hMSH2 Gly322Asp (rs4987188) Single nucleotide polymorphism and the risk of breast cancer in the Polish women

Carcinoma of the breast is the most common cause of death among women worldwide. 1.7 million of new cases was diagnosed in 2012. Same year half a million women died due to breast cancer (GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012). Every year over 17 thousand women in Poland are diagnosed with breast cancer with more than 5 thousand of them eventually succumbing to the illness [i].

 According to authors of “White Book. Overcoming colorectal and breast cancer in Poland in comparison to other European countries” by 2020 the incidence should increase to almost 20 thousand patients yearly [2]. 5year survival rate among breast cancer patients in Poland is one of the lowest in whole Europe. Analyzing European average survival rate of breast cancer patients versus Poland rate, in first year after diagnose the values are 4% lower, and after 5 years they rise to 10% (EUROCARE5, online database – years 2000–2007).

The system of DNA repair takes part in maintaining the genomic integrity which undergoes changes under exo- and endogenous factors. In man, the protein products of genes are directly involved in the repair process, taking part in several repair systems. The repair process usually encompasses two stages: the excision of lesion and the repair synthesis. This is how repair system act via base-excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR). Totally converse is the repair system activity by direct lesion reversal, in which there is merely a single-stage process with maintained integrity of the DNA phosphodiester chain and the system of recombination repair (HR). Defects of the proteins, which directly participate in DNA repair and its control, are associated with an increased susceptibility to malignant changes.

The alternations in the oncogenes and tumor suppressor genes as well as DNA mismatch repair genes have been associated with cancers development [3, 4, 5]. There are seven major DNA mismatch repair genes in humans: MLH1, MLH3, PMS1, PMS2, MSH2, MSH3 and MSH6. hMSH2, also known as MutS protein homolog 2, is a tumor suppressor gene that encodes a protein which plays a crucial role in DNA mismatch repair, but also holds activity in other versatile types of DNA repair such as: homologous recombination, transcription-coupled repair or even base excision repair. Microsatellite instability, which is a notorious effect of hMSH2 mutations, is also an axis feature of Hereditary Nonpolyposis Colorectal Cancer (HNPCC) alias Lynch syndrome [6]. 

State-of-the-art research focuses on the analysis of versatile genetic aspects and on the attempt to associate these with clinical manifestation of carcinogenesis. Large effort has been lately put into investigation of single nucleotide polymorphisms (SNPs), which may underline the differences in ones susceptibility and natural history of diseases. According to NCBI dbSNP there are more than 150 million SNPs in human already discovered [7] and as many as 380 SNPs in hMSH2 only [8].

 A positive correlation between polymorphisms of the hMSH2 gene and occurrence of cancer was reported in colorectal cancer [9, 10], gastroesophageal cancer [11, 12], lung cancer [13] or even gallbladder cancer [14]. In addition, polymorphisms of hMSH2 may also have en effect on cellular response to radiation therapy in breast cancer patients [15]. 

Gly322Asp (1032G>A, rs4987188) is a missense SNP resulting in a Glycine to Aspartic Acid switch at codon 322. However the role of hMSH2 polymorphism and breast cancer development is still unknown. The primary goal of the study was an identification of genetic variants which increase the risk of breast cancer in the population of Polish women.