scholarly journals Germline variants and phenotypic spectrum in a Canadian cohort of individuals with diffuse gastric cancer

2019 ◽  
Vol 27 (2) ◽  
Author(s):  
M. Aronson ◽  
C. Swallow ◽  
A. Govindarajan ◽  
K. Semotiuk ◽  
Z. Cohen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Detection Rate ◽  
Gene Panel ◽  
Diffuse Gastric Cancer ◽  
Cancer Syndrome ◽  
Detection Rates ◽  
Inherited Cancer ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing

Background CDH1 pathogenic variants (PV) cause the majority of inherited diffuse-gastric cancer (DGC), but have low detection rates and vary geographically. This study examines hereditary causes of DGC in patients from Ontario, Canada. Methods Eligible DGC cases at the Zane Cohen Centre (ZCC) underwent multi-gene panel or CDH1 single-site testing if they met 2015 International Gastric Cancer Linkage Consortium (IGCLC) criteria, isolated DGC <50 or family history suggestive of an inherited cancer syndrome. A secondary aim was to review all CDH1 families at the ZCC to assess cancer penetrance. Results 85 DGC patients underwent CDH1 (n=43) or multi-gene panel testing (n=42), and 15 (17.6%) PV or likely PV were identified.  CDH1 detection rate was 9.4% (n=8/85), and 11% (n=7/65) using IGCLC criteria.  No CDH1 PV identified in isolated DGC <40, but one PV identified in isolated DGC<50.  Multi-gene panel from 42 individuals identified 9 PV (21.4%) including CDH1, STK11, ATM, BRCA2, MLH1 and MSH2.  Review of 81 CDH1 carriers revealed that 10% had DGC (median age:48, range:38-59), 41% were unaffected (median age:53, range:26-89).  Three families had lobular-breast cancer (LBC) only.  Non-DGC/LBC malignancies included colorectal, gynecological, kidney/bladder, prostate, testicular and ductal breast. Conclusions Low detection rate of CDH1 in Ontario DGC patients.  No CDH1 PV found in isolated DGC <40, but identified in isolated DGC<50. Multi-gene panels are recommended for all DGC under age 50, and those meeting the IGCLC criteria, given overlapping phenotype with other hereditary conditions. HDGC phenotype is evolving with a spectrum of non-DGC/LBC cancers.

scholarly journals Extended gene panel testing in lobular breast cancer

2021 ◽  
Author(s):  
Elke M. van Veen ◽  
D. Gareth Evans ◽  
Elaine F. Harkness ◽  
Helen J. Byers ◽  
Jamie M. Ellingford ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Detection Rate ◽  
Gene Panel ◽  
Lobular Breast Cancer ◽  
Germline Variants ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
Increased Risk

AbstractPurpose: Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC. Methods: 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53.Results: 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83–66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58–23.95; P < 0.0001); and ATM: OR = 8.01 (95%CI 2.52–29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2. Conclusion: The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC.

scholarly journals 167P Role of the multi-gene panel testing for detection of pathogenic variants in patients with hereditary bilateral breast cancer

2021 ◽  
Vol 32 ◽  
pp. S432-S433
Author(s):  
C. Filorizzo ◽  
D. Fanale ◽  
L. Incorvaia ◽  
N. Barraco ◽  
M. Bono ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bilateral Breast Cancer ◽  
Gene Panel ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing

Hereditary Diffuse Gastric Cancer: Approaches to Screening, Surveillance, and Treatment

2020 ◽  
Vol 72 (1) ◽  
Author(s):  
Nastazja Dagny Pilonis ◽  
Marc Tischkowitz ◽  
Rebecca C. Fitzgerald ◽  
Massimiliano di Pietro
Keyword(s):  
Gastric Cancer ◽  
Hereditary Diffuse Gastric Cancer ◽  
Prophylactic Surgery ◽  
Future Research ◽  
Annual Review ◽  
Publication Date ◽  
Diffuse Gastric Cancer ◽  
Cancer Syndrome ◽  
Pathogenic Variants ◽  
History Of

Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with a significant lifetime risk of diffuse gastric cancer (DGC), a malignancy characterized by late clinical presentation and poor prognosis, as well as lobular breast cancer. HDGC is linked to germline pathogenic variants in the E-cadherin gene ( CDH1) that are inherited in an autosomal dominant pattern; however, in many families with DGC clustering, no genetic cause has been identified. This review discusses key elements that allow risk assessment of potential inherited DGC susceptibility. We provide a practical overview of the recommendations for surveillance and treatment of individuals at risk and patients with early disease. The review also outlines future research avenues to improve our understanding of the genetic background and natural history of the disease, the endoscopic detection of early lesions, and the outcome of prophylactic surgery in young individuals. Expected final online publication date for the Annual Review of Medicine, Volume 72 is January 27, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals One in three highly selected Greek patients with breast cancer carries a loss-of-function variant in a cancer susceptibility gene

2019 ◽  
Vol 57 (1) ◽  
pp. 53-61 ◽  
Author(s):  
Florentia Fostira ◽  
Irene Kostantopoulou ◽  
Paraskevi Apostolou ◽  
Myrto S Papamentzelopoulou ◽  
Christos Papadimitriou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Gene Panel ◽  
Control Analysis ◽  
Loss Of Function ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
Clinical Changes

