TβR-I(6A) is a candidate tumor susceptibility allele

Boris Pasche, Prema Kolachana, Khedoudja Nafa, Jaya Satagopan, Ye Guang Chen, Roger S. Lo, Dara Brener, Diana Yang, Laurie Kirstein, Carole Oddoux, Harry Ostrer, Paolo Vineis, Liliana Varesco, Suresh Jhanwar, Lucio Luzzatto, Joan Massagué, Kenneth Offit

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Abstract

We have previously described a type I transforming growth factor (TGF)- β receptor (TβR-I) polymorphic allele, TβR-I(6A), that has a deletion of three alanines from a nine-alanine stretch. We observed a higher than expected number of TβR-I(6A) homozygotes among tumor and nontumor DNA from patients with a diagnosis of cancer. To test the hypothesis that TβR-I(6A) homozygosity is associated with cancer, we performed a case-control study in patients with a diagnosis of cancer and matched healthy individuals with no history of cancer and who were identical in their gender and their geographical and ethnic background to determine the relative germ-line frequencies of this allele. We found nine TβR-I(6A) homozygotes among 851 patients with cancer. In comparison, there were no TβR-I(6A) homozygotes among 735 healthy volunteers (P < 0.01). We also observed an excess of TβR- I(6A) heterozygotes in cancer cases compared to controls (14.6% versus 10.6%; P = 0.02, Fisher's exact test). A subset analysis revealed that 4 of 112 patients with colorectal cancer were TβR-I(6A) homozygotes (P < 0.01). Using mink lung epithelial cell lines devoid of TβR-I, we established stably transfected TβR-I and TβR-I(6A) cell lines. We found that, compared to TβR-I, TβR-I(6A) was impaired as a mediator of TGF-β antiproliferative signals. We conclude that TβR-I(6A) acts as a tumor susceptibility allele that may contribute to the development of cancer, especially colon cancer, by means of reduced TGF-β-mediated growth inhibition.

Original languageEnglish (US)
Pages (from-to)5678-5682
Number of pages5
JournalCancer Research
Volume59
Issue number22
StatePublished - Nov 15 1999
Externally publishedYes

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Alleles
Homozygote
Neoplasms
Transforming Growth Factors
Alanine
Colonic Neoplasms
Mink
Cell Line
Growth Factor Receptors
Heterozygote
Gene Frequency
Germ Cells
Case-Control Studies
Colorectal Neoplasms
Healthy Volunteers
Epithelial Cells
Lung
DNA
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Pasche, B., Kolachana, P., Nafa, K., Satagopan, J., Chen, Y. G., Lo, R. S., ... Offit, K. (1999). TβR-I(6A) is a candidate tumor susceptibility allele. Cancer Research, 59(22), 5678-5682.

TβR-I(6A) is a candidate tumor susceptibility allele. / Pasche, Boris; Kolachana, Prema; Nafa, Khedoudja; Satagopan, Jaya; Chen, Ye Guang; Lo, Roger S.; Brener, Dara; Yang, Diana; Kirstein, Laurie; Oddoux, Carole; Ostrer, Harry; Vineis, Paolo; Varesco, Liliana; Jhanwar, Suresh; Luzzatto, Lucio; Massagué, Joan; Offit, Kenneth.

In: Cancer Research, Vol. 59, No. 22, 15.11.1999, p. 5678-5682.

