scholarly journals Prevalence of Germline Pathogenic Variants in Cancer Predisposing Genes in Czech and Belgian Pancreatic Cancer Patients

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4430
Author(s):  
Greet Wieme ◽  
Jan Kral ◽  
Toon Rosseel ◽  
Petra Zemankova ◽  
Bram Parton ◽  
...  
Keyword(s):  
Ductal Adenocarcinoma ◽  
Multiple Primary Cancers ◽  
Cancer History ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Predisposition Genes ◽  
Family Cancer History ◽  
Multigene Panel Testing ◽  
Multigene Panel

(1) Background: The proportion and spectrum of germline pathogenic variants (PV) associated with an increased risk for pancreatic ductal adenocarcinoma (PDAC) varies among populations. (2) Methods: We analyzed 72 Belgian and 226 Czech PDAC patients by multigene panel testing. The prevalence of pathogenic variants (PV) in relation to personal/family cancer history were evaluated. PDAC risks were calculated using both gnomAD-NFE and population-matched controls. (3) Results: In 35/298 (11.7%) patients a PV in an established PDAC-predisposition gene was found. BRCA1/2 PV conferred a high risk in both populations, ATM and Lynch genes only in the Belgian subgroup. PV in other known PDAC-predisposition genes were rarer. Interestingly, a high frequency of CHEK2 PV was observed in both patient populations. PV in PDAC-predisposition genes were more frequent in patients with (i) multiple primary cancers (12/38; 32%), (ii) relatives with PDAC (15/56; 27%), (iii) relatives with breast/ovarian/colorectal cancer or melanoma (15/86; 17%) but more rare in sporadic PDAC (5/149; 3.4%). PV in homologous recombination genes were associated with improved overall survival (HR = 0.51; 95% CI 0.34–0.77). (4) Conclusions: Our analysis emphasizes the value of multigene panel testing in PDAC patients, especially in individuals with a positive family cancer history, and underlines the importance of population-matched controls for risk assessment.

Germline pathogenic variants in cancer predisposition genes among women with invasive lobular cancer of breast.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10581-10581
Author(s):  
Siddhartha Yadav ◽  
Chunling Hu ◽  
Susan M. Domchek ◽  
Jeffrey N. Weitzel ◽  
David Goldgar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Population Based ◽  
Cancer Predisposition ◽  
Clinical Cohort ◽  
Breast Cancer Predisposition ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Predisposition Genes ◽  
Multigene Panel Testing ◽  
Multigene Panel

10581 Background: The prevalence of germline pathogenic variants (PVs) in cancer predisposition genes among women with invasive lobular breast cancer (ILC) and the risk of ILC in PV carriers is not well-defined. Methods: The study included 2,999 women with ILC and 32,544 unaffected controls from a population-based cohort; 3,796 women with ILC and 20,323 women with invasive ductal carcinoma (IDC) undergoing clinical multigene panel testing (clinical cohort); and 125,748 exome sequences from unrelated women without a cancer diagnosis in the gnomAD 3.0 dataset. Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected controls in both cohorts and between women with ILC and IDC in the clinical cohort. Results: The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analyses, CDH1 and BRCA2 PVs were associated with high risks of ILC (Odds ratio (OR) > 4), and CHEK2, ATM and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. PV frequencies in these genes in ILC and IDC were similar except for PV frequencies in BRCA1 and CDH1. Conclusions: The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2 and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. While, multigene panel testing may be appropriate for women with ILC, CDH1 should be specifically discussed in the context of low prevalence and attendant gastric cancer risk.

