scholarly journals Multi-Gene Panel Testing in Gastroenterology: Are We Ready for the Results?

2021 ◽  
pp. 1-7
Author(s):  
Flávio Pereira ◽  
Manuel R. Teixeira ◽  
Mário Dinis Ribeiro ◽  
Catarina Brandão
Keyword(s):  
Genetic Testing ◽  
Cancer Susceptibility ◽  
Familial Cancer ◽  
Short Review ◽  
Gene Panel ◽  
Inherited Cancer ◽  
Panel Testing ◽  
Gene Panel Testing ◽  
Patients At Risk ◽  
Familial Cancer Risk

Genetic testing aims to identify patients at risk for inherited cancer susceptibility. In the last decade, there was a significant increase in the request of broader panels of genes as multi-gene panel testing became widely available. However, physicians may be faced with genetic findings for which there is lack of management evidence, despite some progress in understanding their clinical relevance. In this short review, we discuss the advantages and the drawbacks related to multi-gene panel testing in the setting of a Gastrointestinal Familial Cancer Risk clinic. We also summarize the available recommendations on management of pathogenic variant carriers.

Benefits and safety of multigene panel testing in patients at risk for hereditary breast cancer.

2015 ◽  
Vol 33 (28_suppl) ◽  
pp. 16-16
Author(s):  
Nimmi S. Kapoor ◽  
Lisa D. Curcio ◽  
Carlee A. Blakemore ◽  
Amy K. Bremner ◽  
Rachel E. McFarland ◽  
...  
Keyword(s):  
Breast Cancer ◽  
At Risk ◽  
Genetic Testing ◽  
Hereditary Breast Cancer ◽  
Diagnostic Yield ◽  
Gene Panel ◽  
Panel Testing ◽  
Gene Testing ◽  
Gene Panel Testing ◽  
Patients At Risk

16 Background: Recently introduced multi-gene panel testing including BRCA1 and BRCA2 genes (BRCA1/2) for hereditary cancer risk has raised concerns with the ability to detect all deleterious BRCA1/2 mutations compared to older methods of sequentially testing BRCA1/2 separately. The purpose of this study is to evaluate rates of pathogenic BRCA1/2mutations and variants of uncertain significance (VUS) between previous restricted algorithms of genetic testing and newer approaches of multi-gene testing. Methods: Data was collected retrospectively from 966 patients who underwent genetic testing at one of three sites from a single institution. Test results were compared between patients who underwent BRCA1/2testing only (limited group, n = 629) to those who underwent multi-gene testing with 5-43 cancer-related genes (panel group, n = 337). Results: Deleterious BRCA1/2 mutations were identified in 37 patients, with equivalent rates between limited and panel groups (4.0% vs 3.6%, respectively, p = 0.86). Thirty-nine patients had a BRCA1/2 VUS, with similar rates between limited and panel groups (4.5% vs 3.3%, respectively, p = 0.49). On multivariate analysis, there was no difference in detection of either BRCA1/2 mutations or VUS between both groups. Of patients undergoing panel testing, an additional 3.9% (n = 13) had non-BRCA pathogenic mutations and 13.4% (n = 45) had non-BRCA VUSs. Mutations in PALB2, CHEK2, and ATM were the most common non-BRCA mutations identified. Conclusions: Multi-gene panel testing detects pathogenic BRCA1/2 mutations at equivalent rates as limited testing and increases the diagnostic yield. Panel testing increases the VUS rate, mainly due to non-BRCA genes. Patients at risk for hereditary breast cancer can safely benefit from upfront, more efficient, multi-gene panel testing.

Multi-gene panel testing for hereditary cancer susceptibility in a rural Familial Cancer Program

2016 ◽  
Vol 16 (1) ◽  
pp. 159-166 ◽  
Author(s):  
David J. Hermel ◽  
Wendy C. McKinnon ◽  
Marie E. Wood ◽  
Marc S. Greenblatt
Keyword(s):  
Hereditary Cancer ◽  
Cancer Susceptibility ◽  
Familial Cancer ◽  
Gene Panel ◽  
Panel Testing ◽  
Cancer Program ◽  
Gene Panel Testing

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 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 Detection of Germline Mutations in a Cohort of 139 Patients with Bilateral Breast Cancer by Multi-Gene Panel Testing: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2415 ◽  
Author(s):  
Daniele Fanale ◽  
Lorena Incorvaia ◽  
Clarissa Filorizzo ◽  
Marco Bono ◽  
Alessia Fiorino ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Bilateral Breast Cancer ◽  
Significant Proportion ◽  
Susceptibility Genes ◽  
Gene Panel ◽  
Panel Testing ◽  
Cancer Susceptibility Genes ◽  
Gene Panel Testing ◽  
Increased Risk

