Uwe Langsenlehner

A common 936 C/T gene polymorphism of vascular endothelial growth factor is associated with decreased breast cancer risk

A common 936 C/T polymorphism in the gene for the vascular endothelial growth factor (VEGF) has been associated with VEGF plasma levels. In our case‐control study, we investigated the role of this polymorphism for breast cancer risk. VEGF genotype was determined in 500 women with breast cancer and 500 sex‐ and age‐matched healthy control subjects. Carriers of a 936T‐allele were more frequent among controls (29.4%) than among patients (17.6%; p = 0.000014). The odds ratio for carriers of a 936T‐allele for breast cancer was 0.51 (95% confidence interval 0.38–0.70). Additionally, VEGF plasma levels were determined in 21 nonsmoking post‐menopausal controls; carriers of a 936T allele had significantly lower levels (median 23 pg/ml; range 6–50 pg/ml) than noncarriers (37; 21–387; p = 0.034). We conclude that carriers of a VEGF 936T‐allele are at decreased risk for breast cancer, this, however, requiring further confirmation in a larger study.

INTERLEUKIN-10 PROMOTER POLYMORPHISM IS ASSOCIATED WITH DECREASED BREAST CANCER RISK

Interleukin-10 (IL-10) is an immunosuppressive cytokine which may facilitate development of cancer by supporting tumor escape from the immune response. A [TCATA] haplotype formed by polymorphisms at positions −3575, −2763, −1082, −819 and −592 in the promoter of the IL-10 gene is a strong determinant for IL-10 expression. The presence of this haplotype can be determined by analysis of the −592C > A polymorphism. Aim of the present study was to analyze the role of the IL-10 [TCATA] haplotype for breast cancer. We performed a case–control study including 500 female patients with histologically confirmed breast cancer and 500 female, age-matched, healthy control subjects from population-based screening studies. The −592C > A polymorphism was determined by a 5′-nuclease assay (TaqMan). Frequency of the homozygous −592 AA genotype, indicating homozygosity for the [TCATA] haplotype, was 4.2% among patients and 7.3% among controls (p=0.038; odds ratio 0.56; 95% confidence interval 0.32–0.97). IL-10 genotypes were not associated with tumor size, histological grading, estrogen or progesterone receptor status and age at diagnosis. Therefore we conclude that the IL-10 −592C > A promoter polymorphism may be associated with a reduced breast cancer risk.

In vivo confocal laser scanning microscopy of melanocytic skin tumours: diagnostic applicability using unselected tumour images.

Background  In vivo confocal laser scanning microscopy (CLSM) represents a novel imaging tool that allows the noninvasive examination of skin cancer morphology in real time at a ‘quasi‐histopathological’ resolution viewing microanatomical structures and individual cells.

The L10P polymorphism of the transforming growth factor-beta 1 gene is not associated with breast cancer risk

Transforming growth factor-beta 1 (TGF-beta1) is a potent inhibitor of proliferation of epithelial, endothelial and hematopoietic cells and acts as a tumor suppressor. The gene for TGF-beta1, TGFB1, carries a common T/C variation of nucleotide 29, resulting in a leucine (L) to proline (P) polymorphism at codon 10 (TGFB1 L10P). The less common 10P allele has repeatedly been linked to higher TGF-beta1 levels and in at least one study to a lower incidence of breast cancer. To further analyze the role of this polymorphism for breast cancer risk, 500 patients with histologically confirmed breast cancer and 500 sex-and age-matched healthy control subjects were genotyped for the TGFB1 L10P polymorphism by an allele-specific polymerase chain reaction assay. TGFB1 LL, LP and PP genotype frequencies were not significantly different for patients (39.6, 44.2, 16.2%) and controls (36.5, 45.9, 17.6%). We conclude that the TGFB1 L10P polymorphism is not associated with breast cancer risk.

The common 677C>T gene polymorphism of methylenetetrahydrofolate reductase gene is not associated with breast cancer risk.

Methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism and plays a role in DNA biosynthesis, methylation, and repair in actively dividing cells. A common 677C>T polymorphism in the gene for MTHFR, leading to a thermolabile enzyme with decreased activity, has been associated with reduced plasma folate levels and elevated homocysteine levels and could be a risk factor for breast cancer. In the present case-control study, MTHFR genotype was determined in 500 women with clinically verified breast cancer and 500 female age-matched healthy control subjects. The homozygous TT genotype was found in 13.0% patients and 13.1% controls (P = n.s.). The odds ratio of TT homozygotes for breast cancer was 0.99 (95% confidence interval 0.68–1.43). The MTHFR genotype was furthermore not associated with tumor size, histological grading, estrogen or progesterone receptor status and age at diagnosis. In a subgroup of 116 premenopausal patients, no increased frequency of the homozygous 677T genotype was found (13.8%). Therefore, we conclude that the MTHFR 677C>T polymorphism is not associated with individual susceptibility to breast cancer.

The 870G>A Polymorphism of the Cyclin D1 Gene is not Associated with Breast Cancer

A common 870G > A polymorphism in the gene for cyclin D1, CCND1, has been linked to alternative splicing and cancer susceptibility. To analyze its role for breast cancer, we determined the CCND1 genotype in 500 breast cancer patients and 500 controls. CCND1 genotype frequencies were similar among patients and controls. The CCND1 genotype was furthermore not associated with tumor characteristics. We conclude that the CCND1 870G > A polymorphism is not associated with breast cancer.

The 5A/6A Polymorphism of the Matrix Metalloproteinase 3 Gene Promoter and Breast Cancer

Purpose: The matrix metalloproteinase 3 (MMP3), also known as stromelysin-I, is a key-player for carcinogenesis and tumor growth. A 5A/6A promoter polymorphism is associated with differences in MMP3 activity and has been linked to cancer susceptibility in some studies. In the present study we evaluated the role of this polymorphism for breast cancer risk. Experimental Design: A case–control study was performed including 500 patients with histologically confirmed breast cancer and 500 female, age-matched, healthy control subjects from population-based screening studies. The MMP3 5A/6A polymorphism was determined by a 5′-nuclease (TaqMan) assay. Results: Prevalences of 5A/5A, 5A/6A, and 6A/6A genotypes were similar among patients (20.6, 51.8, and 27.6%, respectively) and controls (23.3, 47.3, and 29.4%, P = 0.34). The odds ratio of carriers of a MMP3 5A allele for breast cancer was 1.09 (95% confidence interval, 0.83–1.44). Patients with the 5A/5A genotype had a higher proportion of lymph-node metastases than those with a 5A/6A or 6A/6A genotype (P = 0.010). Conclusions: The MMP3 5A/6A promoter polymorphism does not appear to influence breast cancer susceptibility but may be linked to a higher risk for metastasizing among breast cancer patients.

Association between single nucleotide polymorphisms in the gene for XRCC1 and radiation-induced late toxicity in prostate cancer patients

BACKGROUND AND PURPOSE Polymorphisms in genes responsible for DNA damage signaling and repair might modulate DNA repair capacity and, therefore, affect cell and tissue response to radiation and influence individual radiosensitivity. The purpose of the present prospective investigation was to evaluate the association of single nucleotide polymorphisms in XRCC1 with radiation-induced late side effects in prostate cancer patients treated with radiotherapy. MATERIAL AND METHODS To analyze the role of XRCC1 polymorphisms for late toxicity 603 participants from the Austrian PROCAGENE study treated with three-dimensional conformal radiotherapy were included in the present investigation. Three non-synonymous candidate polymorphisms in the X-ray repair cross-complementing group 1 (XRCC1) gene (Arg194Trp; Arg280His; Arg399Gln) were selected and determined by 5´-nuclease (TaqMan) assays. RESULTS Within a median follow-up time of 35 months, 91 patients (15.7%) developed high-grade late toxicities (defined as late bladder and/or rectal toxicity RTOG≥2). In a Kaplan-Meier analysis, carriers of the XRCC1 Arg280His polymorphism were at decreased risk of high-grade late toxicity (p=0.022), in multivariate analysis including clinical and dosimetric parameters as potential confounders the XRCC1 Arg280His polymorphism remained a significant predictor for high-grade late toxicity (HR=0.221, 95% CI 0.051-0.956; p=0.043). No significant associations were found for the remaining polymorphisms. CONCLUSIONS We conclude that the XRCC1 Arg280His polymorphism may be protective against the development of high-grade late toxicity after radiotherapy in prostate cancer patients.