Uptake of oophorectomy in women with findings on multigene panel testing: Results from the Prospective Registry of Multiplex Testing (PROMPT).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1508-1508 ◽  
Author(s):  
Susan M. Domchek ◽  
Jamie Brower ◽  
Heather Symecko ◽  
Vanessa Marcell ◽  
Michael Francis Walsh ◽  
...  
Keyword(s):  
Cancer Susceptibility ◽  
Personal History ◽  
Variant Of Uncertain Significance ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
History Of ◽  
Multigene Panel Testing ◽  
Multiplex Testing ◽  
Multigene Panel

1508 Background: With the expansion of multigene panel testing for cancer susceptibility, increasing numbers of patients are identified with pathogenic/likely pathogenic variants (P/LP V) in genes which do not have a clearly actionable increased risk of ovarian cancer (OC) (lifetime risk of OC >5%). However, there is concern that patients and/or providers may ascribe OC risk to such genetic findings with the potential for unnecessary oophorectomy (ooph). Methods: The Prospective Registry of Multiplex Testing (PROMPT) is an online registry for individuals with a genetic alteration detected on multiplex panel testing for cancer susceptibility. Participants self-enroll and complete baseline and annual follow-up questionnaires. PROMPT has enrolled 7388 participants (6936; 93.9% women) since September 2014. Results: 1566 women in the PROMPT registry reported ooph, the indications for which were reported as either cancer treatment (n=481, 30.7%) or benign disease (n=432, 27.6%). An additional 186 (12.8%) reported PV in genes associated with lifetime OC risk >5% ( BRCA1, BRCA2, RAD51C, RAD51D, BRIP, or Lynch syndrome genes). The remaining 467 did not have guideline based indications for ooph due to OC risk and are described further here. 92 (19.7%) had a variant of uncertain significance (VUS) in genes associated with OC, 241 (51.6%) had a personal history of breast cancer (BC) and no VUS in OC genes, and 119 (25.5%) had no personal history of BC and no VUS in OC genes. The majority of women had no family history (FH) of OC in first or second degree relatives (Table). Most ooph occurred prior to age 50. Of the 405 women with CHEK2 P/LP, 11.4% reported ooph (59% under age 50 when age known), as did 13.2% (of 228) with CHEK2 VUS, 8.8% (of 261) with ATM P/LP (66.7% under age 50), and 8.3% (of 387) with ATM VUS. In addition, of the 184 women with PALB2 P/LP, 14.1% reported ooph (35.3% under age 50) as did 11.6% (of 198) with PALB2 VUS. Of those who reported provider discussions, 47.2% stated “my provider recommended this” (including >60% in the OC gene VUS group) and an additional 25.2% stated “my provider presented this as an option, but not a requirement”. In those with no FH of OC, 45.8% stated that their provider recommended ooph. Conclusions: 10-15% of women with PV/VUS in genes not associated with a high risk of OC reported ooph without a clear indication. [Table: see text]

scholarly journals Comparison of Colorectal and Endometrial Microsatellite Instability Tumor Analysis and Premm5 Risk Assessment for Predicting Pathogenic Germline Variants on Multigene Panel Testing

2020 ◽  
Vol 38 (34) ◽  
pp. 4086-4094
Author(s):  
Alessandro Mannucci ◽  
C. Sloane Furniss ◽  
Chinedu Ukaegbu ◽  
Miki Horiguchi ◽  
Tara Fehlmann ◽  
...  
Keyword(s):  
High Risk ◽  
Microsatellite Instability ◽  
Prediction Models ◽  
Familial Risk ◽  
Cancer History ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
High Penetrance ◽  
Multigene Panel Testing ◽  
Multigene Panel

