Identification of Germline Mutations in Melanoma Patients with Early Onset, Double Primary Tumors, or Family Cancer History by NGS Analysis of 217 Genes

Jelínková, Sandra; Storchová, Radka; Zemánková, Petra; Vočka, Michal; Kodet, Ondřej; Král, J; Černá, Marta; Volková, Z; Janatová, Markéta; Soukupová, Jana; Stránecký, Viktor; Dundr, Pavel; Foretová, Lenka; Macůrek, Libor; Kleiblová, Petra; Kleibl, Zdeněk

doi:10.3390/biomedicines8100404

Cited by 11 publications

(11 citation statements)

References 57 publications

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“…(From Sokolenko et al, [ 17 ]). A woman diagnosed with breast cancer, melanoma and colorectal cancer with a pathogenic variant in FANCC and P/LP variant in TYR (Stolarova et al, [ 18 ]). A woman diagnosed with lobular breast cancer at 51 years of age, followed by follicular adenoma and thyroid micropapillary carcinoma at 52 years with pathogenic variants in PMS2 and CDH1 (Njoroge et al, [ 19 ]).…”

Section: Phenotypic Consequences Of Minasmentioning

confidence: 99%

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Multilocus Inherited Neoplasia Allele Syndrome (MINAS): an update

et al. 2022

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Multi-locus Inherited Neoplasia Allele Syndrome (MINAS) refers to individuals with germline pathogenic variants in two or more cancer susceptibility genes(CSGs). With increased use of exome/genome sequencing it would be predicted that detection of MINAS would become more frequent. Here we review recent progress in knowledge of MINAS. A systematic literature search for reports of individuals with germline pathogenic variants in 2 or more of 94 CSGs was performed. In addition, participants with multiple primary tumours who underwent genome sequencing as part of the Rare Disease arm of the UK 100,000 Genomes Project were interrogated to detect additional cases. We identified 385 MINAS cases (211 reported in the last 5 years, 6 from 100,000 genomes participants). Most (287/385) cases contained at least one pathogenic variant in either BRCA1 or BRCA2. 108/385 MINAS cases had multiple primary tumours at presentation and a subset of cases presented unusual multiple tumour phenotypes. We conclude that, as predicted, increasing numbers of individuals with MINAS are being have been reported but, except for individuals with BRCA1/BRCA2 MINAS, individual CSG combinations are generally rare. In many cases it appears that the clinical phenotype is that which would be expected from the effects of the constituent CSG variants acting independently. However, in some instances the presence of unusual tumour phenotypes and/or multiple primary tumours suggests that there may be complex interactions between the relevant MINAS CSGs. Systematic reporting of MINAS cases in a MINAS database (e.g. https://databases.lovd.nl/shared/diseases/04296) will facilitate more accurate prognostic predictions for specific CSG combinations.

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Section: Phenotypic Consequences Of Minasmentioning

confidence: 99%

“…A woman diagnosed with breast cancer, melanoma and colorectal cancer with a pathogenic variant in FANCC and P/LP variant in TYR (Stolarova et al, [ 18 ]).…”

Section: Phenotypic Consequences Of Minasmentioning

confidence: 99%

Multilocus Inherited Neoplasia Allele Syndrome (MINAS): an update

et al. 2022

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“…For example, patients with breast cancer or melanoma and a subsequent cancer diagnosis are more likely to harbor a PV in a hereditary cancer predisposition gene in comparison with patients without MPCs. However, past studies have been limited by size and selected for tumor type or advanced disease 4‐6 . We sought to characterize the frequency of germline PVs among patients with multiple primary malignancies in a cohort more generally representative of individuals presenting for hereditary cancer genetic testing because this information can be helpful in counseling patients with MPCs and their families 7,8…”

Section: Introductionmentioning

confidence: 99%

Prevalence and spectrum of pathogenic variants among patients with multiple primary cancers evaluated by clinical characteristics

