Germline alterations in urothelial carcinoma (UC) patients with family history of UC.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 474-474
Author(s):  
Amin Nassar ◽  
Kent William Mouw ◽  
Edward D. Esplin ◽  
Shan Yang ◽  
Tom Callis ◽  
...  
Keyword(s):  
Family History ◽  
Massively Parallel Sequencing ◽  
Copy Number Variations ◽  
Single Nucleotide Variants ◽  
Degree Relative ◽  
Repair Gene ◽  
Therapeutic Implications ◽  
Upper Tract ◽  
Pathogenic Variants ◽  
History Of

474 Background: UC is associated with germline alterations in a small minority of patients (pts). The prevalence of germline alterations in those with familial UC is unknown. We identified genomic alterations among familial UC pts to provide insights into pathogenesis and improve management. Methods: We analyzed deidentified data for UC pts with germline multigene panel testing (Invitae) who had a family history of UC, defined as a 1st-3rd degree relative with UC. Massively parallel sequencing used customized capture bait-sets to analyze exonic regions, flanking intronic sequences, and copy number variations (CNVs) for 1-126 genes. Pathogenic and likely pathogenic (P/LP) variants underwent orthogonal confirmation, per standard policy, including single nucleotide variants (SNVs)/small indels/CNVs. Patient characteristics were compared using the Fisher’s Exact and Wilcoxon-Rank Sum test. Results: 79 UC pts with a family history of UC were identified (67 bladder, 6 upper tract, 6 unknown). Six patients (8%) were excluded as the relation of the family member was unknown. 48/73 (66%) pts had first-degree relatives (fdr) with UC (4 upper tract, 39 bladder, 5 unknown) and 25 (34%) had second-degree (or higher) relatives (sdr) (2 upper tract, 22 bladder, 1 unknown). 56 germline alterations were found in 38 (52%) pts. 14 known pathogenic alterations occurred in 13 (18%) pts: SDHC (1), MITF (2), BRIP1 (1), BRCA2 (1), MSH2 (3), BRCA1 (1), CHEK2 (1), PTCH (1), MUTYH (2), BAP1 (1). 8/48 (17%) pts with fdr had pathogenic variants vs. 5/25 (20%) pts with sdr or more. There was no difference in the prevalence of pathogenic variants based on gender (p=0.37) or age (p=0.77). The limitations are modest sample size and differences in panels of genes. Conclusions: This is the first study to our knowledge to report germline alterations in UC pts with a family history of UC. Pathogenic germline alterations were seen in 18% of pts, which were enriched for DNA damage repair gene alterations, and could have important therapeutic implications. Further study of germline alterations using larger panels in pts with family history of UC may provide novel insights, since most pts did not have pathogenic alterations.

scholarly journals The genetic analysis of a founder Northern American population of European descent identifies FANCI as a candidate familial ovarian cancer risk gene

2020 ◽  
Author(s):  
Caitlin T Fierheller ◽  
Laure Guitton-Sert ◽  
Wejdan M Alenezi ◽  
Timothée Revil ◽  
Kathleen K Oros ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Family History ◽  
Serous Carcinoma ◽  
Ovarian Cancer Risk ◽  
Repair Pathway ◽  
Degree Relative ◽  
Pathogenic Variants ◽  
Familial Ovarian Cancer ◽  
History Of

AbstractSome familial ovarian cancer (OC) could be due to rare risk alleles in genes that each account for a relatively small proportion of cases not due to BRCA1 and BRCA2, major risk genes in the homologous recombination (HR) DNA repair pathway. We report a new candidate OC risk allele, FANCI c.1813C>T in a Fanconi anemia (FA) gene that plays a role upstream of the HR DNA repair pathway. This variant was identified by whole exome sequencing of a BRCA1 and BRCA2 mutation-negative French Canadian (FC) OC family from a population exhibiting founder effects. In FCs, the c.1813C>T allele was detected in 7% (3/43) of familial and 1.6% (7/439) of sporadic OC cases; and in 3.7% (3/82) of familial breast cancer (BC) cases with a family history of OC and in 1.9% (3/158) of BC only families. This allele was significantly associated with FC BRCA1 and BRCA2 mutation-negative OC families (OR=5.6; 95%CI=1.6-19; p=0.006). Although FANCI c.1813C>T was detected in 2.5% (74/2950) of cancer-free FC females, carriers had a personal history of known OC risk reducing factors, and female/male carriers were more likely to have reported a first-degree relative with OC (ρ=0.037; p=0.011). Eight rare potentially pathogenic FANCI variants were identified in 3.3% (17/516) of Australian OC cases, including 10 carriers of FANCI c.1813C>T. Potentially pathogenic FANCI variants were significantly more common in AUS OC cases with a family history of OC than in isolated OC cases (p=0.027). The odds ratios (OR) were >3 for carriers of any of the seven rarest FANCI alleles, and 1.5 for c.1813C>T. Data from the OC Association Consortium revealed that the ORs for the c.1813C>T allele were highest for the most common OC subtypes. Localization of FANCD2, part of the FANCI-FANCD2 (ID2) binding complex in the FA pathway, to sites of induced DNA damage was severely impeded in cells expressing the p.L605F isoform. This isoform was expressed at a reduced level; unstable by formaldehyde or mitomycin C treatment; and exhibited sensitivity to cisplatin but not to olaparib (a poly [ADP-ribose] polymerase inhibitor). By tissue microarray analyses, FANCI protein was robustly expressed in fallopian tube epithelial cells but expressed at low-to-moderate levels in 88% (83/94) of high-grade serous carcinoma OC samples. This is the first study to describe potentially pathogenic variants in OC in a member of the ID2 complex of the FA DNA repair pathway. Our data suggest that potentially pathogenic FANCI variants may modify OC risk in cancer families.

