19q13.2

CED,DPD1,IBDIMDE,LAP,TGF-beta1,TGFB,TGFbeta

Cancer

TGF-β1 has a relevant and complex role in cancer cell growth and development (Roberts et al., 1993). Alterations in TGF-β signalling pathway modify cancer risk. Overall, decreases in TGF-β1 signalling induce an increase in cancer risk, whereas increases in TGF-β secretion and signaling activation enhance the aggressiveness of tumors. TGF-β also stimulates invasion, angiogenesis, and metastasis, and inhibits immune surveillance.

Colorectal cancer

TGF-β1 is involved in colorectal cancer (Kemik et al., 2013), modulating the degree of angiogenesis (Xiong et al., 2002). TGF-β induces a prometastatic program in stromal cells associated with a high risk of colorectal cancer relapse upon treatment (Calon et al., 2012). A polymorphism in TGFB1 (gene promoter -509C allele variant) is a possible risk factor for developing colorectal cancer (Wang et al., 2013).

Breast cancer

The TGFB1 LP10 polymorphism has been associated with breast cancer risk inducing an increase in TGF-β1 cellular expression and elevating plasma TGF-β1 levels, which might suppress the immune regulatory activities of macrophages and increase the risk of breast cancer (Dunning et al., 2003; Lee et al., 2005; Breast Cancer Association Consortium, 2006; Ivanovic et al., 2006; Cox et al., 2007; Sun et al., 2013), although other authors suggest that lower levels of circulating TGF-β1 are associated with a higher metastatic risk and poor disease prognosis (Panis et al., 2013).

Glioma

TGF-β1 is also involved in human gliomas, decreasing anti-tumour immunity (Lee et al., 1997; Dong et al., 2001; Zagzag et al., 2005) and increasing the motility of glioma cells by enhancing the expression of collagen and α2,5,β3 integrin, as well as up-regulating the activity of metalloproteinases MMP-2 and MMP-9 at the cell surface of glioma cells (Wick et al., 2001).

Prostate cancer

Cancer progression and metastasis are associated with an increase in TGF-β1 circulating levels in patients with prostate cancer (Shariat et al., 2004; Ivanovic et al., 2006). Local expression of TGF-β1 is associated with tumor grade, tumor invasion and metastasis. The TGFB1 L10 polymorphism is associated with a poorer outcome and more aggressive tumors in patients with prostate cancer, and the TGFB1 509T polymorphism may play a role in advanced stage prostate cancer affecting TGF-β1 expression and increasing TGF-β1 serum levels (Ewart-Toland and Balmain, 2004). However, an association between single nucleotide polymorphisms of TGFB1 at C-509T and a decreased risk of aggressive prostate cancer has been described (Brand et al., 2008). On the other hand, the codon 10 polymorphism in TGFB1 may have a significant influence on the development of prostate cancer and benign prostatic hyperplasia (Omrani et al., 2009).

Lung cancer

Elevated plasma TGF-β1 levels occur frequently in patients with lung cancer (Kong et al., 1996; Kang et al., 2006). TGF-β1 may offer protection against development of lung cancer acting as a suppressor of tumor initiation (Blobe et al., 2000; Rich et al., 2001; Siegel and Massague, 2003).

Bladder cancer

TGF-β is also overexpressed in bladder cancer. In this context, TGF-β1 may facilitate tumor escape from the immune system (de Visser and Kast, 1999; Wojtowicz-Praga, 2003; Helmy et al., 2007).

