Somatic acquisition and signaling of TGFBR1*6A in cancer.
BACKGROUND
TGFBR1*6A is a common polymorphism of the type I transforming growth factor beta receptor (TGFBR1). Epidemiological studies suggest that TGFBR1*6A may act as a tumor susceptibility allele. How TGFBR1*6A contributes to cancer development is largely unknown.


OBJECTIVE
To determine whether TGFBR1*6A is somatically acquired by primary tumors and metastases during cancer development and whether the 3-amino acid deletion that differentiates TGFBR1*6A from TGFBR1 is part of the mature receptor or part of the signal sequence and to investigate TGFBR1*6A signaling in cancer cells.


METHODS
Tumor and germline tissues from 531 patients with a diagnosis of head and neck, colorectal, or breast cancer recruited from 3 centers in the United States and from 1 center in Spain from June 1, 1994, through June 30, 2004. In vitro translation assays, MCF-7 breast cancer cells stably transfected with TGFBR1*6A, TGFBR1, or the vector alone, DLD-1 colorectal cancer cells that endogenously carry TGFBR1*6A, and SW48 colorectal cancer cells that do not carry TGFBR1*6A.


METHODS
TGFBR1*6A somatic acquisition in cancer. Determination of the amino terminus of the mature TGFBR1*6A and TGFBR1 receptors. Determination of TGF-beta-dependent cell proliferation.


RESULTS
TGFBR1*6A was somatically acquired in 13 of 44 (29.5%) colorectal cancer metastases, in 4 of 157 (2.5%) of colorectal tumors, in 4 of 226 (1.8%) head and neck primary tumors, and in none of the 104 patients with breast cancer. TGFBR1*6A somatic acquisition is not associated with loss of heterozygosity, microsatellite instability, or a mutator phenotype. The signal sequences of TGFBR1 and TGFBR1*6A are cleaved at the same site resulting in identical mature receptors. TGFBR1*6A may switch TGF-beta growth inhibitory signals into growth stimulatory signals in MCF-7 breast cancer cells and in DLD-1 colorectal cancer cells.


CONCLUSIONS
TGFBR1*6A is somatically acquired in 29.5% of liver metastases from colorectal cancer and may bestow cancer cells with a growth advantage in the presence of TGF-beta. The functional consequences of this conversion appear to be mediated by the TGFBR1*6A signal sequence rather than by the mature receptor. The results highlight a new facet of TGF-beta signaling in cancer and suggest that TGFBR1*6A may represent a potential therapeutic target in cancer.
Pasche
Boris
B
Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine, The Feinberg School of Medicine, Northwestern, University, Chicago, Ill 60611, USA. b-pasche@northwestern.edu
Knobloch
Thomas J
TJ
Bian
Yansong
Y
Liu
Junjian
J
Phukan
Sharbani
S
Rosman
Diana
D
Kaklamani
Virginia
V
Baddi
Lisa
L
Siddiqui
Farida S
FS
Frankel
Wendy
W
Prior
Thomas W
TW
Schuller
David E
DE
Agrawal
Amit
A
Lang
Jas
J
Dolan
M Eileen
ME
Vokes
Everett E
EE
Lane
William S
WS
Huang
Chiang-Ching
CC
Caldes
Trinidad
T
Di Cristofano
Antonio
A
Hampel
Heather
H
Nilsson
IngMarie
I
von Heijne
Gunnar
G
Fodde
Riccardo
R
Murty
V V V S
VV
de la Chapelle
Albert
A
Weghorst
Christopher M
CM
D030201:Activin Receptors, Type I / Q000235:genetics*; D000483:Alleles; D000595:Amino Acid Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D009362:Neoplasm Metastasis / Q000235:genetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D017384:Sequence Deletion; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human