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Hereditary Cancer in Clinical Practice
Published in: Hereditary Cancer in Clinical Practice 1/2018

Open Access 01-12-2018 | Research

Evaluation of a 27-gene inherited cancer panel across 630 consecutive patients referred for testing in a clinical diagnostic laboratory

Authors: Sabrina A. Gardner, Katelyn S. Weymouth, Wei S. Kelly, Ekaterina Bogdanova, Wenjie Chen, Daniel Lupu, Joshua Suhl, Qiandong Zeng, Ute Geigenmüller, Debbie Boles, Patricia M. Okamoto, Geraldine McDowell, Melissa A. Hayden, Narasimhan Nagan

Published in: Hereditary Cancer in Clinical Practice | Issue 1/2018

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Abstract

Background

Extensive clinical and genetic heterogeneity of inherited cancers has allowed multi-gene panel testing to become an efficient means for identification of patients with an inherited predisposition to a broad spectrum of syndromic and nonsyndromic forms of cancer. This study reports our experience with a 27-gene inherited cancer panel on a cohort of 630 consecutive individuals referred for testing at our laboratory with the following objectives: 1. Determine the rates for positive cases and those with variants of uncertain clinical significance (VUS) relative to data published in the recent literature, 2. Examine heterogeneity among the constituent genes on the panel, and 3. Review test uptake in the cohort relative to other reports describing outcomes for expanded panel testing.

Methods

Clinical and genomic data were reviewed on 630 individuals tested on a panel of 27 genes selected on the basis of high (≥ 40%) or moderate to low (≤ 40%) lifetime risk of hereditary cancer. These patients were not enriched for adherence to the National Comprehensive Cancer Network (NCCN) criteria for Hereditary Breast and Ovarian Cancer (HBOC) or Lynch Syndrome (LS) and constitute a referral laboratory cohort.

Results

Sixty-five individuals with variants classified as pathogenic or likely pathogenic across 14 genes were identified for an overall positive rate of 10.3%. Although a family history of cancer constituted a major reason for referral, accounting for 84% of our cohort, excluding patients with a known familial variant did not have a significant impact on the observed positive rate (9% vs 10.3%). More than half (58%) of the pathogenic or likely pathogenic variants were observed in high or moderate to low risk genes on the panel, while only 42% occurred in classic HBOC or LS-associated genes.