BackgroundGene panel testing has become the norm for assessing breast cancer (BC) susceptibility, but actual cancer risks conferred by genes included in panels are not established. Contrarily, deciphering the missing hereditability on BC, through identification of novel candidates, remains a challenge. We aimed to investigate the mutation prevalence and spectra in a highly selected cohort of Greek patients with BC, questioning an extensive number of genes, implicated in cancer predisposition and DNA repair, while calculating gene-specific BC risks that can ultimately lead to important associations.MethodsTo further discern BC susceptibility, a comprehensive 94-cancer gene panel was implemented in a cohort of 1382 Greek patients with BC, highly selected for strong family history and/or very young age (<35 years) at diagnosis, followed by BC risk calculation, based on a case–control analysis.ResultsHerein, 31.5% of patients tested carried pathogenic variants (PVs) in 28 known, suspected or candidate BC predisposition genes. In total, 24.8% of the patients carried BRCA1/2 loss-of-function variants. An additional 6.7% carried PVs in additional genes, the vast majority of which can be offered meaningful clinical changes. Significant association to BC predisposition was observed for ATM, PALB2, TP53, RAD51C and CHEK2 PVs. Primarily, compared with controls, RAD51C PVs and CHEK2 damaging missense variants were associated with high (ORs 6.19 (Exome Aggregation Consortium (ExAC)) and 12.6 (Fabulous Ladies Over Seventy (FLOSSIES)), p<0.01) and moderate BC risk (ORs 3.79 (ExAC) and 5.9 (FLOSSIES), p<0.01), respectively.ConclusionStudying a large and unique cohort of highly selected patients with BC, deriving from a population with founder effects, provides important insight on distinct associations, pivotal for patient management.

scholarly journals CDH1 on Multigene Panel Testing: Look Before You Leap

2019 ◽  
Vol 112 (4) ◽  
pp. 330-334 ◽  
Author(s):  
Bryson W Katona ◽  
Dana Farengo Clark ◽  
Susan M Domchek
Keyword(s):  
Gastric Cancer ◽  
Risk Assessment ◽  
Cancer Risk ◽  
Clinical Decision Making ◽  
Cancer Risk Assessment ◽  
Diffuse Gastric Cancer ◽  
Cancer Syndrome ◽  
Panel Testing ◽  
Multigene Panel Testing ◽  
Multigene Panel

Abstract Multigene panel testing (MGPT) has become a critical component of cancer risk assessment in clinical practice. As technology and access improve and costs decrease, more individuals than ever are undergoing MGPT for genetic evaluation. One gene that deserves special consideration when included on MGPT is CDH1, which codes for the cell-cell adhesion protein E-cadherin. Pathogenic and likely pathogenic germline variants in CDH1 have been associated with hereditary diffuse gastric cancer syndrome, and in highly penetrant families, testing for these variants is critical for proper risk management. However, recent data demonstrated that gastric cancer penetrance in unselected CDH1 carriers may be lower than expected. Further complicating matters are the lack of effective screening strategies for gastric cancer and recommendation for risk-reducing total gastrectomy in CDH1 carriers. Therefore, the discovery of an unexpected pathogenic or likely pathogenic CDH1 variant on multigene panel testing, when testing for CDH1 would not normally be considered based on personal or family history alone, creates dilemmas for both patients and providers. In this commentary, we highlight the potential for unexpected CDH1 variants on MGPT, outline the uncertainties associated with these variants, and emphasize the importance of pretest counseling regarding the potential for an unexpected CDH1 variant. Although CDH1 testing is often important for clinical decision-making, individuals and providers need to be aware of the potential for an unexpected CDH1 variant when CDH1 is included on MGPT for cancer risk assessment.

scholarly journals Hereditary Diffuse Gastric Cancer: Multidisciplinary Case Report with Review of the Literature

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Rebecca Wilcox ◽  
Melody Perpich ◽  
Amy Noffsinger ◽  
Mitchell C. Posner ◽  
Kumarasen Cooper
Keyword(s):  
Gastric Cancer ◽  
Case Report ◽  
Hereditary Diffuse Gastric Cancer ◽  
Diffuse Gastric Cancer ◽  
Review Of The Literature ◽  
Cancer Syndrome ◽  
Inherited Cancer ◽  
Prophylactic Gastrectomy ◽  
Signet Ring ◽  
Inherited Cancer Syndrome

Hereditary diffuse gastric cancer (HDGC) is a rare, inherited cancer syndrome with at least one fourth of HDGC patients having an autosomal dominantly inherited mutation of CDH1 (E-Cadherin). Penetrance is relatively high (70–80% lifetime risk for gastric cancer). It is important for pathologists to recognize the syndrome's phenotype in early gastric lesions: patchy intramucosal signet ring cells often associated with pagetoid spread. Due to the insidious nature of this lesion, surveillance is limited and currently prophylactic gastrectomy is an option chosen by many HDGC patients. We present a case report from a multidisciplinary team of authors with a review of the literature that includes the updated guidelines for CDH1 genetic testing.

