated with tremendous increase in risk of developing the prostate cancer. Several germline mutations are associated with clinically aggressiveness of disease and shortened survival. Targeted screening that is based on family history and genomic aberrations should be the next step towards the precision medicine. Men at elevated risk should been performed for early detection are those with familiar history of prostate cancer, or BRCA1, BRCA2, CHEK2, HOXB13 and MMR pathogenic germline mutation carriers, or first line relatives diagnosed with certain types of cancer. Systematic PSA testing in 1–2 years among germline mutation carriers men beginning at age 45 years would contribute to increase in early detection of localized prostate cancer resulting in more chance of curative treatment and improve survival rates

Retrospective Survival Analysis of Patients With Resected Pancreatic Ductal Adenocarcinoma and a Germline BRCA or PALB2 Mutation

2019 ◽  
pp. 1-11 ◽  
Author(s):  
Shun Yu ◽  
Parul Agarwal ◽  
Ronac Mamtani ◽  
Heather Symecko ◽  
Kelsey Spielman ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Germline Mutation ◽  
Germline Mutations ◽  
Ductal Adenocarcinoma ◽  
Negative Group ◽  
Positive Group ◽  
Platinum Based Chemotherapy ◽  
Palb2 Mutation ◽  
Brca1 Brca2

PURPOSE Germline mutations in the homologous recombination genes BRCA1, BRCA2, and PALB2 confer an increased risk for pancreatic ductal adenocarcinoma (PDAC). Tumors associated with mutations in homologous recombination genes are sensitive to DNA-damaging agents. We retrospectively studied patients with resected PDAC and a pathogenic germline mutation in one of these three genes. The planned analyses included overall survival (OS) and changes therein when platinum chemotherapy was used in the perioperative setting. MATERIALS AND METHODS Thirty-two individuals with pathogenic germline mutations in BRCA1, BRCA2, or PALB2 and resected PDAC (mutation positive) were matched in a 1:2 fashion to patients who were noncarriers or untested (mutation negative) by age, year of diagnosis, stage, and sex. Patients were identified via one of two available databases at University of Pennsylvania: the Basser Center for BRCA Registry or the electronic medical record. The primary outcome was OS. RESULTS Patients in the mutation-positive group had a median OS (mOS) of 46.6 months; those in the mutation-negative group had an mOS of 23.2 months (hazard ratio [HR], 0.49; 95% CI, 0.27 to 0.88). With platinum exposure in the perioperative setting, mOS in the mutation-positive group had not yet been met versus a mOS of 23.1 months in the mutation-negative group (HR, 0.12; 95% CI, 0.01 to 1.00). When neither group was treated with platinum, there was no significant OS difference between groups (HR, 0.52; 95% CI 0.12 to 2.24). Patients in the mutation-positive group who received perioperative treatment with platinum had a trend toward improved mOS compared with those who did not (HR, 0.15; 95% CI, 0.02 to 1.23; P = .07). CONCLUSION Platinum-based chemotherapy may confer a survival benefit in patients with resected PDAC and a pathogenic germline BRCA1, BRCA2, or PALB2 mutation. Knowledge of a germline mutation may be important to determine best choice of perioperative chemotherapy.

Chemosensitivity and clinical characteristics of pancreatic malignancies in BRCA mutation carriers.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 278-278 ◽  
Author(s):  
Talia Golan ◽  
Zaheer Kanji ◽  
Ron Epelbaum ◽  
Nicholas Devaud ◽  
Efrat Dagan ◽  
...  
Keyword(s):  
Brca Mutation ◽  
Parametric Models ◽  
Ductal Adenocarcinoma ◽  
Parp Inhibition ◽  
Brca Mutations ◽  
Clinical Databases ◽  
Mutation Carriers ◽  
Platinum Based Chemotherapy ◽  
History Of

278 Background: Somatic inactivation of genes involved in homologous recombination (HR) may confer increased sensitivity to poly (ADP-ribose)- polymerase (PARP) inhibition and DNA cross-linking agents (eg. mitomycin C, platinum-based chemotherapy). Studies in BRCA associated ovarian cancer have demonstrated favorable outcomes with platinum based treatments. The role of BRCA mutations in pancreatic cancer outcome is understudied. In this study, the clinical features and therapeutic responses of BRCA 1/2 mutation carriers with pancreatic malignancies are reported. Methods: Patients with BRCA1/2 -associated pancreatic ductal adenocarcinoma (PDAC) diagnosed between January 1994-June 2012 were identified from clinical databases at three participating institutions. Demographic, clinical, and therapeutic response data were collected and analyzed using non-parametric models. Progression-free (PFS) and overall survival (OS) were analyzed. Results: Overall, 63 patients with PDAC and a BRCA1 (n=17), BRCA2 (n=43) or both (n=1) mutations were included. Mean age at diagnosis was 60.2 (range 33-83), 37 (58.7%) were male, 48 (76.2%) were Jewish, 26 (41.3%) were smokers, 55 (87.3%) had a family history of malignancy of which 18 (32.7%) had a history of PDAC. Twenty-five (39.7%) patients underwent a primary resection, and 30 (47.6%) had stage IV disease at presentation. PFS on platinum-based first-line chemotherapy in 12 metastatic BRCA positive cases (median: 90 days) was not statistically different than that of non-platinum chemotherapy treated carriers (n=18, median: 92 days) (p= 0.6412). Two patients with advanced disease were down-staged from unresectable to resectable using combination gemcitabine/cisplatin therapy. One of these is disease free at 50 months after surgery. Median OS for all 51 patients (excluding patients receiving experimental treatments) was 14.02 months (9.48-18.2). Conclusions: The natural history of BRCA associated PDAC appears similar to non-carriers. The role of platinum agents in these individuals remains unclear as data are not mature, however, to date, no difference in median PFS was observed. Surgical downstaging may be possible in a subset of these patients.

