Germinal defects of SDHx genes in patients with isolated pituitary adenoma

Background: The ‘3PAs’ syndrome, associating pituitary adenoma (PA) and pheochromocytoma/paraganglioma (PPGL), is sometimes associated with mutations in PPGL-predisposing genes, such as SDHx or MAX. In ’3PAs’ syndrome, PAs can occur before PPGL, suggesting a new gateway into SDHx/MAX-related diseases. Objective: To determine the SDHx/MAX mutation prevalence in patients with isolated PAs and characterize PAs of patients with SDHx/MAX mutations. Design: Genes involved in PAs (AIP/MEN1/CDKN1B) or PPGLs (SDHx/MAX) were sequenced in patients with isolated PAs. We then conducted a review of cases of PA in the setting of ’3PAs’ syndrome. Results: A total of 263 patients were recruited. Seven (likely) pathogenic variants were found in AIP, two in MEN1, two in SDHA, and one in SDHC. The prevalence of SDHx mutations reached 1.1% (3/263). Of 31 reported patients with PAs harboring SDHx/MAX mutations (28 published cases and 3 cases reported here), 6/31 (19%) developed PA before PPGL and 8/31 (26%) had isolated PA. The age of onset was later than in patients with AIP/MEN1 mutations. PAs were mainly macroprolactinomas and showed intracytoplasmic vacuoles seen on histopathology. Conclusions: We discovered SDHx mutations in patients bearing PA who had no familial or personal history of PPGL. However, the question of incidental association remains unresolved and data to determine the benefit of SDHx/MAX screening in these patients are lacking. We recommend that patients with isolated PA should be carefully examined for a family history of PPGLs. A family history of PPGL, as well as the presence of intracytoplasmic vacuoles in PA, requires SDHx/MAX genetic testing of patients.

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Family history and pathogenic/likely pathogenic germline variants in prostate cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.143 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 143-143

Author(s):

Rachel Sabol ◽

Elisa Marie Ledet ◽

Ellen Jaeger ◽

Marcus W. Moses ◽

Brian E. Lewis ◽

...

Keyword(s):

Prostate Cancer ◽

Ovarian Cancer ◽

Genetic Testing ◽

Family History ◽

Personal History ◽

Sample Collection ◽

First Degree Relatives ◽

Pathogenic Variants ◽

Damage Repair ◽

History Of

143 Background: Recent literature highlights the importance of germline genetic testing in prostate cancer (PCa) patients. Surprisingly, a literature review indicates that family history records are incomplete in published studies. Methods: Prospective and complete family history data were gathered from 496 men in a single institution with a personal history of PCa who underwent germline genetic testing using a panel of at least 79 genes (Invitae testing) from 2016-2020. Comprehensive FH were obtained in all PCa patients in this database and analysis of prevalent FH was assessed at the time of sample collection. Age, race, metastastes at any time, and Gleason score were also ascertained. MUTYH heterozygotes were not considered pathogenic. Results: Pathogenic/likely pathogenic variants (PV/LPVs) were not associated with age at diagnosis, race, or presence of metastasis. Men with Gleason scores 8-10 at time of diagnosis were more likely to have PV/LPV ( P= 0.004). One or more first degree relatives (FDR) with any cancer with was not predictive for germline PV/LPVs for men with PCa ( P= 0.96). Analysis of patients with one or more FDR with breast, prostate, ovarian, or pancreatic cancer revealed that only FDR with breast cancer ( P = 0.028) or ovarian cancer ( P = 0.015) was predictive for PV/LPVs. Though one or more FDR with prostate cancer did not predict a PV/LPV in the overall panel, further analysis indicate that a history of a FDR with PCa was predictive for PV/LPV in a DNA damage repair (DDR) gene ( P= 0.044). Conclusions: In men with a personal history of PCa, germline PV/LPVs were associated with a FDR with breast or ovarian cancer. A FDR with PCa was predictive for PV/LPV in DDR genes. These data emphasize the contribution of FH to germline genetic testing results in a cohort with complete ascertainment of cancer in first degree relatives.

