IGF2 drives formation of ileal neuroendocrine tumors in patients and mice

in Endocrine-Related Cancer
Authors:
Tanupriya Contractor Raymond and Beverly Sackler Foundation, New Brunswick, New Jersey, USA

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Richard Clausen Raymond and Beverly Sackler Foundation, New Brunswick, New Jersey, USA

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Grant R Harris Raymond and Beverly Sackler Foundation, New Brunswick, New Jersey, USA

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Jeffrey A Rosenfeld Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA

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Darren R Carpizo Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA

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Laura Tang Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Chris R Harris Raymond and Beverly Sackler Foundation, New Brunswick, New Jersey, USA
Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA
Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA

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Correspondence should be addressed to C R Harris: harrisch@cinj.rutgers.edu
DOI:
https://doi.org/10.1530/ERC-19-0505
Volume/Issue:
Volume 27: Issue 3
Article Type:
Research Article
Page Range:
175–186
Online Publication Date:
Mar 2020
Copyright:
© 2020 Society for Endocrinology 2020
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By the strictest of definitions, a genetic driver of tumorigenesis should fulfill two criteria: it should be altered in a high percentage of patient tumors, and it should also be able to cause the same type of tumor to form in mice. No gene that fits either of these criteria has ever been found for ileal neuroendocrine tumors (I-NETs), which in humans are known for an unusual lack of recurrently mutated genes, and which have never been detected in mice. In the following report, we show that I-NETs can be generated by transgenic RT2 mice, which is a classic model for a genetically unrelated disease, pancreatic neuroendocrine tumors (PNETs). The ability of RT2 mice to generate I-NETs depended upon genetic background. I-NETs appeared in a B6AF1 genetic background, but not in a B6 background nor even in an AB6F1 background. AB6F1 and B6AF1 have identical nuclear DNA but can potentially express different allelic forms of imprinted genes. This led us to test human I-NETs for loss of imprinting, and we discovered that the IGF2 gene showed loss of imprinting and increased expression in the I-NETs of 57% of patients. By increasing IGF2 activity genetically, I-NETs could be produced by RT2 mice in a B6 genetic background, which otherwise never developed I-NETs. The facts that IGF2 is altered in a high percentage of patients with I-NETs and that I-NETs can form in mice that have elevated IGF2 activity, define IGF2 as the first genetic driver of ileal neuroendocrine tumorigenesis.

Supplementary Materials

    • Supplemental Figure 1. Whole exome sequence analysis revealed 46 unique alterations (31 single nucleotide changes and 15 copy number alterations) in the I-NET from mouse 31508, and 62 unique alterations (52 single nucleotide changes and 10 copy number alterations) in the PNET of the same mouse. The I-NET from mouse 31462 had 36 mutations (13 single nucleotide changes and 23 copy number alterations), and the PNET from the same mouse had 51 alterations (35 single nucleotide changes and 16 copy number alterations). See also Supplemental Tables 1-4 and Supplemental Figures 2 and 3.
    • Supplemental Figure 2. Tumor samples from mouse 31462 do not have a common copy number variation at chromosome 13. Initial bioinformatics analysis of tail, PNET and I-NET DNAs from mouse 31462 suggested a tumor-specific increase in copy number at chromosome 13:54820000, within the Cdhr2 gene (see Supplemental Table 4). However, subsequent copy number analysis within the presumed amplification sequence, using real-time RTPCR, demonstrates a copy number of 2 in I-NET, PNET and tail samples. Tfrc was used as a copy number control.
    • Supplemental Figure 3. Tumor samples from mouse 31462 do not share a C177A mutation in Armcx3. Initial bioinformatics analysis of tail, I-NET and PNET DNA from mouse 31462 suggested that both I-NET and PNET had an adenine at nucleotide 177 whereas tail DNA had a cytosine (see Supplemental Table 3). However subsequent Sanger DNA sequencing revealed that tail, I-NET and PNET all have a cytosine at this position.
    • Supplemental Figure 4. Analysis for genomic DNA contamination. mRNA prepared from tumors showing loss of imprinting was treated with reverse transcriptase (+), or mock treated (-) prior to PCR and ApaI treatment. In all cases, treatment with reverse transcriptase was required in order to observe a PCR product, indicating the absence of genomic DNA contamination.
    • Supplemental Figure 5. Analysis of H19 imprinting in human ileal neuroendocrine tumors. Each patient was heterozygous for SNP rs10840159, which is found within the transcribed portion of the imprinted H19 gene. One of the alleles of rs10840159 encodes a site for the MscI restriction endonuclease, and the other allele does not. cDNA was prepared, subjected to PCR amplification, and digested with MscI. The larger band (359 bps) represents the allele that lacks an MscI site, while the smaller band is actually two bands (182 bps and 177 bps) from the allele that contains an MscI site. Since none of the 15 tumors expressed both copies of the H19 gene, H19 imprinting is retained for all 15 tumors. Notably, three of the tested tumors (50T, 64T and 73T) showed loss of imprinting of the adjacent gene, IGF2.
    • Supplemental Figure 6. Comparison of Igfbp1 transcription in PNETs from RT2 B6 and RT2 B6 Igfbp1 +/- mice. cDNA was prepared from 28 mice (19 RT2 B6 animals, and 9 RT2 B6 Igfbp1 +/- animals) and assayed for Igfbp1 expression using real time RTPCR. &#xF062;-actin was used as a normalization control. The difference in expression was statistically significant (p < 0.05) by Mann Whitney test.
    • Supplemental Figure 7. Pathological analysis of ileal tumors in RT2B6 Igfbp1 (+/-) mice. A. Hematoxylin and eosin staining of an ileal tumor isolated from an RT2B6 Igfbp1(+/-) mouse. B. Immunohistochemical staining of chromogranin A expression by an ileal tumor isolated from an RT2B6 Igfbp1 (+/-) mouse. C and D: Immunohistochemical staining of CDX2 expression by an ileal tumor (C) and a pancreatic NET (D) isolated from the same RT2B6 Igfbp1 (+/-) animal.
    • Supplemental Figure 8. Comparison of H19os transcription in PNETs from RT2 AB6F1 and RT2 B6AF1 mice. cDNA was prepared from 28 mice (19 RT2 B6 animals, and 9 RT2 B6 Igfbp1 +/- animals) and assayed for Igfbp1 expression using real time RTPCR. Gapdh was used as a normalization control. The difference in expression was statistically significant (p < 0.05) by Mann Whitney test.
    • Supplemental Table 1. Nonsynonymous single nucleotide mutations in tumors of mouse 31508
    • Supplemental Table 2. Copy number alterations in PNETs and INETs of mouse 31508
    • Supplemental Table 3. Nonsynonymous single nucleotide mutations in tumors of mouse 31462
    • Supplemental Table 4. Copy number alterations in PNETs and INETs of mouse 31462

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Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© 2020 Society for Endocrinology 2020
Page(s):
12
Received Date:
10 Jan 2020
Accepted Date:
16 Jan 2020
Print Publication Date:
01 Mar 2020
Online Publication Date:
Mar 2020
Keywords:
carcinoids; neuroendocrine tumours

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