Multigene hereditary cancer panel testing for patients with pancreatic cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 244-244
Author(s):  
Anna K McGill ◽  
Sheila R Solomon ◽  
Megan L Marshall ◽  
Lisa Susswein ◽  
Corrine Fillman ◽  
...  
Keyword(s):  
Family History ◽  
Hereditary Cancer ◽  
Diagnostic Yield ◽  
Ductal Adenocarcinoma ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
History Of ◽  
Brca1 Brca2 ◽  
Cancer Panel

244 Background: Pancreatic ductal adenocarcinoma (PC) is associated with multiple hereditary cancer syndromes. Genes implicated in hereditary PC include ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2 and PMS2. The advent of multi-gene hereditary cancer panel testing streamlines diagnoses and medical management for clinicians and patients. Our objective was to assess the yield of pathogenic/likely pathogenic variants (PV/LPV) in individuals with PC undergoing panel testing as an initial test at GeneDx. Methods: We retrospectively reviewed panel test results of 605 individuals reporting a personal history of PC. Panel testing evaluated up to 32 genes associated with hereditary cancer. Individuals reporting neuroendocrine pathology or previous BRCA1/BRCA2 testing were excluded. Results: In this cohort, 61 PV/LPV were detected in 57 individuals in the following genes: ATM (17), BRCA2 (14), BRCA1 (5), CDKN2A (5), PALB2 (5), CHEK2 (4), MLH1 (2), MUTYH (2), PMS2 (2), BARD1 (1), FANCC (1), MSH2 (1), RAD51D (1) and TP53 (1), corresponding to a positive yield of 9.4% (57/605). Fifty-one of 61 PV/LPV were detected in genes associated with PC (84%) while 10 PV/LPV (16%) were identified in other genes including BARD1, CHEK2, FANCC, MUTYH, and RAD51D. The diagnostic yield among those reporting a family history of PC (33/294, 11.2%) was not statistically different from those without a reported family history (24/311, 7.7%). However, PV/LPV in ATM were detected more often in individuals reporting a family history of PC compared to those without a family history (4.1% vs. 1.6%, p=0.018). Conclusions: In total, 9.4% of patients with PC tested positive for PV/LPV in 14 different genes by panel testing. Although the majority of PV/LPV were identified in known PC genes, 16% of positive findings occurred in genes not typically associated with PC. ATM was most commonly implicated and more frequently reported in patients reporting family histories of PC. Assessing whether these genes are indeed causally related to PC and/or are possibly associated with other cancer types requires further investigation. Based on our results we conclude multi-gene panel testing may be considered as a first option for patients with PC regardless of their family history.

Germline pathogenic variants in patients with pheochromocytoma.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 668-668
Author(s):  
Shirley A Yao ◽  
Elizabeth A Wiley ◽  
Lisa R. Susswein ◽  
Megan L. Marshall ◽  
Natalie J. Carter ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
Single Gene ◽  
Molecular Data ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Testing ◽  
History Of ◽  
Testing Algorithms ◽  
Cancer Panel

668 Background: Approximately 25% of pheochromocytomas (PCC) have a hereditary basis, and germline variants in the SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, VHL, FH, RET, MEN1, and NF1 genes have been associated with a predisposition to PCC and paraganglioma (PGL). Multi-gene hereditary cancer panel testing for PCC has become increasingly more common than single-gene testing algorithms. Identification of a pathogenic or likely pathogenic variant (PV/LPV) in one of these genes has important implications for surveillance in patients and their family members. Here we describe the spectrum of PV/LPV variants identified in individuals with PCC. Methods: We performed a retrospective review of clinical and molecular data for all individuals diagnosed with PCC who underwent panel testing through BioReference Laboratories that included at least SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, VHL, FH, RET, MEN1, and NF1 between January 2016 and February 2017. Results: Seventy-nine individuals underwent testing due to a personal (n = 76) or family (n = 3) history of PCC. The positive yield was 14% (11/79). The majority of PV/LPV were in SDHB (n = 4; 36%), followed by RET (n = 2, 18%), with the remaining variants being identified in SDHA (1), SDHC (1), VHL (1), TMEM127 (1), and MAX (1). Approximately half (6/11) of those with a PV/LPV had a non-syndromic presentation of a unilateral PCC with no reported family history of PCC or PGL. The average age at tumor diagnosis was lower for probands testing positive than those without PV/LPV (34y±14 vs 44y±16). Conclusions: Our data support previous recommendations that patients with apparently sporadic, non-syndromic PCC be considered for genetic testing. Panel testing is a useful tool for identifying individuals with hereditary PCC.