Conclusion

These results provide the actual percentage of family or personal history of cancer that can be attributed to pathogenic or likely pathogenic variants in one or more of the genes on our panel and corroborate the utility of multi-gene panels over sequential testing to identify individuals with an inherited predisposition to cancer.
Appendix
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Literature
1.
Stratton MR, Rahman N. The emerging landscape of breast cancer susceptibility. Nat Genet. 2008;40:17–22.CrossRefPubMed
2.
Yurgelun MB, Allen B, Kaldate RR, Bowles KR, Judkins T, Kaushik P, et al. Identification of a variety of mutations in cancer predisposition genes in patients with suspected lynch syndrome. Gastroenterology. 2015;149:604–13. e620CrossRefPubMedPubMedCentral
3.
Petrucelli N, Daly MB, Pal T. Gene reviews (R): eds R. A. Pagon et al.; 1993.
4.
Hegde M, Ferber M, Mao R, Samowitz W, Ganguly A, Working Group of the American College of Medical G, et al. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. 2014;16:101–16.CrossRefPubMed
5.
Kohlmann W, Gruber SB. Gene reviews (R): eds R. A. Pagon et al.; 1993.
6.
7.
Lincoln SE, Kobayashi Y, Anderson MJ, Yang S, Desmond AJ, Mills MA, et al. A systematic comparison of traditional and multigene panel testing for hereditary breast and ovarian cancer genes in more than 1000 patients. J Mol Diagn. 2015;17:533–44.CrossRefPubMed
8.
Yurgelun MB, Kulke MH, Fuchs CS, Allen BA, Uno H, Hornick JL, et al. Cancer susceptibility gene mutations in individuals with colorectal cancer. J Clin Oncol. 2017;35:1086–95.CrossRefPubMed
9.
Ring KL, Bruegl AS, Allen BA, Elkin EP, Singh N, Hartman AR, et al. Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort. Mod Pathol. 2016;29:1381–9.CrossRefPubMedPubMedCentral
10.
Minion LE, Dolinsky JS, Chase DM, Dunlop CL, Chao EC, Monk BJ. Hereditary predisposition to ovarian cancer, looking beyond BRCA1/BRCA2. Gynecol Oncol. 2015;137:86–92.CrossRefPubMed
11.
Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K, et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015;121:25–33.CrossRefPubMed
12.
LaDuca H, Stuenkel AJ, Dolinsky JS, Keiles S, Tandy S, Pesaran T, et al. Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. Genet Med. 2014;16:830–7.CrossRefPubMedPubMedCentral
13.
Mannan AU, Singh J, Lakshmikeshava R, Thota N, Singh S, Sowmya TS, et al. Detection of high frequency of mutations in a breast and/or ovarian cancer cohort: implications of embracing a multi-gene panel in molecular diagnosis in India. J Hum Genet. 2016;61:515–22.CrossRefPubMed
14.
Susswein LR, Marshall ML, Nusbaum R, Vogel Postula KJ, Weissman SM, Yackowski L, et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016;18:823–32.CrossRefPubMed
15.
De Vos M, Hayward BE, Picton S, Sheridan E, Bonthron DT. Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome. Am J Hum Genet. 2004;74:954–64.CrossRefPubMedPubMedCentral
16.
Aziz N, Zhao Q, Bry L, Driscoll DK, Funke B, Gibson JS, et al. College of American Pathologists’ laboratory standards for next-generation sequencing clinical tests. Arch Pathol Lab Med. 2015;139:481–93.CrossRefPubMed
17.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.CrossRefPubMedPubMedCentral
18.
19.
20.
Genomes Project C, Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491:56–65.CrossRef
21.
Beroud C, Letovsky SI, Braastad CD, Caputo SM, Beaudoux O, Bignon YJ, et al. BRCA share: a collection of clinical BRCA gene variants. Hum Mutat. 2016;37:1318–28.CrossRefPubMed
22.
Plazzer JP, Sijmons RH, Woods MO, Peltomaki P, Thompson B, Den Dunnen JT, et al. The InSiGHT database: utilizing 100 years of insights into lynch syndrome. Familial Cancer. 2013;12:175–80.CrossRefPubMed
23.
Win AK, Dowty JG, Cleary SP, Kim H, Buchanan DD, Young JP, et al. Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer. Gastroenterology. 2014;146:1208–11. e1201-1205CrossRefPubMedPubMedCentral
24.
Peterlongo P, Mitra N, Sanchez de Abajo A, de la Hoya M, Bassi C, Bertario L, et al. IEncreased frequency of disease-causing MYH mutations in colon cancer families. Carcinogenesis. 2006;27:2243–9.CrossRefPubMed
25.
Jenkins MA, Croitoru ME, Monga N, Cleary SP, Cotterchio M, Hopper JL, et al. Risk of colorectal cancer in monoallelic and biallelic carriers of MYH mutations: a population-based case-family study. Cancer Epidemiol Biomark Prev. 2006;15:312–4.CrossRef
26.
Lubbe SJ, Di Bernardo MC, Chandler IP, Houlston RS. Clinical implications of the colorectal cancer risk associated with MUTYH mutation. J Clin Oncol. 2009;27:3975–80.CrossRefPubMed
27.
28.
Shirts BH, Casadei S, Jacobson AL, Lee MK, Gulsuner S, Bennett RL, et al. Improving performance of multigene panels for genomic analysis of cancer predisposition. Genet Med. 2016;18:974–81.CrossRefPubMed
29.
Seal S, Thompson D, Renwick A, Elliott A, Kelly P, Barfoot R, et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet. 2006;38:1239–41.CrossRefPubMed
30.
Nussbaum RL, Yang S, Lincoln SE. Clinical genetics testing laboratories have a remarkably low rate of clinically significant discordance when interpreting variants in hereditary cancer syndrome genes. J Clin Oncol. 2017;35:1259–61.CrossRefPubMed
31.
Wimmer K, Kratz CP, Vasen HF, Caron O, Colas C, Entz-Werle N, et al. Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium ‘care for CMMRD’ (C4CMMRD). J Med Genet. 2014;51:355–65.CrossRefPubMed
32.
Senter L, Clendenning M, Sotamaa K, Hampel H, Green J, Potter JD, et al. The clinical phenotype of lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008;135:419–28.CrossRefPubMedPubMedCentral
Metadata
Title
Evaluation of a 27-gene inherited cancer panel across 630 consecutive patients referred for testing in a clinical diagnostic laboratory
Authors
Sabrina A. Gardner
Katelyn S. Weymouth
Wei S. Kelly
Ekaterina Bogdanova
Wenjie Chen
Daniel Lupu
Joshua Suhl
Qiandong Zeng
Ute Geigenmüller
Debbie Boles
Patricia M. Okamoto
Geraldine McDowell
Melissa A. Hayden
Narasimhan Nagan
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Hereditary Cancer in Clinical Practice / Issue 1/2018
Electronic ISSN: 1897-4287
DOI
https://doi.org/10.1186/s13053-017-0083-8

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