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PMID: 30477151 Published · epublish English Journal Article Review

Heterogeneity in Colorectal Cancer: A Challenge for Personalized Medicine?

International journal of molecular sciences ·Vol. 19 ·No. 12 ·2018-11-23

Molinari C, Marisi G, Passardi A, Matteucci L, De Maio G, Ulivi P

Abstract

High inter-patient variability and high spatial heterogeneity are features of colorectal cancer (CRC). This may influence the molecular characterization of tumor tissue, now mandatory for patients with metastatic CRC who are candidates for treatment with an anti-EGFR mAb, as false-negative results can occur, leading to non optimal therapy. Moreover, temporal molecular heterogeneity during treatment is known to influence the response to therapy and prognosis. We present a literature overview of advances made in characterizing molecular heterogeneity in CRC, underlining that the analysis of liquid biopsy could represent an efficient non-invasive tool to overcome the problem. We believe that understanding CRC heterogeneity is fundamental for a more accurate diagnosis, for selecting the best targets to ensure prolonged antitumor response, and for monitoring minimal residual disease and the onset of resistance to therapy, all essential components of successful personalized treatment.

Keywords
cfDNA colorectal cancer heterogeneity liquid biopsy metastasis response to therapy tumor tissue
MeSH Terms
Biological Variation, Individual Biomarkers, Tumor Colorectal Neoplasms/etiology,pathology Genetic Heterogeneity Humans Liquid Biopsy Molecular Diagnostic Techniques Neoplasm Metastasis Neoplasm Staging Precision Medicine
Chemicals
Biomarkers, Tumor
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Molinari Chiara
Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy. [email protected].
Marisi Giorgia
Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy. [email protected].
Passardi Alessandro ORCID
Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy. [email protected].
Matteucci Laura
Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy. [email protected].
De Maio Giulia
Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy. [email protected].
Ulivi Paola
Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy. [email protected].
References (111)
111 references, click to expand
  1. Clinical and biological significance of circulating tumor cells, circulating tumor DNA, and exosomes as biomarkers in colorectal cancer.
    Oncotarget. 2017 Apr 18;8(33):55632-55645 PMID: 28903450
  2. Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features.
    Ann Oncol. 2014 Oct;25(10):1995-2001 PMID: 25057166
  3. Ovarian neoplasms in patients with colorectal cancer: understanding the role of prophylactic oophorectomy.
    Clin Colorectal Cancer. 2004 Feb;3(4):215-22 PMID: 15025793
  4. Molecular evolution of colorectal cancer: from multistep carcinogenesis to the big bang.
    Cancer Metastasis Rev. 2016 Mar;35(1):63-74 PMID: 26947218
  5. Comparative genomic analysis of primary versus metastatic colorectal carcinomas.
    J Clin Oncol. 2012 Aug 20;30(24):2956-62 PMID: 22665543
  6. Spatio-temporal mutation profiles of case-matched colorectal carcinomas and their metastases reveal unique de novo mutations in metachronous lung metastases by targeted next generation sequencing.
    Mol Cancer. 2016 Oct 18;15(1):63 PMID: 27756406
  7. A Big Bang model of human colorectal tumor growth.
    Nat Genet. 2015 Mar;47(3):209-16 PMID: 25665006
  8. Comparative genomic analysis of primary and synchronous metastatic colorectal cancers.
    PLoS One. 2014 Mar 05;9(3):e90459 PMID: 24599305
  9. Mutations of KRAS and BRAF in primary and matched metastatic sites of colorectal cancer.
    J Clin Oncol. 2008 Sep 1;26(25):4217-9 PMID: 18757341
  10. Tumor progression while on chemotherapy: a contraindication to liver resection for multiple colorectal metastases?
    Ann Surg. 2004 Dec;240(6):1052-61; discussion 1061-4 PMID: 15570210
  11. Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions.