PURPOSE Tumor testing for microsatellite instability and/or mismatch repair-deficiency (MSI/IHC) and clinical prediction models effectively screen for Lynch syndrome (LS)–associated colorectal cancer (CRC) and endometrial cancer (EC), but they have not been assessed for their ability to identify non-LS forms of inherited risk. The aim of this study was to compare MSI/IHC and the PREMM5 prediction model to identify carriers of LS and non-LS pathogenic variants (PVs) among patients with CRC and EC. PATIENTS AND METHODS Data were retrospectively analyzed from two single-institution cohorts: 706 patients with CRC and/or EC referred for genetic evaluation/testing (high-risk cohort) and 1,058 consecutively ascertained patients with CRC (oncology clinic cohort), unselected for familial risk. All participants underwent germline multigene panel testing. PREMM5 scores were calculated from personal/family cancer history. The primary outcome was the proportion of individuals with germline PVs (LS PVs, high-penetrance PVs, and any PVs) who had abnormal MSI/IHC testing and/or PREMM5 score ≥ 2.5%. RESULTS MSI/IHC and PREMM5 had comparable sensitivity for identifying LS carriers in high-risk (89.3% v 85.7%; P = .712) and oncology clinic patients (96.6% v 96.6%; P = 1.000), although MSI/IHC had significantly superior specificity for LS (81.3% v 20.1%; P < .001; 92.3% v 24.3%; P < .001). In both cohorts, PREMM5 had superior sensitivity to MSI/IHC at identifying patients with any high-penetrance PVs and any low-, moderate-, and high-penetrance PVs. Among patients with normal MSI/IHC, PREMM5 identified 84.2% and 83.3% of high-risk patients with CRC/EC and oncology clinic CRC patients with high-penetrance PVs, respectively. CONCLUSION MSI/IHC and PREMM5 effectively identify patients with CRC and/or EC with LS, although MSI/IHC has better specificity for LS. Because PREMM5 identifies non-LS, high-penetrance germline PVs, patients with CRC and/or EC with PREMM5 score ≥ 2.5%, including those with normal MSI/IHC, should be offered multigene panel testing.

scholarly journals Rare Germline Pathogenic Variants Identified by Multigene Panel Testing and the Risk of Aggressive Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1495
Author(s):  
Tú Nguyen-Dumont ◽  
James G. Dowty ◽  
Robert J. MacInnis ◽  
Jason A. Steen ◽  
Moeen Riaz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Risk Prediction ◽  
Prediction Models ◽  
Risk Prediction Models ◽  
Aggressive Prostate Cancer ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Predisposition Genes ◽  
Rare Genetic Variants

While gene panel sequencing is becoming widely used for cancer risk prediction, its clinical utility with respect to predicting aggressive prostate cancer (PrCa) is limited by our current understanding of the genetic risk factors associated with predisposition to this potentially lethal disease phenotype. This study included 837 men diagnosed with aggressive PrCa and 7261 controls (unaffected men and men who did not meet criteria for aggressive PrCa). Rare germline pathogenic variants (including likely pathogenic variants) were identified by targeted sequencing of 26 known or putative cancer predisposition genes. We found that 85 (10%) men with aggressive PrCa and 265 (4%) controls carried a pathogenic variant (p < 0.0001). Aggressive PrCa odds ratios (ORs) were estimated using unconditional logistic regression. Increased risk of aggressive PrCa (OR (95% confidence interval)) was identified for pathogenic variants in BRCA2 (5.8 (2.7–12.4)), BRCA1 (5.5 (1.8–16.6)), and ATM (3.8 (1.6–9.1)). Our study provides further evidence that rare germline pathogenic variants in these genes are associated with increased risk of this aggressive, clinically relevant subset of PrCa. These rare genetic variants could be incorporated into risk prediction models to improve their precision to identify men at highest risk of aggressive prostate cancer and be used to identify men with newly diagnosed prostate cancer who require urgent treatment.

scholarly journals Multigene Panel Testing Increases the Number of Loci Associated with Gastric Cancer Predisposition

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1340 ◽  
Author(s):  
Gianluca Tedaldi ◽  
Francesca Pirini ◽  
Michela Tebaldi ◽  
Valentina Zampiga ◽  
Ilaria Cangini ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Susceptibility Genes ◽  
Cancer Predisposition ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Number Of Patients ◽  
Multigene Panel Testing ◽  
Multigene Panel