Detection of germline deleterious mutations in prostate cancer patients with use of a validated 30-gene sequencing assay.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 223-223
Author(s):  
Panagiotis J. Vlachostergios ◽  
Ana M. Molina ◽  
Himisha Beltran ◽  
David M. Nanus ◽  
Scott T. Tagawa
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Family History ◽  
Positive Family History ◽  
High Susceptibility ◽  
Degree Relative ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
History Of ◽  
Gene Alterations

223 Background: Germline DNA repair gene alterations in men with metastatic prostate cancer (PC) unselected for family history of malignancy occur in a greater frequency compared to localized PC and the general population. We hypothesized that assessing heritable alterations in a broader panel of high-susceptibility genes, may be relevant for detecting familial associations with other cancers in PC patients. Methods: We examined a cohort of 52 PC patients (median age 60, range 45-80) with histologically confirmed PC (17 localized, 35 metastatic). Germline DNA was isolated from blood lymphocytes or buccal swabs, and targeted next-generation sequencing was conducted with use of a previously validated panel of 30 genes associated with an elevated risk for common cancers (Color Genomics). As a reference for gene aberration frequencies we used the Exome Aggregation Consortium (ExAC) database. Results: The majority of patients (48/52, 92%) had a positive family history of cancer in any relative. Nine deleterious pathogenic mutations were identified in germline DNA samples from 8/52 (15%) patients, affecting the following genes: APC (n = 2, 3.8%), BRCA2 (n = 2, 3.8%), CHEK2 (n = 3, 5.7%), ATM (n = 1, 1.9%), RAD51D (n = 1, 1.9%). APC mutations were significantly more frequent in our cohort compared to the ExAC database (0.3%, p < 0.001). The frequency of DNA repair gene alterations (7/52, 13.5%) was also significantly higher compared to the ExAC database (0.3%, p < 0.001). The median overall survival (OS) between patients with and without germline gene alterations was similar (81.5 versus 74 months, respectively). The presence of heritable gene alterations from the 30-gene panel was significantly more frequent in patients with a positive family history of any cancer (p < 0.001) or prostate, breast, ovarian cancer (p = 0.001) in a first degree relative. Conclusions: The use of a targeted panel of high-susceptibility cancer-associated genes in PC not only confirms the enrichment of germline mutations in men with PC. It can also reveal associations of PC with other cancers which may portend implications for treatment and prognosis.

Germline variants in urothelial carcinoma: Analysis of pathogenic and likely pathogenic variants in 645 subjects.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1528-1528
Author(s):  
Sarah Abou Alaiwi ◽  
Amin Nassar ◽  
Kent William Mouw ◽  
David J. Kwiatkowski ◽  
Toni K. Choueiri ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Urothelial Carcinoma ◽  
Copy Number ◽  
Massively Parallel Sequencing ◽  
Checkpoint Inhibitors ◽  
Continuous Variables ◽  
Single Nucleotide Variants ◽  
Degree Relative ◽  
Germline Variants ◽  
History Of