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Germline mutations in Brazilian pancreatic carcinoma patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16749 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16749-e16749

Author(s):

Livia Munhoz Rodrigues ◽

Simone Maistro ◽

Maria Lucia Hirata Katayama ◽

Luiz A.Senna Leite ◽

Joao Glasberg ◽

...

Keyword(s):

Pancreatic Cancer ◽

Genetic Testing ◽

Family History ◽

Pancreatic Carcinoma ◽

Germline Mutations ◽

Family History Of Cancer ◽

First Degree Relatives ◽

Pathogenic Variants ◽

History Of ◽

History Of Cancer

e16749 Background: Pancreatic cancer has the prospect of becoming the second leading cause of cancer death by 2030. The NCCN Guidelines recommend genetic testing for all patients with pancreatic cancer, however, the spectrum of germline mutations has not been extensively evaluated because recent studies with genetic testing have explored only a limited number of genes and have focused predominantly on Caucasian populations. Therefore, our objective is to evaluate the frequency and spectrum of germline mutations in unselected patients with pancreatic cancer in a multiethnic population. Methods: Patients from Instituto do Câncer do Estado de São Paulo (Brazil) with histopathological diagnosis of non-endocrine pancreatic carcinoma were included, regardless of the family history of cancer. These patients answered a life habits and family history of cancer questionnaire and supplied blood for the Next Generation Sequencing (MiSeq platform) with the TruSight Hereditary Cancer panel (Illumina), which includes 115 cancer predisposing genes. Variant analysis was performed with the VarStation, a Brazilian tool that offers post-sequencing computational support and aid for clinical interpretation. Results: To the present moment, 77 patients were evaluated. The mean age of the patients was 62 years (27-83), among whom, 13% with young age (≤50 years) and 47 women (61%). Thirty-eight patients (49%) reported cases of cancer in first-degree relatives. Regarding risk factors, 41 patients (53%) reported smoking, 19 (25%) alcohol ingestion and 20 (26%) had obesity. Seven out of 77 patients presented pathogenic variants in ATM (n = 2) , CHEK2, FANCM (n = 2) or PALB2 (n = 2) genes. Two of these patients ( CHEK2 and FANCM) had early onset pancreatic cancer (≤45 years), both denied smoking habit and family history of cancer in 1st degree relatives. Two patients, who were ATM mutation carriers, reported 1st or 2nd degree relatives with cancer and are alive after 4 and 8 years of diagnosis. Conclusions: In this unselected group of pancreatic cancer patients, 15% were young, almost half reported first-degree relatives with cancer and 9% were carriers of pathogenic variants in genes related with the homologous recombination DNA repair.

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Inherited germline mutations in men with prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e16564 ◽

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]

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Germline pathogenic variants in patients with pheochromocytoma.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.668 ◽

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.

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Inherited germline mutations in men with prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.357 ◽

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]

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Clinical Utility of Telomere Length-Directed Genomic Assessment in Patients with Short Telomere Syndromes

Blood ◽

10.1182/blood-2019-127185 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1222-1222

Author(s):

Abhishek A Mangaonkar ◽

Alejandro Ferrer ◽

Filippo Pinto E Vairo ◽

Margot Cousin ◽

Ryan Kuisle ◽

...