    Genome Biol. 2014 Aug 28;15(8):454 PMID: 25164765
  12. Origins of lymphatic and distant metastases in human colorectal cancer.
    Science. 2017 Jul 07;357(6346):55-60 PMID: 28684519
  13. Implementation of next generation sequencing technology for somatic mutation detection in routine laboratory practice.
    Pathology. 2018 Jun;50(4):389-401 PMID: 29752127
  14. Mitochondrial DNA alteration in primary and metastatic colorectal cancer: Different frequency and association with selected clinicopathological and molecular markers.
    Tumour Biol. 2017 Mar;39(3):1010428317692246 PMID: 28345467
  15. Primary tumor location and bevacizumab effectiveness in patients with metastatic colorectal cancer.
    Ann Oncol. 2013 Oct;24(10):2554-9 PMID: 23864097
  16. Insights into Pathogenic Interactions Among Environment, Host, and Tumor at the Crossroads of Molecular Pathology and Epidemiology.
    Annu Rev Pathol. 2019 Jan 24;14:83-103 PMID: 30125150
  17. Discordance between K-ras mutations in bone marrow micrometastases and the primary tumor in colorectal cancer.
    J Clin Oncol. 2001 Jun 1;19(11):2837-43 PMID: 11387355
  18. Consensus molecular subtypes of colorectal cancer are recapitulated in in vitro and in vivo models.
    Cell Death Differ. 2018 Mar;25(3):616-633 PMID: 29305587
  19. Major challenges related to tumor biological characteristics in accurate mutation detection of colorectal cancer by next-generation sequencing.
    Cancer Lett. 2017 Dec 1;410:92-99 PMID: 28942013
  20. Clinical application of targeted next-generation sequencing for colorectal cancer patients: a multicentric Belgian experience.
    Oncotarget. 2018 Apr 17;9(29):20761-20768 PMID: 29755687
  21. The consensus molecular subtypes of colorectal cancer.
    Nat Med. 2015 Nov;21(11):1350-6 PMID: 26457759
  22. Colorectal cancer liver metastases - a population-based study on incidence, management and survival.
    BMC Cancer. 2018 Jan 15;18(1):78 PMID: 29334918
  23. Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future.
    Cell. 2017 Feb 9;168(4):613-628 PMID: 28187284
  24. Detection of KRAS mutations in circulating tumor cells from patients with metastatic colorectal cancer.
    Cancer Biol Ther. 2015;16(9):1289-95 PMID: 26252055
  25. Intra-patient Inter-metastatic Genetic Heterogeneity in Colorectal Cancer as a Key Determinant of Survival after Curative Liver Resection.
    PLoS Genet. 2016 Jul 29;12(7):e1006225 PMID: 27472274
  26. Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer.
    Science. 2013 Feb 1;339(6119):543-8 PMID: 23239622
  27. Immune checkpoints and immunotherapy for colorectal cancer.
    Gastroenterol Rep (Oxf). 2015 Nov;3(4):289-97 PMID: 26510455
  28. KRAS and BRAF mutations in serum exosomes from patients with colorectal cancer in a Chinese population.
    Oncol Lett. 2017 May;13(5):3608-3616 PMID: 28521461
  29. RAS mutation analysis in circulating tumor DNA from patients with metastatic colorectal cancer: the AGEO RASANC prospective multicenter study.
    Ann Oncol. 2018 May 1;29(5):1211-1219 PMID: 29438522
  30. Patterns of metastasis in colon and rectal cancer.
    Sci Rep. 2016 Jul 15;6:29765 PMID: 27416752
  31. Epidemiology, management and prognosis of colorectal cancer with lung metastases: a 30-year population-based study.
    Gut. 2010 Oct;59(10):1383-8 PMID: 20732912
  32. Heterogeneity of Acquired Resistance to Anti-EGFR Monoclonal Antibodies in Patients with Metastatic Colorectal Cancer.