Germline mutations in Brazilian pancreatic carcinoma patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16749-e16749
Author(s):  
Livia Munhoz Rodrigues ◽  
Simone Maistro ◽  
Maria Lucia Hirata Katayama ◽  
Luiz A.Senna Leite ◽  
Joao Glasberg ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Genetic Testing ◽  
Family History ◽  
Pancreatic Carcinoma ◽  
Germline Mutations ◽  
Family History Of Cancer ◽  
First Degree Relatives ◽  
Pathogenic Variants ◽  
History Of ◽  
History Of Cancer

e16749 Background: Pancreatic cancer has the prospect of becoming the second leading cause of cancer death by 2030. The NCCN Guidelines recommend genetic testing for all patients with pancreatic cancer, however, the spectrum of germline mutations has not been extensively evaluated because recent studies with genetic testing have explored only a limited number of genes and have focused predominantly on Caucasian populations. Therefore, our objective is to evaluate the frequency and spectrum of germline mutations in unselected patients with pancreatic cancer in a multiethnic population. Methods: Patients from Instituto do Câncer do Estado de São Paulo (Brazil) with histopathological diagnosis of non-endocrine pancreatic carcinoma were included, regardless of the family history of cancer. These patients answered a life habits and family history of cancer questionnaire and supplied blood for the Next Generation Sequencing (MiSeq platform) with the TruSight Hereditary Cancer panel (Illumina), which includes 115 cancer predisposing genes. Variant analysis was performed with the VarStation, a Brazilian tool that offers post-sequencing computational support and aid for clinical interpretation. Results: To the present moment, 77 patients were evaluated. The mean age of the patients was 62 years (27-83), among whom, 13% with young age (≤50 years) and 47 women (61%). Thirty-eight patients (49%) reported cases of cancer in first-degree relatives. Regarding risk factors, 41 patients (53%) reported smoking, 19 (25%) alcohol ingestion and 20 (26%) had obesity. Seven out of 77 patients presented pathogenic variants in ATM (n = 2) , CHEK2, FANCM (n = 2) or PALB2 (n = 2) genes. Two of these patients ( CHEK2 and FANCM) had early onset pancreatic cancer (≤45 years), both denied smoking habit and family history of cancer in 1st degree relatives. Two patients, who were ATM mutation carriers, reported 1st or 2nd degree relatives with cancer and are alive after 4 and 8 years of diagnosis. Conclusions: In this unselected group of pancreatic cancer patients, 15% were young, almost half reported first-degree relatives with cancer and 9% were carriers of pathogenic variants in genes related with the homologous recombination DNA repair.

2423Familial cardiomyopathy in patients affected by acute myocarditis is strongly associated to DSP gene mutations

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
L Marteau ◽  
F Kyndt ◽  
C Toquet ◽  
J M Serfaty ◽  
D Guijarro ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Acute Myocarditis ◽  
Gene Mutations ◽  
Myocardial Inflammation ◽  
Ventricular Cardiomyopathy ◽  
Familial History ◽  
Mutation Carriers ◽  
Familial Cardiomyopathy ◽  
History Of ◽  
Familial Screening

Abstract Background The link between acute myocarditis (AM) and familial cardiomyopathy remains unclear. Purpose To assess the clinical significance of AM in families with cardiomyopathy. Methods and results We describe the pedigree of 6 families with at least one familial case of AM and a familial history of cardiomyopathy or sudden death (SD). AM was defined as an infarct-like clinical presentation with normal coronary arteries and myocardial inflammation (MI) documented by cardiac magnetic resonance (CMR), or as an autopsy proven AM. Detailed familial pedigrees are shown in the picture. In family 1 to 5, genetic testing was triggered by the association of a documented case of AM with an index case of cardiomyopathy or early SD. In this setting, all genetic testing revealed a mutation in the desmoplakin (DSP) gene. In family 1, patient II.1 (15 y.o) was diagnosed with AM, 6 months after his sister died suddenly at the age of 12. In family 2, patient II.4 (17 y.o) was diagnosed with AM. His mother had a DCM, with a CMR revealing the presence of MI. In family 3, patient IV.3 (22 y.o) died suddenly from an AM, attested by post-mortem autopsy. Her aunt had a DCM. In family 4, patient II.4 (41 y.o) had an AM, progressing toward a DCM. Her mother had died suddenly at the age of 39, and her niece had a DCM. In family 5, patient V.16 (9 y.o) presented 4 recurrent episodes of AM. Her cousin's mother had a DCM. In family 6, patient IV.3 had 3 episodes of AM, his father had previously been diagnosed with an arrythmogenic right ventricular cardiomyopathy (ARVC) with a desmoglein 2 (DSG2) mutation. Table shows detailed genotype-phenotype relationship in all mutation carriers screened in the 6 families. Phenotypes observed in mutation carriers Mutation DCM ARVC AM Isolated LGE (no cardiomyopathy, no AM) Family 1 (n=3) DSP 0 0 1 1 Family 2 (n=3) DSP 1 0 1 0 Family 3 (n=11) DSP 5 0 1 0 Family 4 (n=3) DSP 2 0 1 0 Family 5 (n=7) DSP 2 0 1 3 Family 6 (n=5) DSG2 0 1 1 1 Family Pedigrees Conclusion AM is strongly associated to desmosomal mutations when a familial history of cardiomyopathy is present, particularly in DSP gene. In these families, DCM phenotype and SD are frequent, and a notable proportion of isolated LGE suggestive of myocardial fibrosis is present in asymptomatic relatives. These results highlight the need for a comprehensive familial screening in case of AM.

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.

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