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The effect of polymorphisms in the promoter region of the MMP-1 gene on the occurrence and invasiveness of hypophyseal adenoma

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Abstract

Background

The matrix metalloproteinase-1 enzyme (MMP-1, also called collagenase 1) plays a key role in turnover of collagen fibers in the intercellular matrix. Insertion of a guanine residue was found within the promoter region of the MMP-1 gene. We found that MMP-1 levels increased approximately twofold over normal when this insertion was present, enabling MMP-1 to facilitate tumor invasion and metastasis. MMP-1 is also believed to play a role in tumor development. The aim of our study is to investigate the effect of polymorphisms in the promoter region of the MMP-1 gene on the development of benign and invasive hypophyseal adenomas.

Patients and methods

Thirty patients with hypophyseal adenomas diagnosed by radiological examination underwent surgical removal, and the diagnosis was confirmed using immunohistochemical staining of the pathology specimens. We found that ten of these patients had invasive adenomas confirmed by radiological examination and immunohistochemical staining. DNA isolation was performed on all specimens, and 5-cc venous blood samples were obtained from all patients as well as 30 volunteers using the Qiagen QIAquick kit. Promoter regions of MMP-1 genes from the DNA samples were amplified using polymerase chain reaction (PCR) and primers designed for the site-directed mutation method. Following PCR, a guanine residue within the promoter region of the MMP-1 gene was identified using the restriction fragment length polymorphism method and the ALU I restriction enzyme. Three genotypes were detected in a genotyping assay: 2G/2G, 1G/2G, and 1G/1G.

Results

Of the surgically treated patients, 36.6% had the 2G/2G genotype, 46.6% had the 1G/2G genotype, and 16.6% had the 1G/1G genotype. The 2G allele frequency was found to be 83.4%. In 90% of cases of invasive adenoma, a homozygous 2G/2G genotype was detected.

Discussion

The risk for development of hypophyseal adenoma may be greater in patients with the 2G allele. In cases of existing hypophyseal adenoma, those with the homozygous 2G allele tend to be invasive.

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Authors and Affiliations

  1. Department of Neurosurgery, Tayfur Ata Sökmen Medical Faculty, Mustafa Kemal University, Hatay, 31700, Turkey

    Murat Altaş

  2. Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, Istanbul, Turkey

    Omer Faruk Bayrak, Mustafa Çulha & Fikrettin Sahin

  3. Department of Medical Genetics, Faculty of Medicine, Yeditepe Universty, Istanbul, Turkey

    Omer Faruk Bayrak & Serhat Sevli

  4. Department of Neurosurgery, Goztepe Education and Research Hospital, İstanbul, Turkey

    Erdogan Ayan, Fatihhan Bolukbası, Kerim Kenan Coskun & İlhan Elmacı

  5. Department of Neurosurgery, Sema Hospital, İstanbul, Turkey

    Gokalp Sılav

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  1. Murat Altaş
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Correspondence to Murat Altaş.

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Comments

The authors studied venous blood DNA of 30 patients’ hypophyseal adenomas and 30 age-matched volunteers for a functional insertion / deletion polymorphism at the position -1607 in the MMP1 gene promoter region - 9 of the 10 patients with an invasive adnoma carried the 2G genotype.

Is this relevant? Not in my mind – because: (1) the study cohort is by far too small – considering many confounding factors; (2) MMP1 expression levels were not analyzed in the adenoma tissue samples; (3) transcriptomic array and differential signalling pathway analyses between the non-invasive and invasive adenoma tissues were not performed – so nothing, so far, links such differential signalome to pathways related to the MMP1 gene; (4) were the 2G genotype a real risk, the carriers should be highly prone to develop multiple neoplasia and morbidities from collagen defects.

This theory-to-experiment approach – favoured, e.g., by Paul Dirac (1902–1984), 1933 Nobel laureate in quantum physics – becomes a needle-in-the-haystack approach in human tissue dynamics with hundreds of thousands of proteins and millions of SNPs. In the age of genomics / transcriptomics / proteomics / anymics / systemic approaches should be undertaken first – otherwise we just go on with the one marker philately.

Juha E Jääskeläinen

Kuopio Finland

The polymorphisms in the promoter region of the MMP-1 gene have been investigated several times for different neoplastic and non-neoplastic diseases and have been found to be a good prognostic factor. The Authors have translated such results in pituitary adenomas and have investigated the potential role of such polymorphisms in the invasiveness and incidence of pituitary adenomas. They found that the risk of pituitaryadenoma may be greater with the 2G allele, and that pituitary adenoma tends to be invasive with the homozygous 2G allele.

Even though at present time their results may be considered too impractical and sophisticated, nevertheless they are quite interesting and in the near future may help predicting the possible recurrence of operated pituitary adenomas.

Felice Esposito, MD, PhD

Luigi M. Cavallo, MD, PhD

Naples, Italy

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Altaş, M., Bayrak, O.F., Ayan, E. et al. The effect of polymorphisms in the promoter region of the MMP-1 gene on the occurrence and invasiveness of hypophyseal adenoma. Acta Neurochir 152, 1611–1617 (2010). https://doi.org/10.1007/s00701-010-0671-0

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