1528 Background: While small studies have supported a genetic cancer predisposition among subjects with urothelial carcinoma (UC), systematic germline evaluation of this population is lacking. Here, we report the prevalence of germline variants among subjects with UC from multiple centers completing panel-based testing at a large, commercial laboratory. Methods: 1149 UC subjects underwent germline testing of 1 to 126 genes using massively parallel sequencing with customized capture bait-sets to analyze exonic regions, flanking intronic sequences, and copy number alterations. Pathogenic (P) and likely pathogenic (LP) were confirmed using orthogonal technology in accordance with Invitae standard operating practices. Analysis was limited to 645 subjects who completed testing of a shared set of 42 genes. P/LP variants including single nucleotide variants/indels/ copy number variants are reported. De-identified personal and family cancer histories were evaluated. Fisher’s Exact test and the Mann-Whitney test were used to analyze categorical and continuous variables respectively. Results: Among the 645 UC subjects with 42-gene testing for any indication, median age at testing was 60 years (6-88) and 326 (51%) were female. P/LP variants were identified in 21 (50%) of the 42 genes in 98 (15%) of subjects, including Lynch syndrome genes (n = 26 [4%]), BRCA1/2 (n = 16 [2.5%]), CHEK2 (n = 15 [2.3%]), and heterozygous MUTYH (n = 12 [1.9%]). Among 18 DNA damage repair (DDR) genes assessed, 90 P/LP variants were detected in 88 subjects (12.2%). There was no significant association between presence of a DDR gene variant and age at diagnosis, gender or reported family history of UC in a first degree relative (n = 48). Among subjects with documented history of UC only without other cancers (n = 195), 24 (12.3%) had P/ LP variants, of which 23 (11.8%) were in a DDR gene. Conclusions: Germline P/LP variants were identified in 15% of UC subjects most of which (92%) were in DDR genes, including 27% in Lynch syndrome genes. PARP and T-cell checkpoint inhibitors may warrant evaluation in subjects with germline DDR mutations. Further validation in unselected UC pts is warranted to propose examining germline P/LP variants in all UC patients.

scholarly journals Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome

2021 ◽  
Author(s):  
Pauline Arnaud ◽  
Hélène Morel ◽  
Olivier Milleron ◽  
Laurent Gouya ◽  
Christine Francannet ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Somatic Mosaicism ◽  
Variant Calling ◽  
Copy Number Variations ◽  
Pathogenic Variant ◽  
Single Nucleotide Variants ◽  
Bioinformatics Analyses ◽  
Single Nucleotide ◽  
Fbn1 Gene ◽  
Pathogenic Variants

Abstract Purpose Individuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands. Methods Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene. Results These five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations. Conclusion This underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.

scholarly journals Eculizumab discontinuation in atypical hemolytic uremic syndrome: TMA recurrence risk and renal outcomes

2021 ◽  
Author(s):  
Gema Ariceta ◽  
Fadi Fakhouri ◽  
Lisa Sartz ◽  
Benjamin Miller ◽  
Vasilis Nikolaou ◽  
...  
Keyword(s):  
Family History ◽  
Hemolytic Uremic Syndrome ◽  
Univariate Analysis ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Renal Response ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
History Of ◽  
Uremic Syndrome

ABSTRACT Background Eculizumab modifies the course of disease in patients with atypical hemolytic uremic syndrome (aHUS), but data evaluating whether eculizumab discontinuation is safe are limited. Methods Patients enrolled in the Global aHUS Registry who received ≥1 month of eculizumab before discontinuing, demonstrated hematologic or renal response prior to discontinuation and had ≥6 months of follow-up were analyzed. The primary endpoint was the proportion of patients suffering thrombotic microangiopathy (TMA) recurrence after eculizumab discontinuation. Additional endpoints included: eGFR changes following eculizumab discontinuation to last available follow-up; number of TMA recurrences; time to TMA recurrence; proportion of patients restarting eculizumab; and changes in renal function. Results We analyzed 151 patients with clinically diagnosed aHUS who had evidence of hematologic or renal response to eculizumab, before discontinuing. Thirty-three (22%) experienced a TMA recurrence. Univariate analysis revealed that patients with an increased risk of TMA recurrence after discontinuing eculizumab were those with a history of extrarenal manifestations prior to initiating eculizumab, pathogenic variants, or a family history of aHUS. Multivariate analysis showed an increased risk of TMA recurrence in patients with pathogenic variants and a family history of aHUS. Twelve (8%) patients progressed to end-stage renal disease after eculizumab discontinuation; 7 (5%) patients eventually received a kidney transplant. Forty (27%) patients experienced an extrarenal manifestation of aHUS after eculizumab discontinuation. Conclusions Eculizumab discontinuation in patients with aHUS is not without risk, potentially leading to TMA recurrence and renal failure. A thorough assessment of risk factors prior to the decision to discontinue eculizumab is essential.