The main gene involved in gastric cancer (GC) predisposition is CDH1, the pathogenic variants of which are associated with diffuse-type gastric cancer (DGC) and lobular breast cancer (LBC). CDH1 only explains a fraction (10–50%) of patients suspected of DGC/LBC genetic predisposition. To identify novel susceptibility genes, thus improving the management of families at risk, we performed a multigene panel testing on selected patients. We searched for germline pathogenic variants in 94 cancer-related genes in 96 GC or LBC Italian patients with early-onset and/or family history of GC. We found CDH1 pathogenic variants in 10.4% of patients. In 11.5% of cases, we identified loss-of-function variants in BRCA1, BRCA2, PALB2, and ATM breast/ovarian cancer susceptibility genes, as well as in MSH2, PMS2, BMPR1A, PRF1, and BLM genes. In 78.1% of patients, we did not find any variants with clear-cut clinical significance; however, 37.3% of these cases harbored rare missense variants predicted to be damaging by bioinformatics tools. Multigene panel testing decreased the number of patients that would have otherwise remained genetically unexplained. Besides CDH1, our results demonstrated that GC pathogenic variants are distributed across a number of susceptibility genes and reinforced the emerging link between gastric and breast cancer predisposition.

scholarly journals Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast

2021 ◽  
Author(s):  
Siddhartha Yadav ◽  
Chunling Hu ◽  
Katherine L. Nathanson ◽  
Jeffrey N. Weitzel ◽  
David E. Goldgar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lobular Carcinoma ◽  
Population Based ◽  
Cancer Predisposition ◽  
Clinical Cohort ◽  
Breast Cancer Predisposition ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Predisposition Genes ◽  
Multigene Panel

PURPOSE To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). RESULTS The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. CONCLUSION The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.

scholarly journals Contribution of New Adenomatous Polyposis Predisposition Genes in an Unexplained Attenuated Spanish Cohort by Multigene Panel Testing

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Víctor Lorca ◽  
Daniel Rueda ◽  
Lorena Martín-Morales ◽  
María Jesús Fernández-Aceñero ◽  
Judith Grolleman ◽  
...  
Keyword(s):  
Adenomatous Polyposis ◽  
Panel Testing ◽  
Predisposition Genes ◽  
Multigene Panel Testing ◽  
Spanish Cohort ◽  
Multigene Panel

scholarly journals No Evidence of Increased Risk of Breast Cancer in Women With Lynch Syndrome Identified by Multigene Panel Testing

2020 ◽  
pp. 51-60 ◽  
Author(s):  
Jessica Stoll ◽  
Eric Rosenthal ◽  
Shelly Cummings ◽  
Jamie Willmott ◽  
Ryan Bernhisel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lynch Syndrome ◽  
Large Cohort ◽  
Average Risk ◽  
Female Population ◽  
Panel Testing ◽  
Increased Risk ◽  
Cancer Rates ◽  
Multigene Panel Testing ◽  
Multigene Panel

PURPOSE Prior estimates of breast cancer risk in women with Lynch syndrome (LS) range from population risk to 18-fold increased risk with reported differences by gene. Here, breast cancer rates were determined in a large cohort of women with pathogenic variants (PVs) in a mismatch repair (MMR) gene detected through multigene panel testing and compared with rates in the US population and women undergoing panel testing. METHODS MMR gene PV carriers were identified among women tested for suspicion of LS or hereditary breast and ovarian cancer (HBOC) who met inclusion criteria. Standardized incidence ratios (SIRs) and 95% CIs of breast cancer were calculated compared with age-matched incidence in the general US female population and with women negative for PVs stratified by the test indication. RESULTS In total, 0.8% of women (30,362 of 441,966 women) carried MMR gene PVs. PVs in PMS2 (37.5%) and MSH6 (29.3%) were more common than in MLH1 (13.7%) and MSH2/EPCAM (19.4%). Women with PVs in PMS2 and MSH6 were tested more frequently for HBOC, whereas those with PVs in MLH1 and MSH2/EPCAM were tested more frequently for LS. Breast cancer rates in women with LS were lower than those in the general female population (SIR, 0.88; 95% CI, 0.81 to 0.96) and did not differ compared with women with negative panel testing for HBOC (SIR, 0.90; 95% CI, 0.82 to 0.99) or LS (SIR, 1.02; 95% CI, 0.78 to 1.30). CONCLUSION In this large cohort of women with LS identified through panel testing, there was no evidence for increased risk of breast cancer compared with the general US population or women undergoing panel testing. These findings support average-risk breast cancer screening in women with LS.

scholarly journals Up-Front Multigene Panel Testing for Cancer Susceptibility in Patients With Newly Diagnosed Endometrial Cancer: A Multicenter Prospective Study

