{"id":51095,"date":"2023-09-30T10:04:07","date_gmt":"2023-09-30T10:04:07","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=51095"},"modified":"2023-10-07T12:05:07","modified_gmt":"2023-10-07T12:05:07","slug":"case-report-the-relationship-of-ccnd1-rs614367-polymorphism-with-clinicopathological-features-in-breast-cancer-subjects","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol16no3\/case-report-the-relationship-of-ccnd1-rs614367-polymorphism-with-clinicopathological-features-in-breast-cancer-subjects\/","title":{"rendered":"The Relationship of CCND1 RS614367 Polymorphism with Clinicopathological Features in Breast Cancer Subjects"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

Breast\ncancer is a malignancy in breast tissue cells, with the highest percentage of\nincidence (43.3%) and mortality (12.9%). In Indonesia, the incidence of breast\nis 42.1 per 100.000 population, with an average mortality rate of 17 per\n100.000. In addition, the average survival of subjects after the first relapse\nor survival from the first relapse is only 17 months.1<\/sup><\/p>\n\n\n\n

The high\nmortality rate of breast cancer and the many risk factors associated with\nbreast cancer have resulted in the identification of a new prognostic marker,\none of which is CCND1 rs614367. Cell-cycle regulator cyclin D1 (CCND1) encodes\na cyclin protein that is important for the cell cycle. The CCL5\/STAT\/CCND1\nsignaling pathway plays an important role in the crosstalk between epithelial\nand immune cells.2<\/sup> The allele frequency of CCND1 rs614367-T was\nhigher in subjects with breast cancer than for controls resulting in a\nsignificant positive association (OR 1.38, p=0.032), restricted explicitly to\nthe CCND1 rs614367-T\/T homozygous genotype (OR 3.64, p=0.016). CCND1 rs614367\nis associated with a substantial and specific increase in risk for TNBC and one\nof the most potent breast cancer risk loci identified. CCND1 is a positive\nestrogen receptor (ER) breast cancer marker.3 <\/sup>Studies in Indonesia\nexamining the relationship between the CCND1 RS614367 polymorphism and the histopathological\ncondition of breast cancer subjects are still very limited, especially in Bali.\nThis study aimed to determine the CCND1 RS614367 polymorphism and its\nrelationship with the clinicopathology of breast cancer subjects.<\/p>\n\n\n\n

Material\nand Methods<\/strong><\/strong><\/p>\n\n\n\n

Study design<\/strong><\/p>\n\n\n\n

This study was\nan analytical cross-sectional to examine the relationship between the CCND1\nrs614367 polymorphism and clinicopathological characteristics in breast cancer\nsubjects.<\/p>\n\n\n\n

Setting<\/strong><\/p>\n\n\n\n

This research was carried\nout at the Integrated Biomedical Laboratory and Biochemistry Laboratory,\nFaculty of Medicine, Udayana University, from May 2022 to November\n2022.<\/p>\n\n\n\n

Participants<\/strong><\/p>\n\n\n\n

The population in this study\nwere breast cancer subjects who had taken venous blood samples and stored them\nat the Department of Biochemistry, Faculty of Medicine, Udayana University as\nStored Biological Materials (BBT). The inclusion criteria were subjects\nwith blood venous samples stored in the\nDepartment of Biochemistry, Faculty of Medicine, Udayana University. The exclusion\ncriteria were venous blood samples that were not suitable for use, inadequate\namount of serum when centrifuged, and contaminated with other samples. <\/p>\n\n\n\n

Research\nFlow<\/strong><\/p>\n\n\n\n

All\nstored biological material from venous blood samples, taken from breast cancer\nsubjects visited Prof. dr. IGNG Ngoerah, were collected consecutively. The\nclinicopathology data was collected in a data collection sheet, such as age,\ncancer subtype, histological grade, tumor stage, distant metastases, tumor\nsize, Ki67, ER, and PR. All research subject data is stored on the researcher’s\ncomputer using a password that the research team can only access to maintain\nthe confidentiality of the research subject’s data<\/p>\n\n\n\n

