Screening for mutations in cancer-predisposition genes

2004 ◽  
pp. 48-60
Author(s):  
Jan Vijg ◽  
Yousin Suh
Keyword(s):  
Cancer Predisposition ◽  
Predisposition Genes

scholarly journals Performance of In Silico Prediction Tools for the Detection of Germline Copy Number Variations in Cancer Predisposition Genes in 4208 Female Index Patients with Familial Breast and Ovarian Cancer

Cancers ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 118
Author(s):  
Louisa Lepkes ◽  
Mohamad Kayali ◽  
Britta Blümcke ◽  
Jonas Weber ◽  
Malwina Suszynska ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
In Silico ◽  
Copy Number ◽  
Gc Content ◽  
Copy Number Variations ◽  
Cancer Predisposition ◽  
Predictive Values ◽  
Prediction Tools ◽  
Predisposition Genes ◽  
Female Index

The identification of germline copy number variants (CNVs) by targeted next-generation sequencing (NGS) frequently relies on in silico CNV prediction tools with unknown sensitivities. We investigated the performances of four in silico CNV prediction tools, including one commercial (Sophia Genetics DDM) and three non-commercial tools (ExomeDepth, GATK gCNV, panelcn.MOPS) in 17 cancer predisposition genes in 4208 female index patients with familial breast and/or ovarian cancer (BC/OC). CNV predictions were verified via multiplex ligation-dependent probe amplification. We identified 77 CNVs in 76 out of 4208 patients (1.81%); 33 CNVs were identified in genes other than BRCA1/2, mostly in ATM, CHEK2, and RAD51C and less frequently in BARD1, MLH1, MSH2, PALB2, PMS2, RAD51D, and TP53. The Sophia Genetics DDM software showed the highest sensitivity; six CNVs were missed by at least one of the non-commercial tools. The positive predictive values ranged from 5.9% (74/1249) for panelcn.MOPS to 79.1% (72/91) for ExomeDepth. Verification of in silico predicted CNVs is required due to high frequencies of false positive predictions, particularly affecting target regions at the extremes of the GC content or target length distributions. CNV detection should not be restricted to BRCA1/2 due to the relevant proportion of CNVs in further BC/OC predisposition genes.

scholarly journals Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome

2015 ◽  
Vol 149 (3) ◽  
pp. 604-613.e20 ◽  
Author(s):  
Matthew B. Yurgelun ◽  
Brian Allen ◽  
Rajesh R. Kaldate ◽  
Karla R. Bowles ◽  
Thaddeus Judkins ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Cancer Predisposition ◽  
Predisposition Genes

Breast cancer ER, PR, and HER2 expression variance by germline cancer predisposition genes.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10526-10526
Author(s):  
Grace Wei ◽  
Marilin Rosa ◽  
Maxine Chang ◽  
Brian J. Czerniecki ◽  
Xia Wang
Keyword(s):  
Breast Cancer ◽  
Cancer Diagnosis ◽  
Breast Cancer Diagnosis ◽  
Cancer Predisposition ◽  
Tumor Evolution ◽  
Breast Cancers ◽  
Her2 Expression ◽  
Expression Levels ◽  
Genetic Test Results ◽  
Predisposition Genes

10526 Background: The association between breast cancer characteristics and survival with estrogen receptor (ER) and progesterone receptor (PR) expression has been primarily studied via binomial categories, ER-positive and ER-negative. In order to better characterize germline genetic influences on these markers, we investigated their IHC expression semi-quantitatively in cancer predisposition germline pathogenic variant (PV) carriers of the following genes: BRCA1, BRCA2, PALB2, TP53, PTEN, CDH1, ATM, CHEK2, and Lynch syndrome genes. The HER2 expression was also analyzed. Methods: We conducted a retrospective chart review of patients with germline panel genetic testing for cancer predisposition genes at Moffitt Cancer Center’s GeneHome clinic. Inclusion criteria included 1) women ≥18 years old, 2) breast cancer diagnosis, 3) cancer predisposition germline panel genetic test results, 4) available ER and PR expression levels, and 5) available HER expression and/or amplification status. ER, PR, and HER2 status were compared between PV carriers and non-PV carriers via Mann-Whitney U at p>0.05. Results: A total of 847 cases were reviewed for the study. Among 658 patients with a breast cancer diagnosis and complete ER PR data, 365 cases (55.5%) were non-PV carriers and 293 cases (44.5%) carried a PV in at least one of the genes listed above. Among 635 cases with available HER2 expression/amplification status, 355 (55.9%) cases were non-PV carriers and 288 (45.4%) cases were PV-carriers. When compared with non-PV carrier controls, BRCA1 PV carriers’ breast tumors had significantly lower ER and/or PR expression. Further, BRCA2 and TP53 PV tumors also displayed moderately lower ER expression. Contrarily, CHEK2 tumors displayed higher ER and PR expression compared to controls. Further, BRCA1 and BRCA2 PV carriers were more likely to have HER2- breast cancers. Conclusions: Differences in ER, PR, HER2 expression levels were observed in germline PV carrier breast cancers, signaling differential impacts by germline PVs on the tumor evolution process. It is likely that tumor differences in PV carriers influence responses to therapies, including hormone therapy, anti-HER2 therapy, and subsequent survival.[Table: see text]

Primer on Hereditary Cancer Predisposition Genes Included Within Somatic Next-Generation Sequencing Panels