Fibrosis

The role of TGF-β1 in fibrosis is widely accepted (Verrecchia and Mauviel, 2002; Schnaper et al., 2003). In the kidney, TGF-β1 mediates apoptosis and epithelial-mesenchimal transition (EMT), causing progressive loss of differentiated renal cells, thus inducing chronic progression of renal disease. TGF-β1-induced apoptosis is likely to have a pathogenetic role in podocyte depletion and glomerulosclerosis, tubular degeneration/atrophy, and loss of glomerular and peritubular capillaries. In addition, EMT induced by TGF-β1 may contribute to tubular atrophy and generation of interstitial myofibroblasts, leading to concomitant tubulointerstitial fibrosis (Bottinger and Bitzer, 2002).
TGF-β1 is involved in liver fibrosis (Kanzler et al., 1999), inducing cirrhosis, liver failure, and portal hypertension, and is also involved in pulmonary fibrosis (Kang et al., 2007), inducing chronic obstructive pulmonary disease. Patients with cystic fibrosis and homozygosity for the common phe508del mutation had an increased risk of severe pulmonary disease if they are also homozygous for C at nucleotide 29 of the TGFB1 gene, corresponding to a change in codon 10 (Drumm et al., 2005). High TGF-β1 protein production has been associated with pulmonary sarcoidosis, which can develop into pulmonary fibrosis (Limper et al., 1994).
Cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT). TGF-β1 induced endothelial cells to undergo EndMT, which contributes to the progression of cardiac fibrosis (Zeisberg et al., 2007). TGFbeta1 mRNA expression is greater in Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy patients than in controls. Expression of TGF-β1 in the early stages of DMD may be critical in initiating muscle fibrosis, and antifibrosis treatment might slow progression of the disease (Bernasconi et al., 1995).

Pulmonary edema

The TGF-β1 latency-associated peptide (LAP) is a ligand for the integrin alpha-V-beta-6, and alpha-V-beta-6-expressing cells induce spatially restricted activation of TGFβ-1 (Munger et al., 1999). Mice lacking this integrin develop exaggerated inflammation and are protected from pulmonary fibrosis. Integrin-mediated local activation of TGF-β is critical to the development of pulmonary edema in acute lung injury and thus, the blockade of either TGF-β or its activation could be effective treatments (Pittet et al., 2001).

Skeleton anomalies, dysplasia - Camurati-Engelmann disease

A 673T-C transition in the TGFB1 gene resulting in a cys225-to-arg (C225R) missense mutation was found in Japanese and European patients with Camurati-Engelmann disease (CED) (Janssens et al., 2000; Kinoshita et al., 2000). That mutation causes the instability of the LAP homodimer and consequently leads to the activation of a constitutively active form of TGFβ-1 and increased proliferation of osteoblasts (Saito et al., 2001). Other mutations in the TGFB1 gene (653G-A transition resulting in an arg218-to-his (R218H) missense amino acid substitution, 652C-T transition resulting in an arg218-to-cys (R218C) missense mutation, tyr81-to-his (Y81H) substitution, 667T-C transition in exon 4, resulting in a cys223-to-arg (C223R) mutation, 667T-G transition in exon 4 resulting in a cys223-to-gly (C223G) mutation) were found in several Japanese and European families with Camurati-Engelmann disease. The most frequent mutation was R218C (Janssens et al., 2000; Kinoshita et al., 2000; Kinoshita et al., 2004). Osteoclast formation was enhanced approximately 5-fold and bone resorption approximately 10-fold in CED patients harbouring the R218C mutation (McGowan et al., 2003); the R218C mutation increases TGFB1 bioactivity and enhances osteoclast formation in vitro. The activation of osteoclast activity was consistent with clinical reports that showed biochemical evidence of increased bone resorption as well as bone formation in CED.

Genetic disorder of the connective tissue - Marfan syndrome

Circulating total TGF-β1 levels are significantly higher in patients with Marfan syndrome than in controls. TGF-β1 levels might serve as a prognostic or therapeutic marker in Marfan syndrome (Matt et al., 2009).

Inflammatory skin disorder - Psoriasis

Although TGF-β1 is known as an anti-inflammation cytokine (Letterio and Roberts, 1998), the inflammatory effect of TGF-β1 on skin has been described in inducible TGF-β1 transgenic mice, where inflammation is correlated with TGF-β1 expression (Han et al., 2001; Mohammed et al., 2010).

Muscle atrophy - Amyotrophic lateral sclerosis (Lou Gehrings disease, motor neurone disease)

In amyotrophic lateral sclerosis (ALS) the plasma concentration of TGF-β1 increases significantly with the duration of illness, suggesting that TGF-β1 is involved in the disease process of ALS (Houi et al., 2002).

Cerebrovascular amyloidosis - Alzheimer

Chronic overproduction of TGFβ1 triggers a pathogenic cascade leading to Alzheimer disease-like cerebrovascular amyloidosis, microvascular degeneration, and local alterations in brain metabolic activity (Wyss-Coray et al., 2000).

Obesity - Diabetes, hypertension

Increased expression and a polymorphism of TGFB1 had been associated with abdominal obesity and body mass index (BMI) in humans (Long et al., 2003).