The\nserum from the blood sample will be PCR processed to determine the CCND1 rs614367\npolymorphism. The PCR instruments used were a set of GoTaq\u00ae Green Master Mix,\nprimer CCND1 rs614367, template DNA, nuclease-free aqua, thermocycler, PCR\ntube, micropipette 200-1000\u00b5l, 20-200\u00b5l, and 1-20 \u00b5l, blue, yellow, white tip,\nelectrophoresis instrument, agarose gel, TAE, microwave, ethidium bromide, Gel\nBox (Electrophoresis Unit).<\/p>\n\n\n\n

DNA\nisolation from venous blood samples was started by placing 200\u00b5l of blood into\na centrifugation tube and adding 200\u00b5l of BB Buffer. Add 20 \u00b5l Proteinase X and\nincubate at 650C for 10 minutes. Add 200\u00b5l Absolute Alcohol, mix immediately,\nthen transfer the mixture to a spin column. Centrifuge at 5000 x g for 1\nminute, remove the excess liquid from the spin column and add 500\u00b5l Wash Buffer\n1. Centrifuge at 5000 x g for 1 minute, remove the excess liquid from the spin\ncolumn and add 500\u00b5l Wash Buffer 2. Centrifuge at 5000 x g for 1 minute\nminutes, discard the liquid that has passed from the spin column and add 500\u00b5l\nWash Buffer 2. Next, centrifuge at 12000 rpm for 3 minutes and remove the\nliquid that has passed from the spin column. Then, transfer the spin column to\na new centrifugation tube. Add 100\u00b5l of Elution Buffer previously warmed at\n650C or H2O, leave for 2 minutes. Centrifuge at 5000 x g for 1 minute and store\nDNA at 40C or -200C.<\/p>\n\n\n\n

DNA\nsample amplification by PCR by inserting a 25 \u00b5L PCR reaction mixture into the\nThermocycler machine. Carry out the primary denaturation process by incubating\nat 94oC for 1 minute, followed by incubation at 72oC for 7 minutes. Then do the\nPCR process for 40 cycles, with each rotation at 94oC for 30 seconds, 57oC for\n30 seconds, and 72 degrees of Celcius for 30 seconds. Visualization of DNA\nsamples by electrophoresis using a gel containing ethidium bromide and\nobservation under ultraviolet (UV) lamps. DNA purification from gel\nelectrophoresis consists of gel dissociation, DNA binding, washing, and DNA\nelution. The purified DNA is then sent to Genetics Science for sequencing.<\/p>\n\n\n\n

Statistical\nmethods<\/strong><\/p>\n\n\n\n

Statistical\nanalysis was performed using SPSS for Windows version 25.0 software. Univariate\nanalysis of proportions for characteristic variables such as histopathological\ngrading, cancer stage (TNM system), occupation, and the presence or absence of\nthe CCND1 rs614367 polymorphism. Bivariate inferential analysis, namely\nchi-square or fisher-exact, when the data does not meet the chi-square\nrequirements to evaluate the relationship between polymorphism and the\nvariables that have been determined. The p value is considered significant if P\n<0.05.<\/p>\n\n\n\n

Results<\/strong><\/p>\n\n\n\n

A total of 45 samples of breast cancer subjects\nhad PCR and electrophoresis carried out at the Biochemistry Laboratory, Faculty\nof Medicine, Udayana University. The basic characteristics of the subjects are\ndescribed in Table 1<\/p>\n\n\n\n

Table 1. The Clinicopathological Characteristics of Subjects<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Clinicopathological Data<\/strong><\/p>\n<\/td>\n

\n

N<\/strong><\/p>\n<\/td>\n

\n

%<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Age<\/strong><\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