A Group Therapy Approach to Facilitate Integration of Risk Information for Women at Risk for Breast Cancer

1998 ◽  
Vol 43 (4) ◽  
pp. 375-380 ◽  
Author(s):  
Mary Jane Esplen ◽  
Brenda Toner ◽  
Jonathan Hunter ◽  
Gordon Glendon ◽  
Kate Butler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
At Risk ◽  
Family History ◽  
Group Therapy ◽  
Perceived Risk ◽  
Positive Family History ◽  
Risk Information ◽  
Degree Relative ◽  
Therapy Approach ◽  
History Of

Objective: To describe and illustrate elements of a group counselling approach designed to enhance the communication of risk information on breast cancer (BC) to women with a family history of this disease. Breast cancer is a leading cause of female cancer death. The most important risk factor for BC is a positive family history in at least 1 first-degree relative, and approximately one-third of women with BC have a family history of the disease. Recent evidence suggests that there is a significant psychological impact associated with having a family history of BC, and this may influence the psychological adjustment and response to being counselled for personal risk. New counselling approaches are required. Method: This paper describes a group therapy approach that incorporates principles of supportive-expressive therapy designed to address the emotional impact of being at risk for BC and to promote accuracy of perceived risk. The key elements of the intervention are described along with clinical illustrations from groups that are part of an ongoing study to develop and standardize the group therapy. Conclusion: Qualitative data from the groups suggest that this model of therapy is both feasible and effective.

scholarly journals Genotype-Phenotype Correlations in Neurofibromatosis Type 1: A Single-Center Cohort Study

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1879
Author(s):  
Marcello Scala ◽  
Irene Schiavetti ◽  
Francesca Madia ◽  
Cristina Chelleri ◽  
Gianluca Piccolo ◽  
...  
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Copy Number Variations ◽  
Single Nucleotide Variants ◽  
Multivariate Statistical ◽  
Gene Deletions ◽  
Pathogenic Variants ◽  
Lisch Nodules ◽  
Next Generation Sequencing Ngs

Neurofibromatosis type 1 (NF1) is a proteiform genetic condition caused by pathogenic variants in NF1 and characterized by a heterogeneous phenotypic presentation. Relevant genotype–phenotype correlations have recently emerged, but only few pertinent studies are available. We retrospectively reviewed clinical, instrumental, and genetic data from a cohort of 583 individuals meeting at least 1 diagnostic National Institutes of Health (NIH) criterion for NF1. Of these, 365 subjects fulfilled ≥2 NIH criteria, including 235 pediatric patients. Genetic testing was performed through cDNA-based sequencing, Next Generation Sequencing (NGS), and Multiplex Ligation-dependent Probe Amplification (MLPA). Uni- and multivariate statistical analysis was used to investigate genotype–phenotype correlations. Among patients fulfilling ≥ 2 NIH criteria, causative single nucleotide variants (SNVs) and copy number variations (CNVs) were detected in 267/365 (73.2%) and 20/365 (5.5%) cases. Missense variants negatively correlated with neurofibromas (p = 0.005). Skeletal abnormalities were associated with whole gene deletions (p = 0.05) and frameshift variants (p = 0.006). The c.3721C>T; p.(R1241*) variant positively correlated with structural brain alterations (p = 0.031), whereas Lisch nodules (p = 0.05) and endocrinological disorders (p = 0.043) were associated with the c.6855C>A; p.(Y2285*) variant. We identified novel NF1 genotype–phenotype correlations and provided an overview of known associations, supporting their potential relevance in the implementation of patient management.

Family history of prostate cancer in patients with localized prostate cancer: an independent predictor of treatment outcome.

1997 ◽  
Vol 15 (4) ◽  
pp. 1478-1480 ◽  
Author(s):  
P A Kupelian ◽  
V A Kupelian ◽  
J S Witte ◽  
R Macklis ◽  
E A Klein
Keyword(s):  
Prostate Cancer ◽  
Treatment Outcome ◽  
Family History ◽  
Treatment Modality ◽  
Proportional Hazards ◽  
Positive Family History ◽  
Specific Antigen ◽  
Tumor Stage ◽  
Degree Relative ◽  
History Of