Keyword(s):

Genetic Testing ◽

Family History ◽

Telomere Length ◽

Clinical Features ◽

Short Telomere ◽

Cryptogenic Cirrhosis ◽

Pathogenic Variants ◽

Likelihood Score ◽

History Of ◽

Age Appropriate

Introduction: Short telomere syndromes (STS) are accelerated aging syndromes affecting hematopoietic, pulmonary, hepatobiliary and/or immunological systems. Clinical assessment of age-appropriate telomere length (TL) is performed using flow cytometry & fluorescence in-situ hybridization (flowFISH). Screening for germline variants in STS-related genes is guided by flowFISH-determined centile categories of TL, with screening recommended for TL <1st centile or 1-10th centile in lymphocytes (L) or granulocytes (G). However, the utility of genetic testing for patients with TL >10th centile and integration of clinical phenotype with flowFISH data in predictive algorithms is currently unclear. Methods: FlowFISH testing was done at reference laboratories in Vancouver (Repeat Diagnostics; Canada) & Johns Hopkins University (JHU, USA). Salient clinical features were pre-determined as, personal history of premature hair greying (onset at age < 30 years), idiopathic pulmonary fibrosis (IPF) or IPF/emphysema overlap (in smokers), cryptogenic cirrhosis or NRH, unexplained cytopenias &/or immunodeficiency, & family history of the above (in >1 1st or 2nd degree relatives). Clinical likelihood score (CLS) was assigned as low (1), intermediate (int, 2) or high (>2), based on the number of aforementioned clinical features present prior to flowFISH testing. Genetic testing was performed using either an in-house or commercial bone marrow failure-specific next generation sequencing (NGS) panel or whole exome sequencing (WES), and data for known variants affecting telomerase or telomeric function (TERT, TERC, DKC1, TINF2, NHP2, NOP10, TCAB1, NAF1, & RTEL1) was recorded. Results: One hundred forty-nine patients at our institution underwent TL assessment at Repeat diagnostics (n=38) and JHU (n=111) laboratories, respectively. Median age was 56 (range: 7-79) years; 88 (59%) being males. Significant family history was present in 40 (27%) patients, while premature greying of hair was present in 13 (9%) patients. Organ-specific clinical features included unexplained cytopenias (n=89, 60%) IPF (n=71, 48%), cryptogenic cirrhosis or NRH (n=21, 14%), & unexplained immunodeficiency (n=14, 9%). CLS stratification included low (n=74, 50%), int (n=54, 36%), & high (n=21, 14%), with higher CLS significantly correlating with lower delta TL for L (p=0.0005) but not G (p=0.3). Genetic testing was performed in 51 (35%) patients (NGS-51, WES-1) among which 13 (26%) patients had a telomere-associated variant; 5 (10%) pathogenic (pv, all TERT). CLS alone was unable to predict likelihood of finding a telomere-associated variant (p=0.4). Based on age-appropriate centile categorization of L & G TL (information for both available in 134 patients), patients were stratified into six groups (table 1). TL <1st centile in L: This group was further divided into two groups; TL<1st centile in both L & G [A1, n=7, CLS low-3 (43%), int-2 (29%), & high-2 (29%)] and TL <1st centile in L and 1-50th centile in G (A2, n=2, CLS low & high) patients. Among the 4 (57%) patients who underwent genetic (NGS-3, WES-1) testing, 3 (75%) had TERTpv in A1 subgroup and 1 A2 subgroup patient had a VUS in TERT.TL <1st centile in G, 1-10th centile in L (n=18): This group included 9 (50%) low, 8 (44%) int and 1 (6) high CLS patients, of which only 1 of 8 NGS-tested patients had TERTpv.TL 1-10th centile in L or G: This group was divided into; 1-10th centile in both L & G [C1, n=28, CLS low-3 (11%), int-14 (50%), high-11(39%)] of whom 8 (22%) underwent NGS with no pathogenic variants but 3 VUS in RTEL1, NAF1 & PARN genes, and 1-10th centile in L, >1-90th centile in G [C2, n=36, CLS low-19 (53%), 16 (44%), 1 (3%)] of whom 8 (22%) underwent NGS with 1 TERTpv and 2 VUS in TINF2TL >10th centile in L & 1-90th centile in G (n=43, 32%): CLS stratification in this group included 27 (63%) low, 12 (28%) int, 4 (9%) high. NGS testing was done in 13 (30%) patients [CLS low-9(69%), int 2(15%), high 2 (15%)], of whom only 2 (15%) had VUS in TINF2 and TERT gene, but no pathogenic variants (figure 1). Conclusion: Our study demonstrates the importance of using a flowFISH assay based predictive algorithm to screen patients with suspected STS for telomere-related genetic alternations, in comparison to a clinical likelihood score. We also demonstrate a limited role for genetic testing in patients with lymphocyte TL >10th centile, regardless of the clinical likelihood score. Disclosures Patnaik: Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