The use of confocal laser-scanning microscopy in microsurgery for invasive squamous cell carcinoma

Background  Ex‐vivo confocal laser‐scanning microscopy offers rapid imaging of excised tissue specimens without conventional histotechnical procedures. As vertical sections are prepared, morphological features can be assessed according to standard criteria used in conventional histopathology.

Long-term follow-up of patients with pituitary macroadenomas after postoperative radiation therapy: analysis of tumor control and functional outcome.

Purpose:Evaluation of long-term tumor control, normalization of hormonal hypersecretion, including incidence and time course of pituitary dysfunction following postoperative radiotherapy of pituitary macroadenomas.Patients and Methods:In a retrospective study, the data of 87 patients with pituitary macroadenomas (61 non-secreting adenomas, 26 secreting adenomas) treated between 1984 and 1994 were analyzed. All patients underwent surgery and received postoperative external-beam radiotherapy with a mean dose of 50.4 Gy (range 46–54 Gy).Results:After a follow-up of 15 years the local tumor control rate achieved was 93.0% for non-secreting adenomas and 100% for secreting adenomas, respectively. Normalization of endocrine hypersecretion was noted in 24 of 26 patients (92%). Detailed endocrinological follow-up data were analyzed by an experienced endocrinologist in 77 patients. After a median follow-up of 10.54 years (mean 10.22; range 1.39–20.75 years), in 75 of 77 patients (97%) a hypopituitarism was observed (partial hypopituitarism, n = 28 [36%], panhypopituitarism, n = 47 [61%]), and 68 out of 77 patients (88%) showed evidence of radiotherapy-induced pituitary disorders. The somatotropic function was most commonly affected, followed by gonadal, thyroid and adrenal function. The gonadal axis showed to be the first to be disturbed. 67 patients (87%) required a hormone replacement therapy.Conclusion:Radiotherapy after pituitary surgery is highly effective in reducing hormonal hypersecretion and preventing recurrences of pituitary adenomas. However, pituitary insufficiencies are commonly observed after radiotherapy requiring a close follow-up to ensure timely diagnosis of pituitary dysfunction and an early inception of hormone replacement therapy.Ziel:Ziel der retrospektiven Analyse war die Evaluation der lokalen Tumorkontrolle sowie der hormonellen Normalisierung nach konventioneller postoperativer Strahlentherapie in der Langzeitbeobachtung. Zusätzlich wurden die Inzidenz und der zeitliche Verlauf von Hypophyseninsuffizienzen untersucht.Patienten und Methodik:Zwischen April 1984 and November 1994 wurden 87 Patienten mit Makroadenomen der Hypophyse (nicht-sezernierende Adenome: n = 61, sezernierende Adenome: n = 26) einer postoperativen Strahlentherapie unterzogen. Die Bestrahlung erfolgte mit einer medianen Dosis von 50,4 Gy (Spannweite 46–54 Gy).Ergebnisse:Nach 15 Jahren betrug die lokale Kontrolle bei nicht-sezernierenden Adenomen 93% und bei sezernierenden Adenomen 100%. Eine Normalisierung der hormonellen Hypersekretion konnte bei 24 von 26 Patienten (92%) erreicht werden. Detaillierte Informationen über die hypophysäre Funktion lagen bei 77 Patienten vor. Nach median 10,54 Jahren wurde bei 75 von 77 Patienten (97%) eine Funktionsstörung des Hypophysenvorderlappens diagnostiziert (partieller Hypopituitarismus: n = 28 [36%], Panhypopituitarismus: n = 47 [61%]). Bei 68 von 77 Patienten (88%) zeigte sich eine radiotherapiebedingte Störung hormoneller Funktionen. Die somatotrope Achse war am häufigsten betroffen, gefolgt von der gonadotropen, der thyreotropen und der adrenokortikotropen Achse. In der Analyse des zeitlichen Verlaufs zeigte die gonadotrope Achse als Erste eine funktionelle Störung. 67 Patienten (87%) entwickelten eine substitutionspflichtige Hypophysenvorderlappeninsuffizienz.Schlussfolgerung:Mit der konventionellen postoperativen Strahlentherapie konnte eine ausgezeichnete lokale Kontrolle in der Langzeitbeobachtung erreicht werden. Die Rate an Hypophyseninsuffizienzen erfordert jedoch in einem hohen Prozentsatz eine Hormonersatztherapie und macht lebenslange endokrinologische Kontrollen notwendig.