Bychkovsky

Yussuf

et al. 2021

Cancer

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Background Multiple primary cancers (MPCs) are a hallmark of cancer predisposition syndromes. Here the frequency of germline pathogenic variants (PVs) among patients with MPCs is reported. Methods Patients with MPCs who underwent multigene panel testing from March 2012 to December 2016 were studied. Eligible patients had an analysis of 21 genes: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, and TP53. The frequencies of PVs by sex, number of cancers, and age at diagnosis were compared with 2‐sided χ2 tests or Fisher exact tests when the number was <10. Results Among the 9714 patients analyzed, most were female (91.1%) and White (71.0%); the median age at testing was 63 years, and the median ages at first and second cancer diagnoses were 49 and 58 years, respectively. Overall, 1320 (13.6%) had PVs. The prevalence of PVs increased with the number of primary cancers (PCs): 13.1% with 2 PCs, 15.9% with 3 PCs, and 18.0% with ≥4 PCs (P = .00056). Differences in the prevalence of PVs by age at diagnosis were significant: 14.7% with 2 PCs at an age < 50 years, 15.8% with 1 PC at an age < 50 years, and 12.0% with all PCs at an age ≥ 50 years (P = 2.07E–05). PVs by the age at second cancer diagnosis were also significant: 14.7% at an age < 50 years, 13.9% at an age of 50 to 69 years, and 11.4% at an age ≥ 70 years (P for trend = .005). Conclusions Among patients with MPCs, there is a high frequency of germline PVs, with a higher frequency found among patients with a higher number of PCs. These findings suggest that genetic testing should be considered even among patients who are older at the diagnosis of an additional primary malignancy.

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“…Paired-end 151 bp reads were generated on an Illumina HiSeq 4000 (Individuals 1 and 2) or NovaSeq (Individuals 3–6). Secondary analysis was performed using Churchill, a comprehensive workflow for analysis of raw reads from genome alignment through to germline and somatic variant identification [ 21 ]. Reads were aligned to the human genome reference sequence (build GRCh37 (Individuals 1–5) or GRCh38 (Individual 6) using BWA (v0.7.15).…”

Section: Methodsmentioning

confidence: 99%

“…CHEK2 germline loss-of-function alterations have been reported at low frequencies in high-throughput analyses of pediatric cancer cohorts, including neuroblastomas, non-Hodgkin lymphomas, thyroid cancer, melanomas, sarcomas, and brain tumors [ 2 , 19 , 20 , 21 , 22 , 23 , 24 ], but the associated clinical phenotypes and outcomes remain poorly described or understood. We present our single-institution experience with six children with CHEK2 germline alterations and cancer or cancer-predisposing conditions, including their clinical presentations and outcomes.…”

Section: Introductionmentioning

confidence: 99%

CHEK2 Alterations in Pediatric Malignancy: A Single-Institution Experience

Abdelghani

Schieffer

Cottrell

et al. 2023

Cancers

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Background: Approximately 10% of pediatric malignancies are secondary to germline alterations in cancer-predisposing genes. Checkpoint kinase 2 (CHEK2) germline loss-of-function variants have been reported in pediatric cancer patients, but clinical phenotypes and outcomes are poorly described. We present our single-institution experience of pediatric oncology patients with CHEK2 germline alterations, including clinical presentations and outcomes. Methods: Pediatric oncology patients with CHEK2 germline alterations were identified among those assessed by clinical or translational research at the Institute for Genomic Medicine at Nationwide Children’s Hospital. A chart review of disease course was conducted on identified patients. Results: We identified 6 patients with germline CHEK2 variants from a cohort of 300 individuals, including 1 patient with concurrent presentation of Burkitt lymphoma and neuroblastoma, 3 patients with brain tumors, 1 patient with Ewing sarcoma, and 1 patient with myelodysplastic syndrome. Three patients had a family history of malignancies. Four patients were in remission; one was undergoing treatment; one patient had developed treatment-related meningiomas. We review prior data regarding CHEK2 variants in this population, challenges associated with variant interpretation, and genetic counseling for individuals with CHEK2 variants. Conclusions: CHEK2 germline loss-of-function alterations occur in patients with a variety of pediatric tumors. Larger multicenter studies will improve our understanding of the incidence, phenotype, and molecular biology of CHEK2 germline variants in pediatric cancers.

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Identification of Germline Mutations in Melanoma Patients with Early Onset, Double Primary Tumors, or Family Cancer History by NGS Analysis of 217 Genes

Cited by 11 publications

References 57 publications

Multilocus Inherited Neoplasia Allele Syndrome (MINAS): an update

Multilocus Inherited Neoplasia Allele Syndrome (MINAS): an update

Prevalence and spectrum of pathogenic variants among patients with multiple primary cancers evaluated by clinical characteristics

CHEK2 Alterations in Pediatric Malignancy: A Single-Institution Experience

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