Top

Published in:

01-01-2021 | Lymphoma | Original Article

Germline variants discovered in lymphoma patients undergoing tumor profiling: a case series

Authors: Anthony J. Scott, Molly C. Tokaz, Michelle F. Jacobs, Arul M. Chinnaiyan, Tycel J. Phillips, Ryan A. Wilcox

Published in: Familial Cancer | Issue 1/2021

Abstract

Clinical tumor sequencing protocols often depend on obtaining germline DNA from patients to aid in the identification of de novo variants in the tumor, and therefore come with the possibility for the incidental discovery of germline variants. Ninety-one adult patients with lymphoma were consented and enrolled in MIONCOSEQ, an IRB-approved tumor profiling protocol that utilizes an exome sequencing platform. Charts were retrospectively reviewed for germline variants from sequencing results, personal and/or family history of cancer and genetic counseling referral. After review of the 91 lymphoma cases, seven (8%) cases revealed germline variants. Only one of these, CHEK2 p.I157T, has been previously recovered as a germline variant in lymphoma. Two of the seven patients received genetic counseling, two died before genetic counseling could be arranged and three did not follow-up with a genetics provider. None of the patients had a personal or family history that would have otherwise suggested an indication for cancer genetics referral, especially notable as lymphoma is not traditionally associated with inherited cancer syndromes. Importantly, as only two of seven patients had appropriate genetic counseling for their variant, timely genetic counseling should be a critical part of all tumor profiling platforms that use non-tumor DNA.

Goodman AM, Choi M, Wieduwilt M et al (2017) Next generation sequencing reveals potentially actionable alterations in the majority of patients with lymphoid malignancies. JCO Precis Oncol. https://doi.org/10.1200/PO.16.00004CrossRefPubMedPubMedCentral

Mandelker D, Zhang L, Kemel Y et al (2017) Mutation detection in patients with advanced cancer by universal sequencing of cancer-related genes in tumor and normal DNA vs guideline-based germline testing. JAMA 318(9):825–835. https://doi.org/10.1001/jama.2017.11137CrossRefPubMedPubMedCentral

Meric-Bernstam F, Brusco L, Daniels M et al (2016) Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol. Ann Oncol 27(5):795–800. https://doi.org/10.1093/annonc/mdw018CrossRefPubMedPubMedCentral

Slavin TP, Banks KC, Chudova D et al (2018) Identification of incidental germline mutations in patients with advanced solid tumors who underwent cell-free circulating tumor DNA sequencing. J Clin Oncol. https://doi.org/10.1200/JCO.18.00328CrossRefPubMedPubMedCentral

Cerhan JR, Slager SL (2015) Familial predisposition and genetic risk factors for lymphoma. Blood 126(20):2265–2273. https://doi.org/10.1182/blood-2015-04-537498CrossRefPubMedPubMedCentral

Goldin LR, Björkholm M, Kristinsson SY, Turesson I, Landgren O (2009) Highly increased familial risks for specific lymphoma subtypes. Br J Haematol 146(1):91–94. https://doi.org/10.1111/j.1365-2141.2009.07721.xCrossRefPubMedPubMedCentral

Leeksma OC, de Miranda NF, Veelken H (2017) Germline mutations predisposing to diffuse large B-cell lymphoma. Blood Cancer J 7(2):e532. https://doi.org/10.1038/bcj.2017.15CrossRefPubMedPubMedCentral

Hill DA, Wang SS, Cerhan JR et al (2006) Risk of non-Hodgkin lymphoma (NHL) in relation to germline variation in DNA repair and related genes. Blood 108(9):3161–3167. https://doi.org/10.1182/blood-2005-01-026690CrossRefPubMedPubMedCentral

Roychowdhury S, Iyer MK, Robinson DR et al (2011) Personalized oncology through integrative high-throughput sequencing: a pilot study. Sci Transl Med 3(111):111ra21. https://doi.org/10.1126/scitranslmed.3003161CrossRef

10.

Hertz DL, Glatz A, Pasternak AL et al (2018) Integration of germline pharmacogenetics into a tumor sequencing program. JCO Precis Oncol 2:1–15. https://doi.org/10.1200/po.18.00011CrossRef

11.

Galanina N, Bejar R, Choi M et al (2018) Comprehensive genomic profiling reveals diverse but actionable molecular portfolios across hematologic malignancies: implications for next generation clinical trials. Cancers (Basel) 11(1):1–10. https://doi.org/10.3390/cancers11010011CrossRef

12.

Monti S, Chapuy B, Takeyama K et al (2012) Integrative analysis reveals an outcome-associated and targetable pattern of p53 and cell cycle deregulation in diffuse large B cell lymphoma. Cancer Cell 22(3):359–372. https://doi.org/10.1016/j.ccr.2012.07.014CrossRefPubMedPubMedCentral

13.

Young KH, Leroy K, Møller MB et al (2008) Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study. Blood 112(8):3088–3098. https://doi.org/10.1182/blood-2008-01-129783CrossRefPubMedPubMedCentral

14.