    Clin Cancer Res. 2017 May 15;23(10):2414-2422 PMID: 27780856
  33. Consensus molecular subtype classification of colorectal adenomas.
    J Pathol. 2018 Nov;246(3):266-276 PMID: 29968252
  34. Prognostic and Predictive Relevance of Primary Tumor Location in Patients With RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses of the CRYSTAL and FIRE-3 Trials.
    JAMA Oncol. 2017 Feb 1;3(2):194-201 PMID: 27722750
  35. KRAS mutation analysis: a comparison between primary tumours and matched liver metastases in 305 colorectal cancer patients.
    Br J Cancer. 2011 Mar 15;104(6):1020-6 PMID: 21364579
  36. Detection and recovery of circulating colon cancer cells using a dielectrophoresis-based device: KRAS mutation status in pure CTCs.
    Cancer Lett. 2013 Jul 10;335(1):225-31 PMID: 23419522
  37. Cancer genome landscapes.
    Science. 2013 Mar 29;339(6127):1546-58 PMID: 23539594
  38. Location of Primary Tumor and Benefit From Anti-Epidermal Growth Factor Receptor Monoclonal Antibodies in Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer.
    Oncologist. 2016 Aug;21(8):988-94 PMID: 27382031
  39. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2016: A Systematic Analysis for the Global Burden of Disease Study.
    JAMA Oncol. 2018 Nov 1;4(11):1553-1568 PMID: 29860482
  40. Genomic Landscape of Cell-Free DNA in Patients with Colorectal Cancer.
    Cancer Discov. 2018 Feb;8(2):164-173 PMID: 29196463
  41. Clinical utility of KRAS status in circulating plasma DNA compared to archival tumour tissue from patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor therapy.
    Eur J Cancer. 2015 Nov;51(17):2678-85 PMID: 26508156
  42. Guidelines for resection of colorectal cancer liver metastases.
    Gut. 2006 Aug;55 Suppl 3:iii1-8 PMID: 16835351
  43. High concordance rate of KRAS/BRAF mutations and MSI-H between primary colorectal cancer and corresponding metastases.
    Oncol Rep. 2017 Feb;37(2):785-792 PMID: 28000889
  44. Molecular-Subtype-Specific Biomarkers Improve Prediction of Prognosis in Colorectal Cancer.
    Cell Rep. 2017 May 9;19(6):1268-1280 PMID: 28494874
  45. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer.
    J Clin Oncol. 2009 Dec 10;27(35):5924-30 PMID: 19884556
  46. European cancer mortality predictions for the year 2018 with focus on colorectal cancer.
    Ann Oncol. 2018 Apr 1;29(4):1016-1022 PMID: 29562308
  47. Primary colorectal cancers and their subsequent hepatic metastases are genetically different: implications for selection of patients for targeted treatment.
    Clin Cancer Res. 2012 Feb 1;18(3):688-99 PMID: 22173549
  48. High Intra- and Inter-Tumoral Heterogeneity of RAS Mutations in Colorectal Cancer.
    Int J Mol Sci. 2016 Dec 01;17(12): PMID: 27916952
  49. Sialic acid and epithelial differentiation in colorectal polyps and cancer--a morphological, mucin and lectin histochemical study.
    Pathology. 1992 Oct;24(4):233-42 PMID: 1289763
  50. Heterogeneity of KRAS status may explain the subset of discordant KRAS status between primary and metastatic colorectal cancer.
    Dis Colon Rectum. 2011 Sep;54(9):1170-8 PMID: 21825899
  51. Primary tumor sidedness and benefit from FOLFOXIRI plus bevacizumab as initial therapy for metastatic colorectal cancer. Retrospective analysis of the TRIBE trial by GONO.
    Ann Oncol. 2018 Apr 20;29(7):1528-1534 PMID: 29873679
  52. Pan-cancer analysis of the extent and consequences of intratumor heterogeneity.
    Nat Med. 2016 Jan;22(1):105-13 PMID: 26618723
  53. KRAS mutation status is highly homogeneous between areas of the primary tumor and the corresponding metastasis of colorectal adenocarcinomas: one less problem in patient care.