<50 years old<\/p>\n<\/td>\n

\n

14<\/p>\n<\/td>\n

\n

31.1<\/p>\n<\/td>\n<\/tr>\n

\n

\u226550 years old<\/p>\n<\/td>\n

\n

31<\/p>\n<\/td>\n

\n

68.9<\/p>\n<\/td>\n<\/tr>\n

\n

T stage<\/strong><\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

T1<\/p>\n<\/td>\n

\n

3<\/p>\n<\/td>\n

\n

6.7<\/p>\n<\/td>\n<\/tr>\n

\n

T2<\/p>\n<\/td>\n

\n

7<\/p>\n<\/td>\n

\n

15.6<\/p>\n<\/td>\n<\/tr>\n

\n

T3<\/p>\n<\/td>\n

\n

8<\/p>\n<\/td>\n

\n

17.8<\/p>\n<\/td>\n<\/tr>\n

\n

T4<\/p>\n<\/td>\n

\n

27<\/p>\n<\/td>\n

\n

60.0<\/p>\n<\/td>\n<\/tr>\n

\n

N stage<\/strong><\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

N0<\/p>\n<\/td>\n

\n

13<\/p>\n<\/td>\n

\n

28.9<\/p>\n<\/td>\n<\/tr>\n

\n

N1<\/p>\n<\/td>\n

\n

22<\/p>\n<\/td>\n

\n

48.9<\/p>\n<\/td>\n<\/tr>\n

\n

N2<\/p>\n<\/td>\n

\n

7<\/p>\n<\/td>\n

\n

15.6<\/p>\n<\/td>\n<\/tr>\n

\n

N3<\/p>\n<\/td>\n

\n

3<\/p>\n<\/td>\n

\n

6.7<\/p>\n<\/td>\n<\/tr>\n

\n

M stage<\/strong><\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

M0<\/p>\n<\/td>\n

\n

29<\/p>\n<\/td>\n

\n

64.4<\/p>\n<\/td>\n<\/tr>\n

\n

M1<\/p>\n<\/td>\n

\n

16<\/p>\n<\/td>\n

\n

35.6<\/p>\n<\/td>\n<\/tr>\n

\n

ER status<\/strong><\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

Negative<\/p>\n<\/td>\n

\n

16<\/p>\n<\/td>\n

\n

35.6<\/p>\n<\/td>\n<\/tr>\n

\n

Positive<\/p>\n<\/td>\n

\n

29<\/p>\n<\/td>\n

\n

64.4<\/p>\n<\/td>\n<\/tr>\n

\n

PR status<\/strong><\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

Negative<\/p>\n<\/td>\n

\n

23<\/p>\n<\/td>\n

\n

51.1<\/p>\n<\/td>\n<\/tr>\n

\n

Positive<\/p>\n<\/td>\n

\n

22<\/p>\n<\/td>\n

\n

48.9<\/p>\n<\/td>\n<\/tr>\n

\n

HER2 status<\/strong><\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

Negative<\/p>\n<\/td>\n

\n

21<\/p>\n<\/td>\n

\n

46.7<\/p>\n<\/td>\n<\/tr>\n

\n

Positive<\/p>\n<\/td>\n

\n

24<\/p>\n<\/td>\n

\n

53.3<\/p>\n<\/td>\n<\/tr>\n

\n

Histological type<\/strong><\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

Luminal A<\/p>\n<\/td>\n

\n

9<\/p>\n<\/td>\n

\n

20.0<\/p>\n<\/td>\n<\/tr>\n

\n

Luminal B<\/p>\n<\/td>\n

\n

13<\/p>\n<\/td>\n

\n

28.9<\/p>\n<\/td>\n<\/tr>\n

\n

HER2<\/p>\n<\/td>\n

\n

9<\/p>\n<\/td>\n

\n

20.0<\/p>\n<\/td>\n<\/tr>\n

\n

TNBC<\/p>\n<\/td>\n

\n

6<\/p>\n<\/td>\n

\n

13.3<\/p>\n<\/td>\n<\/tr>\n

\n

Luminal-HER2<\/p>\n<\/td>\n

\n

8<\/p>\n<\/td>\n

\n

17.8<\/p>\n<\/td>\n<\/tr>\n

\n

Grade<\/strong><\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

 I-II<\/p>\n<\/td>\n

\n

25<\/p>\n<\/td>\n

\n

55.6<\/p>\n<\/td>\n<\/tr>\n

\n

 III<\/p>\n<\/td>\n

\n

20<\/p>\n<\/td>\n

\n

44.4<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

The results of CCND1 rs614367 gene polymorphism sequencing in breast cancer subjects showed that 25 (55.5%) and 20 (44.5%) subjects had C and T alleles, which were then subjected to bivariate analysis. The frequency of polymorphism alleles was described in Table 2.<\/p>\n\n\n\n