Patients with unilateral breast cancer (UBC) have an increased risk of developing bilateral breast cancer (BBC). The annual risk of contralateral BC is about 0.5%, but increases by up to 3% in BRCA1 or BRCA2 pathogenic variant (PV) carriers. Our study was aimed to evaluate whether all BBC patients should be offered multi-gene panel testing, regardless their cancer family history and age at diagnosis. We retrospectively collected all clinical information of 139 BBC patients genetically tested for germline PVs in different cancer susceptibility genes by NGS-based multi-gene panel testing. Our investigation revealed that 52 (37.4%) out of 139 BBC patients harbored germline PVs in high- and intermediate-penetrance breast cancer (BC) susceptibility genes including BRCA1, BRCA2, PTEN, PALB2, CHEK2, ATM, RAD51C. Nineteen out of 53 positively tested patients harbored a PV in a known BC susceptibility gene (no-BRCA). Interestingly, in the absence of an analysis performed via multi-gene panel, a significant proportion (14.4%) of PVs would have been lost. Therefore, offering a NGS-based multi-gene panel testing to all BBC patients may significantly increase the detection rates of germline PVs in other cancer susceptibility genes beyond BRCA1/2, avoiding underestimation of the number of individuals affected by a hereditary tumor syndrome.

Impact of hereditary multigene panel testing for cancer survivors.

2016 ◽  
Vol 34 (3_suppl) ◽  
pp. 261-261
Author(s):  
Nimmi S. Kapoor ◽  
Jennifer Swisher ◽  
Rachel E. McFarland ◽  
Mychael Patrick ◽  
Lisa D. Curcio
Keyword(s):  
Ovarian Cancer ◽  
Genetic Testing ◽  
Cancer Survivors ◽  
Gene Mutation ◽  
Gene Panel ◽  
Personal History ◽  
Panel Testing ◽  
Pathogenic Mutations ◽  
Gene Panel Testing ◽  
History Of

261 Background: Recently, genetic testing for hereditary cancer syndromes has seen numerous advances in testing spectrum, capability, and efficiency. This may have important implications for cancer survivors and their families. The purpose of this study is to evaluate the impact of reflex genetic testing with newer multi-gene panels on patients with prior negative BRCA1/2 tests. Methods: Data was collected retrospectively from patients who underwent multi-gene panel testing at one of three sites from a single institution between 8/2013-6/2015. Those with a personal history of breast or ovarian cancer and a prior negative BRCA1/2 test were included. Results: Of 914 patients who underwent multi-gene panel tests, 187 met study inclusion criteria. Ten patients (5.3%) were found to carry 11 pathogenic mutations, including 6 patients with mutations in CHEK2, 2 patients with mutations in PTEN, and 1 patient each with mutations in the following genes: BARD1, NF1, and RAD51C. One patient had two pathogenic mutations identified—CHEK2 and BARD1. Of 10 patients with mutations, 9 had a personal history of breast cancer diagnosed at a median age of 43 (range 35-52) and 1 had ovarian cancer diagnosed at age 65. A majority of mutation carriers underwent panel testing years after their cancer diagnosis (median 6 years, range 0.5-32 years) and none with delayed testing had undergone prophylactic contralateral mastectomy prior to the discovery of their gene mutation. All patients with mutations had a family history of at least one cancer, with most having a variety of cancer diagnoses in multiple relatives. Positive panel testing results altered clinical management in most patients, including addition of breast MRI, colonoscopy, or thyroid ultrasound depending on the gene mutation. After discovery of a PTEN mutation 19 years after her initial cancer treatment, one woman underwent bilateral prophylactic mastectomy and was found to have occult ductal carcinoma in situ. Conclusions: Cancer survivorship must incorporate advances in technology that may be beneficial even years after treatment has ended. Multi-gene panel testing can be applied in survivorship settings as a useful tool to guide screening recommendations.

Expanded yield of multiplex panel testing in fully accrued prospective trial.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1525-1525
Author(s):  
Gregory Idos ◽  
Allison W. Kurian ◽  
Charite Nicolette Ricker ◽  
Duveen Sturgeon ◽  
Julie Culver ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Genetic Testing ◽  
Cancer Risk ◽  
Clinical Utility ◽  
Diagnostic Yield ◽  
Pathogenic Mutation ◽  
Gene Panel ◽  
Cancer Risk Assessment ◽  
Panel Testing ◽  
Gene Panel Testing