    Am J Cancer Res. 2017 Sep 01;7(9):1978-1989 PMID: 28979819
  54. Associations between primary tumor RAS, BRAF and PIK3CA mutation status and metastatic site in patients with chemo-resistant metastatic colorectal cancer.
    Acta Oncol. 2018 Aug;57(8):1057-1062 PMID: 29380640
  55. Different metastatic pattern according to the KRAS mutational status and site-specific discordance of KRAS status in patients with colorectal cancer.
    BMC Cancer. 2012 Aug 09;12:347 PMID: 22876814
  56. KRAS mutation analysis of single circulating tumor cells from patients with metastatic colorectal cancer.
    BMC Cancer. 2017 May 3;17(1):311 PMID: 28468669
  57. Somatic mutation detection using various targeted detection assays in paired samples of circulating tumor DNA, primary tumor and metastases from patients undergoing resection of colorectal liver metastases.
    Mol Oncol. 2016 Dec;10(10):1575-1584 PMID: 28949453
  58. Molecular morphometric analysis shows relative intra-tumoural homogeneity for KRAS mutations in colorectal cancer.
    Virchows Arch. 2011 Nov;459(5):487-93 PMID: 22016105
  59. A genetic model for colorectal tumorigenesis.
    Cell. 1990 Jun 1;61(5):759-67 PMID: 2188735
  60. Molecular pathological epidemiology of colorectal neoplasia: an emerging transdisciplinary and interdisciplinary field.
    Gut. 2011 Mar;60(3):397-411 PMID: 21036793
  61. Blockade of EGFR and MEK intercepts heterogeneous mechanisms of acquired resistance to anti-EGFR therapies in colorectal cancer.
    Sci Transl Med. 2014 Feb 19;6(224):224ra26 PMID: 24553387
  62. Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment.
    Ann Oncol. 2015 Apr;26(4):731-6 PMID: 25628445
  63. RAS testing of liquid biopsy correlates with the outcome of metastatic colorectal cancer patients treated with first-line FOLFIRI plus cetuximab in the CAPRI-GOIM trial.
    Ann Oncol. 2018 Jan 1;29(1):112-118 PMID: 28950295
  64. Evaluation of liquid biopsies for detection of emerging mutated genes in metastatic colorectal cancer.
    Eur J Surg Oncol. 2018 Jul;44(7):975-982 PMID: 29452859
  65. Incidence and prognosis of synchronous colorectal carcinomatosis.
    Future Oncol. 2013 Apr;9(4):541-9 PMID: 23560376
  66. Treatment-Induced Mutagenesis and Selective Pressures Sculpt Cancer Evolution.
    Cold Spring Harb Perspect Med. 2017 Aug 1;7(8): PMID: 28289245
  67. Genomic alterations accompanying tumour evolution in colorectal cancer: tracking the differences between primary tumours and synchronous liver metastases by whole-exome sequencing.
    BMC Cancer. 2018 Jul 20;18(1):752 PMID: 30029640
  68. Liquid Biopsy in Clinical Management of Breast, Lung, and Colorectal Cancer.
    Front Med (Lausanne). 2018 Jan 30;5:9 PMID: 29441349
  69. Detection of circulating tumor DNA in early- and late-stage human malignancies.
    Sci Transl Med. 2014 Feb 19;6(224):224ra24 PMID: 24553385
  70. Dynamic molecular analysis and clinical correlates of tumor evolution within a phase II trial of panitumumab-based therapy in metastatic colorectal cancer.
    Ann Oncol. 2018 Jan 1;29(1):119-126 PMID: 28945848
  71. Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients.
    Ann Oncol. 2017 Jun 1;28(6):1325-1332 PMID: 28419195
  72. Are KRAS/BRAF mutations potent prognostic and/or predictive biomarkers in colorectal cancers?
    Anticancer Agents Med Chem. 2012 Feb;12(2):163-71 PMID: 22043994
  73. Concordant analysis of KRAS, BRAF, PIK3CA mutations, and PTEN expression between primary colorectal cancer and matched metastases.