Research output: Contribution to journalArticle

Pasche, B, Kolachana, P, Nafa, K, Satagopan, J, Chen, YG, Lo, RS, Brener, D, Yang, D, Kirstein, L, Oddoux, C, Ostrer, H, Vineis, P, Varesco, L, Jhanwar, S, Luzzatto, L, Massagué, J & Offit, K 1999, 'TβR-I(6A) is a candidate tumor susceptibility allele', Cancer Research, vol. 59, no. 22, pp. 5678-5682.
Pasche B, Kolachana P, Nafa K, Satagopan J, Chen YG, Lo RS et al. TβR-I(6A) is a candidate tumor susceptibility allele. Cancer Research. 1999 Nov 15;59(22):5678-5682.
Pasche, Boris ; Kolachana, Prema ; Nafa, Khedoudja ; Satagopan, Jaya ; Chen, Ye Guang ; Lo, Roger S. ; Brener, Dara ; Yang, Diana ; Kirstein, Laurie ; Oddoux, Carole ; Ostrer, Harry ; Vineis, Paolo ; Varesco, Liliana ; Jhanwar, Suresh ; Luzzatto, Lucio ; Massagué, Joan ; Offit, Kenneth. / TβR-I(6A) is a candidate tumor susceptibility allele. In: Cancer Research. 1999 ; Vol. 59, No. 22. pp. 5678-5682.
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abstract = "We have previously described a type I transforming growth factor (TGF)- β receptor (TβR-I) polymorphic allele, TβR-I(6A), that has a deletion of three alanines from a nine-alanine stretch. We observed a higher than expected number of TβR-I(6A) homozygotes among tumor and nontumor DNA from patients with a diagnosis of cancer. To test the hypothesis that TβR-I(6A) homozygosity is associated with cancer, we performed a case-control study in patients with a diagnosis of cancer and matched healthy individuals with no history of cancer and who were identical in their gender and their geographical and ethnic background to determine the relative germ-line frequencies of this allele. We found nine TβR-I(6A) homozygotes among 851 patients with cancer. In comparison, there were no TβR-I(6A) homozygotes among 735 healthy volunteers (P < 0.01). We also observed an excess of TβR- I(6A) heterozygotes in cancer cases compared to controls (14.6{\%} versus 10.6{\%}; P = 0.02, Fisher's exact test). A subset analysis revealed that 4 of 112 patients with colorectal cancer were TβR-I(6A) homozygotes (P < 0.01). Using mink lung epithelial cell lines devoid of TβR-I, we established stably transfected TβR-I and TβR-I(6A) cell lines. We found that, compared to TβR-I, TβR-I(6A) was impaired as a mediator of TGF-β antiproliferative signals. We conclude that TβR-I(6A) acts as a tumor susceptibility allele that may contribute to the development of cancer, especially colon cancer, by means of reduced TGF-β-mediated growth inhibition.",
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AU - Pasche, Boris

AU - Kolachana, Prema

AU - Nafa, Khedoudja

AU - Satagopan, Jaya

AU - Chen, Ye Guang

AU - Lo, Roger S.

AU - Brener, Dara

AU - Yang, Diana

AU - Kirstein, Laurie

AU - Oddoux, Carole

AU - Ostrer, Harry

AU - Vineis, Paolo

AU - Varesco, Liliana

AU - Jhanwar, Suresh

AU - Luzzatto, Lucio

AU - Massagué, Joan

AU - Offit, Kenneth

PY - 1999/11/15

Y1 - 1999/11/15

N2 - We have previously described a type I transforming growth factor (TGF)- β receptor (TβR-I) polymorphic allele, TβR-I(6A), that has a deletion of three alanines from a nine-alanine stretch. We observed a higher than expected number of TβR-I(6A) homozygotes among tumor and nontumor DNA from patients with a diagnosis of cancer. To test the hypothesis that TβR-I(6A) homozygosity is associated with cancer, we performed a case-control study in patients with a diagnosis of cancer and matched healthy individuals with no history of cancer and who were identical in their gender and their geographical and ethnic background to determine the relative germ-line frequencies of this allele. We found nine TβR-I(6A) homozygotes among 851 patients with cancer. In comparison, there were no TβR-I(6A) homozygotes among 735 healthy volunteers (P < 0.01). We also observed an excess of TβR- I(6A) heterozygotes in cancer cases compared to controls (14.6% versus 10.6%; P = 0.02, Fisher's exact test). A subset analysis revealed that 4 of 112 patients with colorectal cancer were TβR-I(6A) homozygotes (P < 0.01). Using mink lung epithelial cell lines devoid of TβR-I, we established stably transfected TβR-I and TβR-I(6A) cell lines. We found that, compared to TβR-I, TβR-I(6A) was impaired as a mediator of TGF-β antiproliferative signals. We conclude that TβR-I(6A) acts as a tumor susceptibility allele that may contribute to the development of cancer, especially colon cancer, by means of reduced TGF-β-mediated growth inhibition.

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