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Clinical Implications of Identifying Pathogenic Variants in Individuals With Thoracic Aortic Dissection

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.118.002476 ◽

2019 ◽

Vol 12 (6) ◽

Cited By ~ 10

Author(s):

Brooke N. Wolford ◽

Whitney E. Hornsby ◽

Dongchuan Guo ◽

Wei Zhou ◽

Maoxuan Lin ◽

...

Keyword(s):

Family History ◽

Aortic Dissection ◽

Age Of Onset ◽

Family Members ◽

Aortic Disease ◽

Pathogenic Variant ◽

Carrier Status ◽

Thoracic Aortic Dissection ◽

Pathogenic Variants ◽

History Of

Background: Thoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or family members. Methods: We performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity. Results: Twenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, and TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 versus 57 years), higher rates of root aneurysm (54% versus 30%), less hypertension (15% versus 57%), lower rates of smoking (19% versus 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed that pathogenic variant carrier status was significantly associated with age <50 (odds ratio [OR], 5.5; 95% CI, 1.6–19.7), no history of hypertension (OR, 5.6; 95% CI, 1.4–22.3), and family history of aortic disease (mother: OR, 5.7; 95% CI, 1.4–22.3, siblings: OR, 5.1; 95% CI, 1.1–23.9, children: OR, 6.0; 95% CI, 1.4–26.7). Conclusions: Clinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with a thoracic aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset <50 years, family history of thoracic aortic disease, and no history of hypertension.

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Population-wide Screening for Germline Variants of Hereditary Cancer Genes in 12K Unselected Japanese Colorectal Cancers and 27K Controls

10.1101/2020.03.15.989947 ◽

2020 ◽

Author(s):

Masashi Fujita ◽

Xiaoxi Liu ◽

Yusuke Iwasaki ◽

Chikashi Terao ◽

Sadaaki Takata ◽

...

Keyword(s):

Family History ◽

Mismatch Repair ◽

Universal Screening ◽

Screening Strategy ◽

Mismatch Repair Genes ◽

Germline Variants ◽

Pathogenic Variants ◽

Predisposing Genes ◽

History Of ◽

Repair Genes

AbstractBackground & AimsColorectal cancer (CRC) is one of the most common cancers in Western countries and Japan. Currently, a few % of CRCs can be attributed to recognizable hereditary germline variants of known CRC susceptibility genes, predominantly the DNA mismatch repair genes. To establish a universal screening strategy for hereditary CRCs, it is necessary to explore the prevalence of hereditary CRC and pathogenic variants of multiple cancer-predisposing genes in non-European populations.MethodsWe analyzed the coding regions of 27 cancer-predisposing genes, including mismatch repair genes, APC, and BRCA1/2, in 12,503 unselected Japanese CRC patients and 23,705 controls aged ≥ 60 years without any personal or family history of cancer by target sequencing and genome-wide SNP chip data. Their clinical significance was assessed using ClinVar and the guidelines by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP).ResultsWe identified 4,804 variants in the 27 genes and annotated them as 397 pathogenic variants, 941 benign variants, and 3,466 variants of uncertain significance, of which 43.6% were registered in neither ClinVar nor dbSNP. In total, 3.3% of the unselected CRC patients and 1.5% of the controls had a pathogenic variant of the 27 genes. The pathogenic variants of MSH2 (odds ratio (OR) =18.1), MLH1 (OR=8.6), MSH6 (OR=4.9), APC (OR=49.4), BRIP1 (OR=3.6), BRCA1 (OR=2.6), BRCA2 (OR=1.9), and TP53 (OR=1.7) were significantly associated with CRC development in the Japanese population (P-values < 0.01, FDR<0.05). Furthermore, we confirmed copy number variants (CNVs) of MSH2/EPCAM, MLH1, and APC by multiplex ligation-dependent probe amplification (MLPA) and quantitative PCR in this cohort (n = 23), including whole gene duplications of MSH2 and APC. These pathogenic variants were significantly associated with the diagnostic age and personal/family history of other types of cancer. In total, at least 3.5% of the Japanese CRC population had a pathogenic variant or CNV of the 27 cancer-predisposing genes.ConclusionsThis is the largest study of CRC heredity in the Asian population and would contribute to the development of guidelines for genetic testing and variant interpretation for heritable CRCs. Universal screening for CRC risk should be assessed in multiple genes, including BRCA1/2 and BRIP1. These data would facilitate risk assessment of cancer and optimize the screening strategy.