1525 Background: Genetic testing is a powerful tool for stratifying cancer risk. Multiplex gene panel (MGP) testing allows simultaneous analysis of multiple high- and moderate- penetrance genes. However, the diagnostic yield and clinical utility of panels remain to be further delineated. Methods: A report of a fully accrued trial (N = 2000) of patients undergoing cancer-risk assessment. Patients were enrolled in a multicenter prospective cohort study where diagnostic yield and off-target mutation detection was evaluated of a 25 gene MGP comprised of APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53. Patients were enrolled if they met standard testing guidelines or were predicted to have a ≥2.5% mutation probability by validated models. Differential diagnoses (DDx) were generated after expert clinical genetics assessment, formulating up to 8 inherited cancer syndromes ranked by estimated likelihood. Results: 1998/2000 patients had reported MGP test results. Women constituted 81% of the sample, and 40% were Hispanic; 241 tested positive for at least 1 pathogenic mutation (12.1%) and 689 (34.5%) patients carried at least 1 variant of uncertain significance. The most frequently identified mutations were in BRCA1 (17%, n = 41), BRCA2 (15%, n = 36), APC (8%, n = 19), CHEK2 (7%, n = 17), ATM (7%, n = 16). 39 patients (16%) had at least 1 pathogenic mutation in a mismatch repair (MMR) gene ( MLH1, n = 10; MSH2, n = 10; MSH6, n = 8; PMS2, n = 11). 43 individuals (18%) had MUTYH mutations – 41 were monoallelic. Among 19 patients who had mutations in APC – 16 were APC I1307K. Only 65% (n = 159) of PV results were included in the DDx, with 35% (n = 86) of mutations not clinically suspected. Conclusions: In a diverse cohort, multiplex panel use increased genetic testing yield substantially: 35% carried pathogenic mutations in unsuspected genes, suggesting a significant contribution of expanded multiplex testing to clinical cancer risk assessment. The identification of off-target mutations broadens our understanding of cancer risk and genotype-phenotype correlations. Follow-up is ongoing to assess the clinical utility of multiplex gene panel testing. Clinical trial information: NCT02324062.

Performance of mutation risk prediction models in a racially diverse multi-gene panel testing cohort.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1523-1523
Author(s):  
Gregory Idos ◽  
Katherine G Roth ◽  
Leah Naghi ◽  
Charite Nicolette Ricker ◽  
Julie Culver ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Genetic Testing ◽  
Prediction Models ◽  
Brca2 Mutation ◽  
Pathogenic Mutation ◽  
Gene Panel ◽  
Panel Testing ◽  
Gene Panel Testing ◽  
Brca1 Brca2 ◽  
Racial Ethnic

1523 Background: Mutation carrier prediction models are clinically useful tools for identifying candidates for genetic counseling and testing. Consensus guidelines recommend germline genetic testing for those with a carrier probability (CP) of approximately 5% or higher. However, prediction models may perform less well among racial/ethnic minorities. Our hypothesis is that pathogenic mutations (PM) are identifiable in a clinically meaningful fraction of racially/ethnically diverse patients with a CP of < 5%. Methods: We conducted a multicenter prospective clinical trial of patients undergoing cancer-risk assessment using a 25 gene panel, which include APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53. Patients were recruited from August 2014 to November 2016 at three centers. Patients were enrolled if they met standard clinical criteria for genetic testing or were predicted to have a ≥2.5% probability of inherited cancer susceptibility using validated prediction models. We evaluated the CP of patients with a PM in BRCA1, BRCA2, and/or a mismatch repair (MMR) gene using the following models: (1) BRCApro, (2) MMRpro and (3) PREMM1,2,6. Results: Of 2000 patients enrolled in this cohort, 80.6% are female (n = 1612). Regarding race/ethnicity, the cohort is 40.1% Non-Hispanic White (n = 802), 37.4% Hispanic (n = 748), 11.5% Asian (n = 230), 3.9% Black (n = 78), and 7.1% Other (n = 142). Among 241 (12.1%) patients who tested positive for a pathogenic mutation, 76 (31.5%) patients had a BRCA1 or BRCA2 mutation. Of those, 52 (68.4%) patients had a BRCApro CP of < 5%. Thirty-eight (15.8%) patients had a pathogenic mutation in an MMR gene: 19 (50.0%) had an MMRpro CP of < 5%, while 13 (34.2%) had a PREMM1,2,6 CP of < 5%. The racial/ethnic distribution of BRCA1/2 or MMR mutation carriers is similar to that of the whole cohort. Conclusions: In a diverse cohort of patients undergoing 25-gene multiple-gene panel testing, half or more carriers of BRCA1/2 or MMR mutations had a CP of < 5%, the consensus guideline-recommended cutoff for genetic testing. These results support a lower threshold for genetic testing guidelines. Clinical trial information: NCT02324062.

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.

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