    Sci Rep. 2015 Feb 02;5:8065 PMID: 25639985
  74. Quantitative cell-free DNA, KRAS, and BRAF mutations in plasma from patients with metastatic colorectal cancer during treatment with cetuximab and irinotecan.
    Clin Cancer Res. 2012 Feb 15;18(4):1177-85 PMID: 22228631
  75. Multiplex picodroplet digital PCR to detect KRAS mutations in circulating DNA from the plasma of colorectal cancer patients.
    Clin Chem. 2013 Dec;59(12):1722-31 PMID: 23938455
  76. Right- vs. Left-Sided Metastatic Colorectal Cancer: Differences in Tumor Biology and Bevacizumab Efficacy.
    Int J Mol Sci. 2017 Jun 09;18(6): PMID: 28598398
  77. Integrative analysis of exogenous, endogenous, tumour and immune factors for precision medicine.
    Gut. 2018 Jun;67(6):1168-1180 PMID: 29437869
  78. Blood-based detection of RAS mutations to guide anti-EGFR therapy in colorectal cancer patients: concordance of results from circulating tumor DNA and tissue-based RAS testing.
    Mol Oncol. 2017 Feb;11(2):208-219 PMID: 28106345
  79. Multiregion ultra-deep sequencing reveals early intermixing and variable levels of intratumoral heterogeneity in colorectal cancer.
    Mol Oncol. 2017 Feb;11(2):124-139 PMID: 28145097
  80. Analysis of KRAS, NRAS, PIK3CA, and BRAF mutational profile in poorly differentiated clusters of KRAS-mutated colon cancer.
    Hum Pathol. 2017 Apr;62:91-98 PMID: 28025078
  81. Somatic mutation profiles in primary colorectal cancers and matching ovarian metastases: Identification of driver and passenger mutations.
    J Pathol Clin Res. 2016 Apr 15;2(3):166-74 PMID: 27499925
  82. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer.
    Nature. 2012 Jun 28;486(7404):532-6 PMID: 22722830
  83. Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer.
    Sci Transl Med. 2016 Feb 24;8(327):327ra24 PMID: 26912903
  84. Cancer heterogeneity: implications for targeted therapeutics.
    Br J Cancer. 2013 Feb 19;108(3):479-85 PMID: 23299535
  85. Optimal detection of clinically relevant mutations in colorectal carcinoma: sample pooling overcomes intra-tumoral heterogeneity.
    Mod Pathol. 2018 Feb;31(2):343-349 PMID: 29027537
  86. Predictors and survival of synchronous peritoneal carcinomatosis of colorectal origin: a population-based study.
    Int J Cancer. 2011 Jun 1;128(11):2717-25 PMID: 20715167
  87. Co-evolution of somatic variation in primary and metastatic colorectal cancer may expand biopsy indications in the molecular era.
    PLoS One. 2015 May 14;10(5):e0126670 PMID: 25974029
  88. Epidemiology and management of liver metastases from colorectal cancer.
    Ann Surg. 2006 Aug;244(2):254-9 PMID: 16858188
  89. Comprehensive molecular characterization of human colon and rectal cancer.
    Nature. 2012 Jul 18;487(7407):330-7 PMID: 22810696
  90. Comparison of the molecular profile of brain metastases from colorectal cancer and corresponding primary tumors.
    Future Oncol. 2017 Jan;13(2):135-144 PMID: 27578453
  91. Gastrointestinal cancer and brain metastasis: a rare and ominous sign.
    Cancer. 2011 Aug 15;117(16):3630-40 PMID: 21319152
  92. High-depth sequencing of over 750 genes supports linear progression of primary tumors and metastases in most patients with liver-limited metastatic colorectal cancer.