Multigene hereditary cancer testing in sarcoma patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1518-1518
Author(s):  
Sarah A. Jackson ◽  
Melanie D. Baxter ◽  
Jessica Mester ◽  
Lisa Susswein ◽  
Megan L. Marshall ◽  
...  
Keyword(s):  
Family History ◽  
Hereditary Cancer ◽  
Demographic Data ◽  
Personal History ◽  
Cancer Risk Assessment ◽  
Family History Information ◽  
Panel Testing ◽  
Potential Clinical Benefit ◽  
Gene Panel Testing ◽  
History Of

1518 Background: In multi-gene hereditary cancer testing, multiple syndromes may be interrogated simultaneously, increasing the likelihood of detecting an underlying cancer predisposition. We characterized the yield and distribution of pathogenic or likely pathogenic variants (PV/LPV) in patients with a personal history of sarcoma undergoing panel testing through our clinical diagnostic laboratory. Methods: We retrospectively reviewed panel test results, demographic data, and personal/family history information from patients reporting a personal history of sarcoma. Patients included in this study underwent panel testing (NGS and del/dup) of up to 61 genes at this laboratory and concurrent or prior TP53 analysis at this or an outside laboratory. Chi-square and Fisher’s exact tests were used to compare groups. Results: Among 374 sarcoma patients, 53 (14.2%) harbored one or more PV/LPV in 14 genes: TP53, BRCA2, CHEK2, BRCA1, ATM, MSH6, MLH1, NBN, BAP1, BRIP1, FLCN, MSH2, PTEN, and RB1. Thirty-nine (10.4%) individuals reported both a personal and family history of sarcoma; however, PV/LPV were not more likely to be detected among this group than those with personal history alone (p = 1.0). PV/LPV were most often detected in BRCA1/2 (15/374, 4.0%) or TP53 (12/374, 3.2%). Notably, four probands with BRCA1/2 PV/LPV reported a family history of sarcoma, including one kindred in which the variant was present in two brothers, both affected with sarcoma. Additionally, seven patients were found to have PV/LPV (1.9%) in genes causative for Lynch syndrome. Among patients with PV/LPV in genes other than TP53, nearly half (17/41, 41.5%) met National Comprehensive Cancer Network TP53 testing criteria. Conclusions: The majority of PV/LPV were identified in genes for which association with sarcoma risk is not well-established. While several of these genes have been implicated in somatic pathways related to sarcoma development, it is unclear whether these germline findings are causative, play no role, or modify sarcoma risk. Although these data do not inherently associate non- TP53 genes with sarcoma risk, they suggest a potential clinical benefit can be gained from performing hereditary cancer risk assessment and multi-gene panel testing in sarcoma patients.

scholarly journals Expanding the search for germline pathogenic variants for breast cancer. How far should we go and how high should we jump? The missed opportunity!

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Hikmat Abdel-Razeq
Keyword(s):  
Breast Cancer ◽  
Brca1 And Brca2 ◽  
Healthy Women ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
History Of ◽  
Risk Reducing ◽  
Current Guidelines ◽  
Missed Opportunity

Since the identification of BRCA1 and BRCA2 genes 3 decades ago, genetic testing and genetic counseling have become an integral part of routine clinical practice. The risk of breast cancer among carriers of germline pathogenic variants, like BRCA1 and BRCA2, is well established. Risk-reducing interventions, including bilateral mastectomies and salpingo-oophorectomies are both effective and have become more acceptable. Many researchers and professional societies view current guidelines as restrictive and may miss many at-risk women, and are calling to expand testing to include all patients with breast cancer, regardless of their personal or family history of cancer, while others are calling for wider adoption to even include all healthy women at age 30 or older. This review will address expanding testing in two directions; horizontally to include more patients, and even healthy women, and vertically to include more genes using next-generation sequencing-based multi-gene panel testing.

scholarly journals Apparently Heterozygous TP53 Pathogenic Variants May Be Blood Limited in Patients Undergoing Hereditary Cancer Panel Testing

2020 ◽  
Vol 22 (3) ◽  
pp. 396-404 ◽  
Author(s):  
Jessica L. Mester ◽  
Sarah A. Jackson ◽  
Kristen Postula ◽  
Amy Stettner ◽  
Sheila Solomon ◽  
...  
Keyword(s):  
Hereditary Cancer ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Cancer Panel

