Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2017

Open Access 01-12-2017 | Research

Association of a novel point mutation in MSH2 gene with familial multiple primary cancers

Authors: Hai Hu, Hong Li, Feng Jiao, Ting Han, Meng Zhuo, Jiujie Cui, Yixue Li, Liwei Wang

Published in: Journal of Hematology & Oncology | Issue 1/2017

Login to get access

Abstract

Background

Multiple primary cancers (MPC) have been identified as two or more cancers without any subordinate relationship that occur either simultaneously or metachronously in the same or different organs of an individual. Lynch syndrome is an autosomal dominant genetic disorder that increases the risk of many types of cancers. Lynch syndrome patients who suffer more than two cancers can also be considered as MPC; patients of this kind provide unique resources to learn how genetic mutation causes MPC in different tissues.

Methods

We performed a whole genome sequencing on blood cells and two tumor samples of a Lynch syndrome patient who was diagnosed with five primary cancers. The mutational landscape of the tumors, including somatic point mutations and copy number alternations, was characterized. We also compared Lynch syndrome with sporadic cancers and proposed a model to illustrate the mutational process by which Lynch syndrome progresses to MPC.

Results

We revealed a novel pathologic mutation on the MSH2 gene (G504 splicing) that associates with Lynch syndrome. Systematical comparison of the mutation landscape revealed that multiple cancers in the proband were evolutionarily independent. Integrative analysis showed that truncating mutations of DNA mismatch repair (MMR) genes were significantly enriched in the patient. A mutation progress model that included germline mutations of MMR genes, double hits of MMR system, mutations in tissue-specific driver genes, and rapid accumulation of additional passenger mutations was proposed to illustrate how MPC occurs in Lynch syndrome patients.