    Genome Biol. 2015 Feb 12;16:32 PMID: 25808843
  93. Understanding the role of primary tumour localisation in colorectal cancer treatment and outcomes.
    Eur J Cancer. 2017 Oct;84:69-80 PMID: 28787661
  94. Evolution of intratumoral genetic heterogeneity during colorectal cancer progression.
    Carcinogenesis. 2005 May;26(5):916-22 PMID: 15731168
  95. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.
    Ann Oncol. 2016 Aug;27(8):1386-422 PMID: 27380959
  96. Paired Primary and Metastatic Tumor Analysis of Somatic Mutations in Synchronous and Metachronous Colorectal Cancer.
    Cancer Res Treat. 2017 Jan;49(1):161-167 PMID: 27384156
  97. Droplet digital PCR of circulating tumor cells from colorectal cancer patients can predict KRAS mutations before surgery.
    Mol Oncol. 2016 Oct;10(8):1221-31 PMID: 27311775
  98. Heterogeneity of epidermal growth factor receptor status and mutations of KRAS/PIK3CA in circulating tumor cells of patients with colorectal cancer.
    Clin Chem. 2013 Jan;59(1):252-60 PMID: 23136247
  99. Intratumor genetic heterogeneity in advanced human colorectal adenocarcinoma.
    Int J Cancer. 2001 Aug 1;93(3):346-52 PMID: 11433398
  100. Genomic and epigenetic instability in colorectal cancer pathogenesis.
    Gastroenterology. 2008 Oct;135(4):1079-99 PMID: 18773902
  101. Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer.
    Cancer Cell. 2018 Jan 8;33(1):125-136.e3 PMID: 29316426
  102. Intratumoral morphological heterogeneity can be an indicator of genetic heterogeneity in colorectal cancer.
    Exp Mol Pathol. 2018 Feb;104(1):76-81 PMID: 29337243
  103. Multi-regional sequencing reveals intratumor heterogeneity and positive selection of somatic mtDNA mutations in hepatocellular carcinoma and colorectal cancer.
    Int J Cancer. 2018 Sep 1;143(5):1143-1152 PMID: 29569724
  104. Clinical utility of circulating DNA analysis for rapid detection of actionable mutations to select metastatic colorectal patients for anti-EGFR treatment.
    Ann Oncol. 2017 Sep 1;28(9):2149-2159 PMID: 28911069
  105. The role of exosomes on colorectal cancer: A review.
    J Gastroenterol Hepatol. 2018 Apr;33(4):792-799 PMID: 29156509
  106. Intra-tumour heterogeneity: a looking glass for cancer?
    Nat Rev Cancer. 2012 Apr 19;12(5):323-34 PMID: 22513401
  107. Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA.
    Nat Med. 2014 Apr;20(4):430-5 PMID: 24658074
  108. Cancer statistics, 2013.
    CA Cancer J Clin. 2013 Jan;63(1):11-30 PMID: 23335087
  109. Concordance of predictive markers for EGFR inhibitors in primary tumors and metastases in colorectal cancer: a review.
    Oncologist. 2011;16(9):1239-49 PMID: 21742964
  110. Concordance of blood- and tumor-based detection of RAS mutations to guide anti-EGFR therapy in metastatic colorectal cancer.
    Ann Oncol. 2017 Jun 1;28(6):1294-1301 PMID: 28368441
  111. Genetic and Epigenetic Intra-tumour Heterogeneity in Colorectal Cancer.
    World J Surg. 2017 May;41(5):1375-1383 PMID: 28097409
Article Info
Journal
International journal of molecular sciences
Abbr.
Int J Mol Sci
ISSN
1422-0067
DOI
10.3390/ijms19123733
Email
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
[email protected]
Published
2018-11-23
Epub
2018-00-23
Language
English
Region
Switzerland
NLM ID
101092791
PMCID
PMC6321493
Subset
IM
External Links
PubMed source DOI: 10.3390/ijms19123733 PMC Full Text View journal details
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