Table 2: Polymorphism of CCND1 rs614367 in Breast Cancer Subjects<\/strong><\/p>\n\n\n\n\n\n\n\n
\n

Target All<\/strong><\/p>\n<\/td>\n

\n

n<\/strong><\/p>\n<\/td>\n

\n

%<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

C<\/p>\n<\/td>\n

\n

25<\/p>\n<\/td>\n

\n

55,5 %<\/p>\n<\/td>\n<\/tr>\n

\n

T<\/p>\n<\/td>\n

\n

20<\/p>\n<\/td>\n

\n

44,5 %<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Bivariate\nanalysis showed a significant relationship between the CCND1 rs614367 gene\npolymorphism and the clinicopathological features, as described in Table 3.\nBased on the analysis results, subjects aged \u226550 had a significant 4.45 risk of\nhaving the T allele type (p=0.037). In addition, subjects with metastases (M1)\nwere also at a significant 4.89 times risk of having the T allele type (p=0.015).\nSubjects with histological grade III also had a significant 4.77 times risk of\nhaving the T allele type (p=0.013) (Table 3).<\/p>\n\n\n\n

Table 3: Relationship between CCND1 rs614367 polymorphism and Clinicopathology Features in Breast Cancer Subjects<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Clinicopathology<\/strong><\/p>\n<\/td>\n

\n

Allele type<\/strong><\/p>\n<\/td>\n

\n

OR (95%CI)<\/strong><\/p>\n<\/td>\n

\n

p<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

C<\/strong><\/p>\n<\/td>\n

\n

T<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Age<\/strong><\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

<50 years old<\/p>\n<\/td>\n

\n

11<\/p>\n<\/td>\n

\n

3<\/p>\n<\/td>\n

\n

4.45<\/p>\n

(1.03-19.16)<\/p>\n<\/td>\n

\n

0.037<\/p>\n<\/td>\n<\/tr>\n

\n

\u226550 years old<\/p>\n<\/td>\n

\n

14<\/p>\n<\/td>\n

\n

17<\/p>\n<\/td>\n<\/tr>\n

\n

Metastasis<\/strong><\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n

 <\/td>\n <\/td>\n<\/tr>\n
\n

M0<\/p>\n<\/td>\n

\n

20<\/p>\n<\/td>\n

\n

9<\/p>\n<\/td>\n

\n

4.89<\/p>\n

(1.31-18.23)<\/p>\n<\/td>\n

\n

0.015<\/p>\n<\/td>\n<\/tr>\n

\n

M1<\/p>\n<\/td>\n

\n

5<\/p>\n<\/td>\n

\n

11<\/p>\n<\/td>\n<\/tr>\n

\n

Grade<\/strong><\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n

\n

 <\/p>\n<\/td>\n

 <\/td>\n <\/td>\n<\/tr>\n
\n

I-II<\/p>\n<\/td>\n

\n

18<\/p>\n<\/td>\n

\n

7<\/p>\n<\/td>\n

\n

4.77<\/p>\n

(1.35-16.96)<\/p>\n<\/td>\n

\n

0.013<\/p>\n<\/td>\n<\/tr>\n

\n

III<\/p>\n<\/td>\n

\n

7<\/p>\n<\/td>\n

\n

13<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Discussion<\/strong><\/strong><\/p>\n\n\n\n