Conclusion

Our findings demonstrate that both germline and somatic alterations are driving forces of carcinogenesis, which may resolve the carcinogenic theory of Lynch syndrome.
Appendix
Available only for authorised users
Literature
1.
Moertel CG, Dockerty MB, Baggenstoss AH. Multiple primary malignant neoplasms. II. Tumors of different tissues or organs. Cancer. 1961;14:231–7.CrossRefPubMed
2.
Carr R, Langdon J. Multiple primaries in mouth cancer—the price of success. Br J Oral Maxillofac Surg. 1989;27:394–9.CrossRefPubMed
3.
Curado MP, Cancer IAfRo, Organization WH: Cancer incidence in five continents. 2008.
4.
5.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F: Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359-86. doi: 10.​1002/​ijc.​29210. Epub 2014 Oct 9.
6.
Savoia P, Osella-Abate S, Deboli T, Marenco F, Stroppiana E, Novelli M, Fierro M, Bernengo M. Clinical and prognostic reports from 270 patients with multiple primary melanomas: a 34-year single-institution study. J Eur Acad Dermatol Venereol. 2012;26:882–8.CrossRefPubMed
7.
Luciani A, Balducci L: Multiple primary malignancies. In Seminars in oncology Elsevier; Semin Oncol. 2004;31(2):264-73.
8.
Chen D, Yan J, Mou Y. Metachronous pancreatic head ductal carcinoma three years after resection of gallbladder cancer. Int J Clin Exp Med. 2013;6:828.PubMedPubMedCentral
9.
Pătraşcu T, Doran H, Catrina E, Mihalache O, Degeratu D, Predescu G. Synchronous tumors of the gastrointestinal tract. Chirurgia (Bucur). 2009;105:93–6.
10.
Koubkova L, Hrstka R, Dobes P, Vojtesek B, Vyzula R: Second primary cancers–causes, incidence and the future. klinická onkologie . Klin Onkol. 2014;27(1):11–17.
11.
Heyne KH, Lippman S, Lee J, Lee J, Hong WK. The incidence of second primary tumors in long-term survivors of small-cell lung cancer. J Clin Oncol. 1992;10:1519–24.CrossRefPubMed
12.
Stewart DJ, Goel R, Gertler SZ, Huan S, Tomiak EM, Yau J, Cripps C, Evans WK. Concurrent use of multiple low dose chemotherapy agents with differing mechanisms of action as a strategy vs passive resistance: a pilot study. Int J Oncol. 1999;15:693–9.PubMed
13.
Ueno M, Muto T, Oya M, Ota H, Azekura K, Yamaguchi T. Multiple primary cancer: an experience at the cancer institute hospital with special reference to colorectal cancer. Int J Clin Oncol. 2003;8:162–7.CrossRefPubMed
14.
Jiao F, Yao LJ, Zhou J, Hu H, Wang LW. Clinical features of multiple primary malignancies: a retrospective analysis of 72 Chinese patients. Asian Pac J Cancer Prev. 2014;15:331–4.CrossRefPubMed
15.
Lynch HT, Snyder CL, Shaw TG, Heinen CD, Hitchins MP. Milestones of Lynch syndrome: 1895-2015. Nat Rev Cancer. 2015;15:181–94.CrossRefPubMed
16.
Plazzer JP, Sijmons RH, Woods MO, Peltomaki P, Thompson B, Den Dunnen JT, Macrae F. The InSiGHT database: utilizing 100 years of insights into Lynch syndrome. Familial Cancer. 2013;12:175–80.CrossRefPubMed
17.
Shih HA, Nathanson KL, Seal S, Collins N, Stratton MR, Rebbeck TR, Weber BL. BRCA1 and BRCA2 mutations in breast cancer families with multiple primary cancers. Clin Cancer Res. 2000;6:4259–64.PubMed
18.
Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer. 1953;6:963–8.CrossRefPubMed
19.
Noronha V, Berliner N, Ballen KK, Lacy J, Kracher J, Baehring J, Henson JW. Treatment-related myelodysplasia/AML in a patient with a history of breast cancer and an oligodendroglioma treated with temozolomide: case study and review of the literature. Neuro-Oncology. 2006;8:280–3.CrossRefPubMedPubMedCentral
20.
Ono M, Watanabe T, Shimizu C, Hiramoto N, Goto Y, Yonemori K, Kouno T, Ando M, Tamura K, Katsumata N, Fujiwara Y. Therapy-related acute promyelocytic leukemia caused by hormonal therapy and radiation in a patient with recurrent breast cancer. Jpn J Clin Oncol. 2008;38:567–70.CrossRefPubMed
21.
Sonobe S, Inoue K, Tachibana S, Shiojiri M, Maeda T, Nakanishi N, Moritaka T, Ikura Y, Kawaguchi T. A case of pulmonary mucoepidermoid carcinoma responding to carboplatin and paclitaxel. Jpn J Clin Oncol. 2014;44:493–6.CrossRefPubMed
22.
23.
Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, Del Angel G, Levy-Moonshine A, Jordan T, Shakir K, Roazen D, Thibault J, et al. From FastQ data to high confidence variant calls: the genome analysis toolkit best practices pipeline. Curr Protoc Bioinformatics. 2013;11:11 10 11–33.
24.
25.
Koboldt DC, Zhang Q, Larson DE, Shen D, McLellan MD, Lin L, Miller CA, Mardis ER, Ding L, Wilson RK. VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res. 2012;22:568–76.CrossRefPubMedPubMedCentral
26.
Cibulskis K, Lawrence MS, Carter SL, Sivachenko A, Jaffe D, Sougnez C, Gabriel S, Meyerson M, Lander ES, Getz G. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 2013;31:213–9.CrossRefPubMedPubMedCentral
27.
Larson DE, Harris CC, Chen K, Koboldt DC, Abbott TE, Dooling DJ, Ley TJ, Mardis ER, Wilson RK, Ding L. SomaticSniper: identification of somatic point mutations in whole genome sequencing data. Bioinformatics. 2012;28:311–7.CrossRefPubMed
28.
Saunders CT, Wong WS, Swamy S, Becq J, Murray LJ, Cheetham RK. Strelka: accurate somatic small-variant calling from sequenced tumor-normal sample pairs. Bioinformatics. 2012;28:1811–7.CrossRefPubMed
29.
Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29:308–11.CrossRefPubMedPubMedCentral
30.
Newburger DE, Kashef-Haghighi D, Weng Z, Salari R, Sweeney RT, Brunner AL, Zhu SX, Guo X, Varma S, Troxell ML, et al. Genome evolution during progression to breast cancer. Genome Res. 2013;23:1097–108.CrossRefPubMedPubMedCentral
31.
Sefc K, Regner F, Glössl J, Steinkellner H. Genotyping of grapevine and rootstock cultivars using microsatellite markers. VITIS J Grapevine Res. 2015;37:15.
32.