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Prevalence of pathogenic variants in DNA damage response genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer

10.1101/2020.02.21.958256 ◽

2020 ◽

Author(s):

Tiffiney R. Hartman ◽

Elena V. Demidova ◽

Randy W. Lesh ◽

Lily Hoang ◽

Marcy Richardson ◽

...

Keyword(s):

Risk Assessment ◽

Dna Damage ◽

Genetic Testing ◽

Cancer Risk ◽

Dna Damage Response ◽

Early Onset ◽

Personal History ◽

Pathogenic Variants ◽

Damage Response ◽

History Of

ABSTRACTPurposePathogenic variants (PVs) in a number of genes are known to increase the risk of hereditary renal cancer (hRC). However, many early-onset RC (eoRC) patients undergoing genetic testing lack PVs in hRC genes; thus, their genetic risk remains undefined. To determine if PVs in DNA damage response (DDR) genes are enriched in a convenience sample of eoRC patients undergoing genetic testing.Materials and MethodsRetrospective review of results for 844 unselected eoRC patients, undergoing genetic testing with a multi-gene cancer panel by Ambry Genetics [between July 2012 and December 2016]. The patients were tested with CancerNext and/or CancerNext Expanded panels for a variety of indications. Identified PVs were compared with patient characteristics.ResultsMean age of RC diagnosis was 48 years [range 24-60]. In addition to eoRC, 57.9% patients tested reported at least one additional cancer; breast cancer being the most common (40.1% of females, 2.5% of males). PVs in cancer risk genes were identified in 12.8% of patients—3.7% in RC-specific genes, and 8.55% in DDR genes. DDR gene PVs were most commonly identified in CHEK2, BRCA1/2, and ATM. Among the 2.1% of patients with a BRCA1/2 PV, <50% reported a personal history of hereditary breast/ovarian-associated cancer. No association between age of RC diagnosis, and prevalence of PVs in RC-specific or DDR genes was observed.ConclusionsMulti-gene panel testing including DDR genes may provide a more comprehensive risk assessment in unselected eoRC patients, and their families. Validation in larger datasets is needed to characterize the association with eoRC.

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Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2020-0501 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Emily Breidbart ◽

Liyong Deng ◽

Patricia Lanzano ◽

Xiao Fan ◽

Jiancheng Guo ◽

...

Keyword(s):

Genetic Testing ◽

Exome Sequencing ◽

Large Scale ◽

Age Of Onset ◽

Family Members ◽

Ethnically Diverse ◽

Monogenic Diabetes ◽

Diabetes Diagnosis ◽

Pathogenic Variants ◽

Atypical Diabetes

Abstract Objectives There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY. Methods We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A. The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%. Results Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A. Less frequently, mutations were identified in PDX1, HNF4A, HNF1B, and KCNJ11. For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation. Conclusions Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.

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