The CCND1 gene plays an important role in the cell\ncycle and cell viability against mutagens, primarily through CCL5 signaling.\nCCND1, a gene with a length of 13,388 base pairs and codes for 295 amino acids,\nhas several polymorphisms, some of which are related to breast cancer, namely\nCCND1 rs9344 and CCND rs614367.4<\/sup> <\/p>\n\n\n\n

This study showed that the distribution of subjects\nwith the CCND1 rs614367 mutation showed a significant relationship with older\nage. The distribution at an older age also suggested the interaction of\npolymorphism with degenerative processes.5<\/sup> Here, it also showed that\nthere was a lower incidence of metastases in subjects with the C allele,\nsimilar with the analysis by Shan et al., who found that C alleles were mostly\nfound in the CCND rs614367 mutation as well as a lower number of metastatic\nevents in the population (3). The lower incidence of metastases may be\ndue to the effect of the CCND rs614367 mutation on CCL5 signaling activity.\nCCL5 protein or commonly called RANTES (regulated on activation, normal T cell\nexpressed and secreted), physiologically plays a role in leukocyte migration in\nthe event of infection. However, in chronic inflammatory processes such as\ntumorigenesis, CCL5 plays an essential role in the recruitment and maintenance\nof CD8+ T cell function, thereby maintaining the cytotoxic function of the\ncells.6<\/sup> <\/p>\n\n\n\n

In general, the mutation in the CCND1 gene impairs\nCCL5 signaling and reduces the recruitment of CD8+ T cells, thereby increasing\nthe risk of malignancy. The low incidence of metastases in this study may be due\nto the specific mutation CCND rs614367 differently affecting CCL5, but the\nexact mechanism for this is still unknown.7<\/sup> Recent research by\nBekampyte et al. got different results. Namely, the incidence of metastases was\nhigher in the CCND1 rs9344 mutation. This can happen because the rs9344\nmutation CCND1b protein synthesis undergoes alternative splicing, resulting in\nan abnormal protein in the C-terminal domain and overexpression of CCND1b.8<\/sup>\nBoth of these phenomena are related to metastasis.9<\/sup> <\/p>\n\n\n\n

Subjects with the C allele mutation on CCND rs614367\ntend to have a lower tumor stage than the T allele. This phenomenon is also in\nline with the study by Shan et al. This can be attributed to the role of the\nCCND1 protein, which encodes a central protein for the cell cycle and\ncarcinogenesis, cyclin D1. The activity of cyclin D can be influenced by\nestrogen. However, previous studies have shown that the degree of\noverexpression of CCND1 does not have a significant relationship with the\nclinicopathological characteristics of breast cancer.10<\/sup> <\/p>\n\n\n\n

Conclusion<\/strong><\/p>\n\n\n\n

So far, this study is the first study in Indonesia\nto analyze the clinicopathological relationship of breast cancer subjects with\nthe CCND rs614367 polymorphism. The limitation of this study is that only\nsamples from a single center were taken. The CCND rs614367 mutation in this\nstudy showed more distribution of the C allele and a lower incidence of\nmetastases and tumor grading compared to the T allele. Further research is\nneeded to ensure the validity and consistency of the results of this study.
\n<\/strong><\/p>\n\n\n\n

Acknowledgement<\/strong><\/p>\n\n\n\n

The authors acknowledged Faculty of Medicine, Udayana University, that has given tremendeous support in finishing this study.<\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

Authors stated that this study had no conflict of interest.<\/p>\n\n\n\n

Funding Sources<\/strong><\/p>\n\n\n\n

This study received grant from Faculty of Medicine, Udayana University, and not related to any company.<\/p>\n\n\n\n

References<\/strong><\/p>\n\n\n\n

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  10. Li Z, Cui J, Yu Q, Wu X, Pan A, Li L. Evaluation of CCND1 amplification and CyclinD1 expression: diffuse and strong staining of CyclinD1 could have same predictive roles as CCND1 amplification in ER positive breast cancers. American journal of translational research. 2016;8(1):142-53.<\/li><\/ol>\n","protected":false},"excerpt":{"rendered":"

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