Inherited germline mutations in men with prostate cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16564-e16564
Author(s):  
Robert Reid ◽  
Marcie DiGiovanni ◽  
Ryan Bernhisel ◽  
Krystal Brown ◽  
Jennifer Saam ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genetic Testing ◽  
Family History ◽  
Hereditary Cancer ◽  
Clinical Information ◽  
Nccn Guidelines ◽  
Commercial Laboratory ◽  
Pathogenic Variants ◽  
Age Of Diagnosis ◽  
History Of

e16564 Background: Recent studies have demonstrated a high prevalence of pathogenic variants (PVs) in genes that confer hereditary cancer risk among men with metastatic prostate cancer (PC); however, PC does not currently receive attention as an indication for genetic testing. We assessed the clinical features of men with PC who received clinical testing as well as the distribution of PVs identified. Methods: A commercial laboratory database was queried to identify men with PC who underwent testing with a multi-gene hereditary cancer panel from September 2013–September 2016. Clinical information was obtained from provider-completed test request forms. Individuals with PC only were evaluated separately from those who had ≥1 additional malignancy. Personal/family history was evaluated relative to the 2013 NCCN guidelines for hereditary breast and ovarian cancer (HBOC) testing. Results: Overall, 700 men with a personal history of PC were identified: 384 (54.9%) with only PC and 316 (45.1%) with PC and ≥1 additional malignancy. The most common additional malignancies were colorectal (115) and breast cancer (105). The median age of diagnosis in men with only PC was 57.5, which is younger than tested men who had an additional malignancy (62) and the SEER data (2009-2013) for all men with PC (66). HBOC testing criteria were met by 75.9% of men, including 44 (6.3%) who met based only on a personal/family history of PC and 202 (28.9%) who met in part due to a personal/family history of PC. PVs were identified in 14.0% of all men: 11.5% of men with PC only and 17.1% of men with PC and a second malignancy (see Table). Conclusions: PC patients selected for genetic testing here were younger than men diagnosed with PC from the general population (SEER), and almost half had a diagnosis of an additional malignancy. They also have a high positive mutation rate across a broad spectrum of genes. [Table: see text]

Mosaic TP53 pathogenic variants on multi-gene hereditary cancer panel testing: Clinical characteristics and follow-up testing.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 1580-1580
Author(s):  
Sarah A. Jackson ◽  
Maegan Roberts ◽  
Jessica L. Mester ◽  
Megan L. Marshall ◽  
Kristen J. Vogel Postula ◽  
...  
Keyword(s):  
Hereditary Cancer ◽  
Clinical Characteristics ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Cancer Panel

Inherited germline mutations in men with prostate cancer.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 357-357
Author(s):  
Robert Reid ◽  
Marcie DiGiovanni ◽  
Ryan Bernhisel ◽  
Krystal Brown ◽  
Jennifer Saam ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genetic Testing ◽  
Family History ◽  
Hereditary Cancer ◽  
Clinical Information ◽  
Nccn Guidelines ◽  
Pathogenic Variants ◽  
Seer Data ◽  
Age Of Diagnosis ◽  
History Of

357 Background: Recent studies have demonstrated a high prevalence of pathogenic variants (PVs) in genes that confer hereditary cancer risk among men with metastatic prostate cancer (PC); however, PC does not currently receive attention as an indication for genetic testing. We assessed the clinical features of men with PC who received clinical testing as well as the distribution of PVs identified. Methods: Men with PC who underwent testing with a multi-gene hereditary cancer panel (Myriad Genetic Laboratories) from September 2013–September 2017 were included. Clinical information was obtained from provider-completed test request forms. Individuals with PC only were evaluated separately from those who had ≥1 additional malignancy. Personal/family history was evaluated relative to the 2013 NCCN guidelines for hereditary breast and ovarian cancer (HBOC) testing. Results: Overall, 1004 men with a personal history of PC were identified: 606 (60.4%) with only PC and 398 (39.6%) with PC and ≥1 additional malignancy. The most common additional malignancies were breast (136) and colorectal cancer (134). The median age of diagnosis in men with only PC was 59, which is younger than tested men who had an additional malignancy (63) and the SEER data (2009-2013) for all men with PC (66). HBOC testing criteria were met by 78.0% of men, including 68 (6.8%) who met based only on a personal/family history of PC and 330 (32.9%) who met in part due to a personal/family history of PC. PVs were identified in 12.9% of all men: 11.2% of men with PC only and 15.4% of men with PC and a second malignancy (Table). Conclusions: PC patients selected for genetic testing here were younger than men diagnosed with PC from the general population (SEER), and about a third had a diagnosis of an additional malignancy. They also have a high positive mutation rate across a broad spectrum of genes. [Table: see text]