Gene Panel Testing for Inherited Cancer Risk

2014 ◽  
Vol 12 (9) ◽  
pp. 1339-1346 ◽  
Author(s):  
Michael J. Hall ◽  
Andrea D. Forman ◽  
Robert Pilarski ◽  
Georgia Wiesner ◽  
Veda N. Giri
Keyword(s):  
Cancer Risk ◽  
Gene Panel ◽  
Inherited Cancer ◽  
Panel Testing ◽  
Gene Panel Testing

E-cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer

1999 ◽  
Vol 14 (3) ◽  
pp. 249-255 ◽  
Author(s):  
Parry J. Guilford ◽  
Justin B.W. Hopkins ◽  
William M. Grady ◽  
Sanford D. Markowitz ◽  
Joseph Willis ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Germline Mutations ◽  
Diffuse Gastric Cancer ◽  
Cancer Syndrome ◽  
Inherited Cancer ◽  
Inherited Cancer Syndrome ◽  
E Cadherin

Detection of Inherited Mutations in Brazilian Breast Cancer Patients Using Multi-Gene panel Testing

2021 ◽  
Author(s):  
Rodrigo Santa Cruz Guindalini ◽  
Danilo Vilela Viana ◽  
João Paulo Fumio Whitaker Kitajima ◽  
Vinícius Marques Rocha ◽  
Rossana Verónica Mendoza López ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Latin American ◽  
Cancer Susceptibility ◽  
Gene Panel ◽  
Breast Cancer Patients ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Gene Panel Testing ◽  
Predisposition Genes

Abstract Genetic diversity of germline variants in breast cancer (BC) predisposition genes, is unexplored in miscegenated people, such as Latin American populations. We evaluated 1,662 Brazilian BC patients, who underwent hereditary multi-gene panel testing (20–38 cancer susceptibility genes), to determine the spectrum and prevalence of (likely) pathogenic variants (P/LP) and variants of uncertain significance (VUS). In total, 161 (9.7%) participants carried germline P/LP variants in BRCA1/2 and 162 (9.7%) in other cancer predisposition genes. Overall, 341 distinctive P/LP variants were identified in 22 genes, including BRCA1(28%), BRCA2(19%), TP53(11%), MUTYH heterozygous (10%), ATM(9%), CHEK2(6%), and PALB2(5%). The Brazilian variant TP53 R337H (c.1010G > A, p.Arg337His), detected in 1.6% of BC patients and 0.09% of reference controls (RC), was strongly associated with odds of disease (OR = 17.67; 95%CI:9.21–34.76; p < 0.001). Heterozygous MUTYH c.1187G > A and MUTYH c.536A > G, detected in 0.78% (0.90% RC) and 0.48% (0.40% RC) of the patients, respectively, were not associated with the odds of BC, the former with OR = 0.87 (95%CI:0.49–1.53; p = 0.63) and the latter with OR = 1.20 (95%CI:0.58–2.49; p = 0.63). Besides, 766 individuals (46.1%) had 1 or more VUS. Concluding, the use of multi-gene panel testing doubled the identification of mutation carriers in Brazilian BC patients. Special attention should be given to TP53 mutations.

scholarly journals Insights into Genetic Susceptibility to Melanoma by Gene Panel Testing: Potential Pathogenic Variants in ACD, ATM, BAP1, and POT1

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1007 ◽  
Author(s):  
Lorenza Pastorino ◽  
Virginia Andreotti ◽  
Bruna Dalmasso ◽  
Irene Vanni ◽  
Giulia Ciccarese ◽  
...  
Keyword(s):  
Rare Variants ◽  
Diagnostic Yield ◽  
Susceptibility Genes ◽  
Gene Panel ◽  
Missing Heritability ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
Novel Variants ◽  
Uncertain Significance

The contribution of recently established or candidate susceptibility genes to melanoma missing heritability has yet to be determined. Multigene panel testing could increase diagnostic yield and better define the role of candidate genes. We characterized 273 CDKN2A/ARF and CDK4-negative probands through a custom-designed targeted gene panel that included CDKN2A/ARF, CDK4, ACD, BAP1, MITF, POT1, TERF2IP, ATM, and PALB2. Co-segregation, loss of heterozygosity (LOH)/protein expression analysis, and splicing characterization were performed to improve variant classification. We identified 16 (5.9%) pathogenic and likely pathogenic variants in established high/medium penetrance cutaneous melanoma susceptibility genes (BAP1, POT1, ACD, MITF, and TERF2IP), including two novel variants in BAP1 and 4 in POT1. We also found four deleterious and five likely deleterious variants in ATM (3.3%). Thus, including potentially deleterious variants in ATM increased the diagnostic yield to about 9%. Inclusion of rare variants of uncertain significance would increase the overall detection yield to 14%. At least 10% of melanoma missing heritability may be explained through panel testing in our population. To our knowledge, this is the highest frequency of putative ATM deleterious variants reported in melanoma families, suggesting a possible role in melanoma susceptibility, which needs further investigation.

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