Weitzel JN, Chao EC, Nehoray B et al (2018) Somatic TP53 variants frequently confound germ-line testing results. Genet Med 20(8):809–816. https://doi.org/10.1038/gim.2017.196CrossRefPubMed

15.

Byrd PJ, Stewart GS, Smith A et al (2016) A hypomorphic PALB2 allele gives rise to an unusual form of FA-N associated with lymphoid tumour development. PLoS Genet 12(3):e1005945. https://doi.org/10.1371/journal.pgen.1005945CrossRefPubMedPubMedCentral

16.

Antoniou AC, Casadei S, Heikkinen T et al (2014) Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371(6):497–506. https://doi.org/10.1056/NEJMoa1400382CrossRefPubMedPubMedCentral

17.

Tung N, Lin NU, Kidd J et al (2016) Frequency of germline mutations in 25 cancer susceptibility genes in a sequential series of patients with breast cancer. J Clin Oncol 34(13):1460–1468. https://doi.org/10.1200/JCO.2015.65.0747CrossRefPubMedPubMedCentral

18.

Liu A, Takakuwa T, Fujita S et al (2008) ATR alterations in Hodgkin’s lymphoma. Oncol Rep 19(4):999–1005PubMed

19.

Zighelboim I, Schmidt AP, Gao F et al (2009) ATR mutation in endometrioid endometrial cancer is associated with poor clinical outcomes. J Clin Oncol 27(19):3091–3096. https://doi.org/10.1200/JCO.2008.19.9802CrossRefPubMedPubMedCentral

20.

Tanaka A, Weinel S, Nagy N et al (2012) Germline mutation in ATR in autosomal-dominant oropharyngeal cancer syndrome. Am J Hum Genet 90(3):511–517. https://doi.org/10.1016/j.ajhg.2012.01.007CrossRefPubMedPubMedCentral

21.

Bartek J, Lukas J (2003) Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 3(5):421–429. https://doi.org/10.1016/s1535-6108(03)00110-7CrossRefPubMed

22.

Havranek O, Kleiblova P, Hojny J et al (2015) Association of germline CHEK2 gene variants with risk and prognosis of non-hodgkin lymphoma. PLoS ONE 10(10):e0140819. https://doi.org/10.1371/journal.pone.0140819CrossRefPubMedPubMedCentral

23.

Karczewski KJ, Francioli LC, Tiao G et al (2019) Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes. bioRxiv: 531210

24.

Pardanani A, Lasho TL, Laborde RR et al (2013) CSF3R T618I is a highly prevalent and specific mutation in chronic neutrophilic leukemia. Leukemia 27(9):1870–1873. https://doi.org/10.1038/leu.2013.122CrossRefPubMedPubMedCentral

25.

Kosmider O, Itzykson R, Chesnais V et al (2013) Mutation of the colony-stimulating factor-3 receptor gene is a rare event with poor prognosis in chronic myelomonocytic leukemia. Leukemia 27(9):1946–1949. https://doi.org/10.1038/leu.2013.182CrossRefPubMed

26.

Kaasinen E, Kuismin O, Rajamäki K et al (2019) Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans. Nat Commun 10(1):1252. https://doi.org/10.1038/s41467-019-09198-7CrossRefPubMedPubMedCentral

27.

Gaidzik VI, Schlenk RF, Moschny S et al (2009) Prognostic impact of WT1 mutations in cytogenetically normal acute myeloid leukemia: a study of the German-Austrian AML Study Group. Blood 113(19):4505–4511. https://doi.org/10.1182/blood-2008-10-183392CrossRefPubMed

28.

Little M, Wells C (1997) A clinical overview of WT1 gene mutations. Hum Mutat 9(3):209–225CrossRefPubMed

Title: Germline variants discovered in lymphoma patients undergoing tumor profiling: a case series
Authors: Anthony J. Scott
Molly C. Tokaz
Michelle F. Jacobs
Arul M. Chinnaiyan
Tycel J. Phillips
Ryan A. Wilcox
Publication date: 01-01-2021
Publisher: Springer Netherlands
Keyword: Lymphoma
Published in: Familial Cancer / Issue 1/2021
Print ISSN: 1389-9600
Electronic ISSN: 1573-7292
DOI: https://doi.org/10.1007/s10689-020-00192-3

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2021

Two cases of somatic STK11 mosaicism in Danish patients with Peutz–Jeghers syndrome

Prospective observational data informs understanding and future management of Lynch syndrome: insights from the Prospective Lynch Syndrome Database (PLSD)

Multiple primary cancers (renal papillary, lymphoma and teratoma) and hepatic cysts in association with a pathogenic germline mutation in the MET gene

Complete response of hereditary leiomyomatosis and renal cell cancer (HLRCC)-associated renal cell carcinoma to nivolumab and ipilimumab combination immunotherapy by: a case report

Report of the fifth meeting of the European Consortium 'Care for CMMRD' (C4CMMRD), Leiden, The Netherlands, July 6th 2019

The CAPP II trial of aspirin in Lynch syndrome/HNPCC: is it time for everyone to be treated?

Keynote webinar | Spotlight on antibody–drug conjugates in cancer