Family cancer patterns and variation by race and ethnicity among individuals with pathogenic variants in multi-gene cancer predisposition panels at a large urban comprehensive cancer center.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13540-e13540
Author(s):  
Sushma Tatineni ◽  
Kristen Purrington ◽  
Hadeel Assad ◽  
Nadine Abdallah ◽  
Meri Tarockoff ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Colon Cancer ◽  
Family History ◽  
Cancer Risk ◽  
Race And Ethnicity ◽  
Cancer Predisposition ◽  
Comprehensive Cancer Center ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
History Of

e13540 Background: The identification of pathogenic variants and variants of unknown significance (VUS) in multi-gene cancer predisposition testing raises new questions regarding cancer risk and management. We evaluated the personal and family cancer patterns and variation by race and ethnicity, among individuals positive for pathogenic variants in non-BRCA1/ 2 cancer predisposing genes. Methods: The Karmanos Cancer Institute (KCI) Cancer Genetics database was queried from May 13, 2013 through December 31, 2018. There were 3,544 unrelated individuals evaluated for hereditary cancer predisposition of whom 1,868 had 18-gene panel testing at 6 sites across Michigan. Data was collected on personal and family cancer history including ages at diagnosis utilizing a 3-generation pedigree, self-identified race and ethnicity and results of genetic testing. We describe the prevalence of pathogenic variants by proband cancer diagnosis, family history, race, and ethnicity. Results: The race/ethnic distribution of the tested cohort included 67.5% non-Hispanic White (NHW), 24.4% African American (AA), 2.1% Arab, 1.8% Ashkenazi Jewish (AJ), 1.0% Hispanic, and 3.4% other. The distribution of cancer diagnoses included 40.6% breast, 5.5% ovarian, 4.1% colon, 3.5% endometrial, 2.0% pancreas and 39.7% unaffected. Pathogenic variants were seen in 151 (8.1%) individuals and VUS in 309 (16.5%). The five most common pathogenic variants were CHEK2 (40), MUTYH (22), ATM (20), and PALB2 (18). The most common pathogenic variants by race and ethnicity were CHEK2 (NHW), RAD51C (AA), PALB2 (Arab), CHEK2, MSH6 (AJ), and none in Hispanics. Variants associated with the four most common cancer types were breast ( CHEK2 ), ovarian ( CHEK2, MUTYH, BRIP1), colon ( ATM), and endometrial ( MSH6, PALB2). Of 40 individuals with CHEK2 variants, 92.5% were NHW, and 34 (85%), 31 (78%), 10 (25%), 1 (2.5%) had family history of breast cancer, breast cancer before age 50, ovarian, and colon cancer, respectively. Of 20 with ATM variants, 95% were NHW, 13 had family history data and 10 (76.9%), 8 (61.5%), 2 (15.4%), 1 (7.7%) had family history of breast, breast cancer before age 50, ovarian, and colon cancer, respectively. Conclusions: Pathogenic variants seen using multigene panel testing differ by race, ethnicity and personal/family history of cancer. This data will inform genetic counseling strategies in regards to cancer risk and management. Data on additional genes updated through 2019 will be presented.

Pathogenic Variants in BRIP1, RAD51C, and RAD51D Identified with Multi-Gene Panel Testing for Hereditary Cancers

2020 ◽  
Author(s):  
Shelly Cummings ◽  
Susana San Roman ◽  
Jennifer Saam ◽  
Ryan Bernhisel ◽  
Krystal Brown ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Risk ◽  
Cancer Diagnosis ◽  
Fold Increase ◽  
Ovarian Cancer Risk ◽  
Risk Genes ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
History Of

Abstract Background: Professional society guidelines recommend risk-reducing salpingo-oophorectomy (RRSO) for women with pathogenic variants (PVs) in ovarian cancer-risk genes. Personalization of that intervention is based on gene-specific phenotypes; however, the age of ovarian cancer diagnosis in women with PVs in moderate penetrance ovarian cancer-risk genes is not well characterized. Women who had hereditary cancer panel testing from September 2013-May 2019 were included (N=631,950). Clinical/demographic information was compared for women with a PV in BRIP1, RAD51C, or RAD51D versus in BRCA1 or BRCA2. Results: PVs in BRIP1, RAD51C, or RAD51D were identified in 0.5% of all tested women but in 1.6% of women with a history of ovarian cancer (~3-fold increase). PVs in BRCA1 or BRCA2 were identified in 2.4% of all tested women but in 6.1% of women with a history of ovarian cancer (~2.5-fold increase). The proportion of women with a personal or family history of ovarian cancer was similar among women with a PV in BRIP1, RAD51C, RAD51D, BRCA1, or BRCA2. The median age at ovarian cancer diagnosis was 53 years in BRCA1, 59 years for BRCA2, 65 years for BRIP1, 62 years for RAD51C, and 57 years for RAD51D.Conclusions: These data reinforce the importance of identifying PVs in moderate penetrance ovarian cancer-risk genes. The age at ovarian cancer diagnosis was older for women with PVs in BRIP1, RAD51C, or RAD51D, suggesting that it is safe to delay RRSO until age 45-50 in RAD51D PV carriers and possibly, until age 50-55 in BRIP and RAD51C PV carriers.

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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