2019 ◽  
pp. 1-11
Author(s):  
Zade Akras ◽  
Brandon Bungo ◽  
Brandie H. Leach ◽  
Jessica Marquard ◽  
Manmeet Ahluwalia ◽  
...  
Keyword(s):  
Hereditary Cancer ◽  
Cancer Susceptibility ◽  
Cancer Predisposition ◽  
Comprehensive Overview ◽  
Germline Variants ◽  
Cancer Susceptibility Genes ◽  
Germline Genes ◽  
Number Of Genes ◽  
Predisposition Genes ◽  
Hereditary Cancer Predisposition

PURPOSE It has been estimated that 5% to 10% of cancers are due to hereditary causes. Recent data sets indicate that the incidence of hereditary cancer may be as high as 17.5% in patients with cancer, and a notable subset is missed if screening is solely by family history and current syndrome-based testing guidelines. Identification of germline variants has implications for both patients and their families. There is currently no comprehensive overview of cancer susceptibility genes or inclusion of these genes in commercially available somatic testing. We aimed to summarize genes linked to hereditary cancer and the somatic and germline panels that include such genes. METHODS Germline predisposition genes were chosen if commercially available for testing. Penetrance was defined as low, moderate, or high according to whether the gene conferred a 0% to 20%, 20% to 50%, or 50% to 100% lifetime risk of developing the cancer or, when percentages were not available, was estimated on the basis of existing literature descriptions. RESULTS We identified a total of 89 genes linked to hereditary cancer predisposition, and we summarized these genes alphabetically and by organ system. We considered four germline and six somatic commercially available panel tests and quantified the coverage of germline genes across them. Comparison between the number of genes that had germline importance and the number of genes included in somatic testing showed that many but not all germline genes are tested by frequently used somatic panels. CONCLUSION The inclusion of cancer-predisposing genes in somatic variant testing panels makes incidental germline findings likely. Although somatic testing can be used to screen for germline variants, this strategy is inadequate for comprehensive screening. Access to genetic counseling is essential for interpretation of germline implications of somatic testing and implementation of appropriate screening and follow-up.

scholarly journals Expanding cancer predisposition genes with ultra-rare cancer-exclusive human variations

2020 ◽  
Author(s):  
Roni Rasnic ◽  
Nathan Linial ◽  
Michal Linial
Keyword(s):  
Genetic Predisposition ◽  
Rare Variants ◽  
Genetic Alterations ◽  
Cancer Predisposition ◽  
Rare Cancer ◽  
Uk Biobank ◽  
Independent Evidence ◽  
High Penetrance ◽  
Predisposition Genes ◽  
The Uk

AbstractIt is estimated that up to 10% of cancer incidents are attributed to inherited genetic alterations. Despite extensive research, there are still gaps in our understanding of genetic predisposition to cancer. It was theorized that ultra-rare variants partially account for the missing heritable component. We harness the UK BioBank dataset of ∼500,000 individuals, 14% of which were diagnosed with cancer, to detect ultra-rare, possibly high-penetrance cancer predisposition variants. We report on 115 cancer-exclusive ultra-rare variations (CUVs) and nominate 26 variants with additional independent evidence as cancer predisposition variants. We conclude that population cohorts are valuable source for expanding the collection of novel cancer predisposition genes.

scholarly journals Psychological and Behavioral Implications of Screening for Breast or Ovarian Cancer Predisposition Genes BRCA1 and BRCA2

1999 ◽  
Vol 12 (2) ◽  
pp. 87-92
Author(s):  
Karen T. Lesniak ◽  
Tonya G. Callaway ◽  
Becky Althaus ◽  
Charles A. Guarnaccia ◽  
Joanne L. Blum
Keyword(s):  
Ovarian Cancer ◽  
Cancer Predisposition ◽  
Brca1 And Brca2 ◽  
Predisposition Genes

Constitutional de novo deletion CNV encompassing REST predisposes to diffuse hyperplastic perilobar nephroblastomatosis (HPLN)

2020 ◽  
pp. jmedgenet-2020-107087
Author(s):  
Zerin Hyder ◽  
Adele Fairclough ◽  
Mike Groom ◽  
Joan Getty ◽  
Elizabeth Alexander ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Cancer Predisposition ◽  
Tumour Suppressor ◽  
Comparative Genomic Hybridisation ◽  
Comparative Genomic ◽  
Predisposition Genes ◽  
Work Up

BackgroundNephroblastomatosis is a recognised precursor for the development of Wilms tumour (WT), the most common childhood renal tumour. While the majority of WT is sporadic in origin, germline intragenic mutations of predisposition genes such as WT1, REST and TRIM28 have been described in apparently isolated (non-familial) WT.Despite constitutional CNVs being a well-studied cause of developmental disorders, their role in cancer predisposition is less well defined, so that the interpretation of cancer risks associated with specific CNVs can be complex.ObjectiveTo highlight the role of a constitutional deletion CNV (delCNV) encompassing the REST tumour suppressor gene in diffuse hyperplastic perilobar nephroblastomatosis (HPLN).Methods/resultsArray comparative genomic hybridisation in an infant presenting with apparently sporadic diffuse HPLN revealed a de novo germline CNV, arr[GRCh37] 4q12(57,385,330–57,947,405)x1. The REST tumour suppressor gene is located at GRCh37 chr4:57,774,042–57,802,010.ConclusionThis delCNV encompassing REST is associated with nephroblastomatosis. Deletion studies should be included in the molecular work-up of inherited predisposition to WT/nephroblastomatosis. Detection of delCNVs involving known cancer predisposition genes can yield insights into the relationship between underlying genomic architecture and associated tumour risk.

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