PURPOSE To determine if familial prostate cancer patients have a less favorable prognosis than patients with sporadic prostate cancer after treatment for localized disease with either radiotherapy (RT) or radical prostatectomy (RP). PATIENTS AND METHODS One thousand thirty-eight patients treated with either RT (n = 583) or RP (n = 455) were included in this analysis. These patients were noted as having a positive family history if they confirmed the diagnosis of prostate cancer in a first-degree relative. The outcome of interest was biochemical relapse-free survival (bRFS). We used proportional hazards to analyze the effect of the presence of family history and other potential confounding variables (ie, age, treatment modality, stage, biopsy Gleason sum [GS], and initial prostate-specific antigen [iPSA] levels) on treatment outcome. RESULTS Eleven percent of all patients had a positive family history. The 5-year bRFS rates for patients with negative and positive family histories were 52% and 29%, respectively (P < .001). The potential confounders with bRFS rates were iPSA levels, biopsy GS, and clinical tumor stage; treatment modality and age did not appear to be associated with outcome. After adjusting for potential confounders, family history of prostate cancer remained strongly associated with biochemical failure. CONCLUSION This is the first study to demonstrate that the presence of a family history of prostate cancer correlates with treatment outcome in a large unselected series of patients. Our findings suggest that familial prostate cancer may have a more aggressive course than nonfamilial prostate cancer, and that clinical and/or pathologic parameters may not adequately predict this course.

scholarly journals Familial pancreatic cancer with PALB2 and NBN pathogenic variants: a case report

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Kodai Abe ◽  
Arisa Ueki ◽  
Yusaku Urakawa ◽  
Minoru Kitago ◽  
Tomoko Yoshihama ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Family History ◽  
Genetic Analysis ◽  
Pathogenic Variant ◽  
Familial Pancreatic Cancer ◽  
Case Presentation ◽  
Pathogenic Variants ◽  
Pancreatic Cancers ◽  
Epidemiological Surveys ◽  
History Of

Abstract Background Family history is one of the risk factors for pancreatic cancer. It is suggested that patients with pancreatic cancer who have a familial history harbor germline pathogenic variants of BRCA1 and/or BRCA2 (BRCA1/2), PALB2, or ATM. Recently, some germline variants of familial pancreatic cancers (FPCs), including PALB2, have been detected. Several countries, including Japan, perform screening workups and genetic analysis for pancreatic cancers. We have been carrying out active surveillance for FPC through epidemiological surveys, imaging analyses, and genetic analysis. Case presentation Here, we present the case of a female patient harboring pathogenic variants of PALB2 and NBN, with a family history of multiple pancreatic cancer in her younger brother, her aunt, and her father. Moreover, her father harbored a PALB2 pathogenic variant and her daughter harbored the same NBN pathogenic variant. Given the PALB2 and NBN variants, we designed surveillance strategies for the pancreas, breast, and ovary. Conclusions Further studies are required to develop strategies for managing FPCs to facilitate prompt diagnosis before their progression.

Does a family history of RA influence the clinical presentation and treatment response in RA?

2015 ◽  
Vol 75 (6) ◽  
pp. 1120-1125 ◽  
Author(s):  
Thomas Frisell ◽  
Saedis Saevarsdottir ◽  
Johan Askling
Keyword(s):  
Family History ◽  
Disease Activity ◽  
Treatment Response ◽  
Clinical Presentation ◽  
Degree Relative ◽  
Eular Response ◽  
Logistic Regression Models ◽  
Drug Survival ◽  
Early Ra ◽  
History Of

ObjectivesTo assess whether family history of rheumatoid arthritis (RA), among the strongest risk factors for developing RA, also carries information on the clinical presentation and treatment response.MethodsThe prospective Swedish Rheumatology register was linked to family history of RA, defined as diagnosed RA in any first-degree relative, ascertained through the Swedish Multi-Generation and Patient registers. Clinical presentation was examined among patients with early RA 2000–2011 (symptom onset <12 months before inclusion, N=6869), and response to methotrexate (MTX) monotherapy in the subset starting this treatment (N=4630). Response to tumour necrosis factor inhibitors (TNFi) was examined among all patients with RA starting a TNFi as the first biological disease-modifying antirheumatic drug 2000–2011 (N=9249). Association of family history with clinical characteristics, drug survival, European League Against Rheumatism (EULAR) response and change in disease activity at 3 and 6 months was estimated using linear and generalised logistic regression models. Correlation in relatives’ response measures was also assessed.ResultsPatients with early RA with family history of RA were more often rheumatoid factor positive, but with no other clinically meaningful differences in their clinical presentation. Family history of RA did not predict response to MTX or TNFi, with the possible exception of no versus good EULAR response to TNFi at 6 months (OR=1.4, 95% CI 1.1 to 1.7). Having a relative who discontinued TNFi within a year increased the odds of doing the same (OR=3.7, 95% CI 1.8 to 7.5), although we found no significant familial correlations in change in disease activity measures.ConclusionsFamily history of RA did not modify the clinical presentation of RA or predict response to standard treatment with MTX or TNFi. Treatment response, particularly drug survival, may itself be familial.

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