Sikkema-Raddatz B, Johansson LF, Boer EN, Almomani R, Boven LG, Berg MP, Spaendonck-Zwarts KY, Tintelen JP, Sijmons RH, Jongbloed JD. Targeted next-generation sequencing can replace Sanger sequencing in clinical diagnostics. Hum Mutat. 2013;34:1035–42.CrossRefPubMed
33.
Chang N, Sun C, Gao L, Zhu D, Xu X, Zhu X, Xiong J-W, Xi JJ. Genome editing with RNA-guided Cas9 nuclease in zebrafish embryos. Cell Res. 2013;23:465–72.CrossRefPubMedPubMedCentral
34.
Jiao F, Hu H, Han T, Yuan C, Wang L, Jin Z, Guo Z, Wang L. Long noncoding RNA MALAT-1 enhances stem cell-like phenotypes in pancreatic cancer cells. Int J Mol Sci. 2015;16:6677–93.CrossRefPubMedPubMedCentral
35.
Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502:333–9.CrossRefPubMedPubMedCentral
36.
37.
38.
Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S, Gu B, Hart J, Hoffman D, Hoover J, et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016;44:D862–8.CrossRefPubMed
39.
Lipton L, Johnson V, Cummings C, Fisher S, Risby P, Sadat AE, Cranston T, Izatt L, Sasieni P, Hodgson S. Refining the Amsterdam criteria and Bethesda guidelines: testing algorithms for the prediction of mismatch repair mutation status in the familial cancer clinic. J Clin Oncol. 2004;22:4934–43.CrossRefPubMed
40.
41.
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Borresen-Dale AL, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21.CrossRefPubMedPubMedCentral
42.
Helleday T, Eshtad S, Nik-Zainal S. Mechanisms underlying mutational signatures in human cancers. Nat Rev Genet. 2014;15:585–98.CrossRefPubMed
43.
Eshleman JR, Casey G, Kochera ME, Sedwick WD, Swinler SE, Veigl ML, Willson JK, Schwartz S, Markowitz SD. Chromosome number and structure both are markedly stable in RER colorectal cancers and are not destabilized by mutation of p53. Oncogene. 1998;17:719–25.CrossRefPubMed
44.
Ouyang L, Lee J, Park CK, Mao M, Shi Y, Gong Z, Zheng H, Li Y, Zhao Y, Wang G, et al. Whole-genome sequencing of matched primary and metastatic hepatocellular carcinomas. BMC Med Genet. 2014;7:2.
45.
Brannon AR, Vakiani E, Sylvester BE, Scott SN, McDermott G, Shah RH, Kania K, Viale A, Oschwald DM, Vacic V, et al. Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions. Genome Biol. 2014;15:454.CrossRefPubMedPubMedCentral
46.
Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–7.CrossRef
47.
Cancer Genome Atlas Research N. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507:315–22.CrossRef
48.
Hemminki A, Peltomaki P, Mecklin JP, Jarvinen H, Salovaara R, Nystrom-Lahti M, de la Chapelle A, Aaltonen LA. Loss of the wild type MLH1 gene is a feature of hereditary nonpolyposis colorectal cancer. Nat Genet. 1994;8:405–10.CrossRefPubMed
49.
Nagasaka T, Rhees J, Kloor M, Gebert J, Naomoto Y, Boland CR, Goel A. Somatic hypermethylation of MSH2 is a frequent event in Lynch syndrome colorectal cancers. Cancer Res. 2010;70:3098–108.CrossRefPubMedPubMedCentral
50.
Knudson AG Jr. Hereditary cancer, oncogenes, and antioncogenes. Cancer Res. 1985;45:1437–43.PubMed
51.
Armaghany T, Wilson JD, Chu Q, Mills G. Genetic alterations in colorectal cancer. Gastrointest Cancer Res. 2012;5:19–27.PubMedPubMedCentral
52.
Miyaki M, Iijima T, Yasuno M, Kita Y, Hishima T, Kuroki T, Mori T. High incidence of protein-truncating mutations of the p53 gene in liver metastases of colorectal carcinomas. Oncogene. 2002;21:6689–93.CrossRefPubMed
53.
Austin ED, Phillips JA, Cogan JD, Hamid R, Yu C, Stanton KC, Phillips CA, Wheeler LA, Robbins IM, Newman JH, Loyd JE. Truncating and missense BMPR2 mutations differentially affect the severity of heritable pulmonary arterial hypertension. Respir Res. 2009;10:87.CrossRefPubMedPubMedCentral
54.
Warren S, Gate O. Multiple primary malignant tumors survey of literature and statistical study. Am J CanCer. 1932;16:1358–414.
55.
Belcheva A, Irrazabal T, Robertson SJ, Streutker C, Maughan H, Rubino S, Moriyama EH, Copeland JK, Kumar S, Green B, et al. Gut microbial metabolism drives transformation of MSH2-deficient colon epithelial cells. Cell. 2014;158:288–99.CrossRefPubMed
56.
Kemmerich K, Dingler FA, Rada C, Neuberger MS. Germline ablation of SMUG1 DNA glycosylase causes loss of 5-hydroxymethyluracil- and UNG-backup uracil-excision activities and increases cancer predisposition of Ung−/−Msh2−/− mice. Nucleic Acids Res. 2012;40:6016–25.CrossRefPubMedPubMedCentral
Metadata
Title
Association of a novel point mutation in MSH2 gene with familial multiple primary cancers
Authors
Hai Hu
Hong Li
Feng Jiao
Ting Han
Meng Zhuo
Jiujie Cui
Yixue Li
Liwei Wang
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2017
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-017-0523-y

Other articles of this Issue 1/2017

Journal of Hematology & Oncology 1/2017 Go to the issue

Research

AC-93253 iodide, a novel Src inhibitor, suppresses NSCLC progression by modulating multiple Src-related signaling pathways

Research

Transcriptome sequencing in pediatric acute lymphoblastic leukemia identifies fusion genes associated with distinct DNA methylation profiles

Erratum

Erratum to: Interim analysis of survival in a prospective, multi-center registry cohort of cutaneous melanoma tested with a prognostic 31-gene expression profile test

Letter to the Editor

High WT1 expression is an early predictor for relapse in patients with acute promyelocytic leukemia in first remission with negative PML-RARa after anthracycline-based chemotherapy: a single-center cohort study

Research

A novel lncRNA uc.134 represses hepatocellular carcinoma progression by inhibiting CUL4A-mediated ubiquitination of LATS1

Research

RETRACTED ARTICLE: MicroRNA-330-3p promotes cell invasion and metastasis in non-small cell lung cancer through GRIA3 by activating MAPK/ERK signaling pathway
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
Image Credits