2021 ◽  
pp. 1588-1602
Author(s):  
Monica D. Levine ◽  
Rachel Pearlman ◽  
Heather Hampel ◽  
Casey Cosgrove ◽  
David Cohn ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Type Ii ◽  
Newly Diagnosed ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Multigene Panel Testing ◽  
Multigene Panel

PURPOSE Clinical utility of up-front multigene panel testing (MGPT) is directly related to the frequency of pathogenic variants (PVs) in the population screened and how genetic findings can be used to guide treatment decision making and cancer prevention efforts. The benefit of MGPT for many common malignancies remains to be determined. In this study, we evaluated up-front MGPT in unselected patients with endometrial cancer (EC) to determine the frequency of PVs in cancer susceptibility genes. METHODS Patients with EC were prospectively enrolled at nine Ohio institutions from October 1, 2017, to December 31, 2020. Nine hundred and sixty-one patients with newly diagnosed EC underwent clinical germline MGPT for 47 cancer susceptibility genes. In addition to estimating the prevalence of germline PVs, the number of individuals identified with Lynch syndrome (LS) was compared between MGPT and tumor-based screening. RESULTS Likely pathogenic variants or PVs were identified in 97 of 961 women (10.1%). LS was diagnosed in 29 of 961 patients (3%; 95% CI, 2.1 to 4.3), with PVs in PMS2 most frequent. MGPT revealed nine patients with LS in addition to the 20 identified through routine tumor-based screening. BRCA1 and BRCA2 PVs were found in 1% (10 of 961; 95% CI, 0.6 to 1.9) of patients and that group was significantly enriched for type II ECs. CONCLUSION This prospective, multicenter study revealed potentially actionable germline variants in 10% of unselected women with newly diagnosed EC, supporting the use of up-front MGPT for all EC patients. The discovery that BRCA1 or BRCA2 heterozygotes frequently had type II cancers points to therapeutic opportunities for women with aggressive histologic EC subtypes.

scholarly journals Molecular Diagnosis of Neurofibromatosis by Multigene Panel Testing

2021 ◽  
Vol 12 ◽  
Author(s):  
Zeng-Yun-Ou Zhang ◽  
Yuan-Yuan Wu ◽  
Xin-ying Cai ◽  
Wen-Liang Fang ◽  
Feng-Li Xiao
Keyword(s):  
Mutation Rate ◽  
Genetic Disorder ◽  
Missense Variant ◽  
Neurogenic Tumors ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Clinical Diagnoses ◽  
Exon 1 ◽  
Multigene Panel Testing ◽  
Multigene Panel

Neurofibromatosis (NF) is an autosomal genetic disorder for which early and definite clinical diagnoses are difficult. To identify the diagnosis, five affected probands with suspected NF from unrelated families were included in this study. Molecular analysis was performed using multigene panel testing and Sanger sequencing. Ultradeep sequencing was used to analyze the mutation rate in the tissues from the proband with mosaic mutations. Three different pathogenic variants of the NF1 gene were found in three probands who mainly complained of café-au-lait macules (CALMs), including one frameshift variant c.5072_5073insTATAACTGTAACTCCTGGGTCAGGGAGTACACCAA:p.Tyr1692Ilefs in exon 37, one missense variant c.3826C &gt; T:p.Arg1276Ter in exon 28, and one splicing variant c.4110 + 1G &gt; T at the first base downstream of the 3′-end of exon 30. One NF1 gene mosaic variant was found in a proband who complained of cutaneous neurofibroma with the frameshift variant c.495_498del:p.Thr165fs in exon 5, and ultradeep sequencing showed the highest mutation rate of 10.81% in cutaneous neurofibromas. A frameshift variant, c.36_39del:p.Ser12fs in exon 1 of the NF2 gene, was found in a proband who presented with skin plaques and intracranial neurogenic tumors. All of these pathogenic variants were heterozygous, one was not reported, and one not in Chinese before. This study expands the pathogenic variant spectrum of NF and demonstrates the clinical diagnosis.

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