First Author: Radu Cristina

Co-Authors: Stefan Anda

Tripon Florin

Crauciuc George

Coordinators: Banescu Claudia, MD

Demian Smaranda, MD

The importance of XRCC1 Arg399Gln DNA repair gene in the determining of lymphoma response to

chemotherapy, radiotherapy and outcome

What is Lymphoma?Lymphoma is the name for a group of blood cancers that develop in the lymphatic system.

• The two main types of lymphoma are non-Hodgkin's (about 90% of cases) and Hodgkin's (about 10%)

• The main symptoms are enlargement of lymph nodes, sweating, fever, weight loss

• The cause of lymphoma is unknown, but some risk factors have been identified

• Lymphoma cannot be prevented, but survival rates after treatment are good

• Treatments are similar to those for other cancers, and they include chemotherapy, radiotherapy and specialized drug therapy.

What is a DNA repair gene?• XRCC1 gene • genomic stability • polymorphism

Obtaining clinical conclusions by analysing pathological characteristics.

Which is the purpose of our research?

Investigate in a case-control study if XRCC1 Arg399Gln gene plays a role in malignant lymphoma response to chemotherapy, radiotherapy and outcome.

Using the results as a starting point for future studies.

Main purpose

Evaluate the relation between survival probabilities and genotype, treatment ,ECOG.

Specific purposes

Material and method

• Retrospective case-control study (94 cases, 113 controls matched for age, sex and ethnicity);

• Patient medical charts (Hematology Department of Targu-Mures County Emergency Hospital) their diagnosis, Ann Arbor stage, survival time, treatment;

• Genetic results from Genetics Department of Targu-Mures County Emergency Hospital. Genetic DNA was extracted from peripheral blood, than was submitted to PCR- RFLP technique.

• Softwares used: GraphPad, MedCalc, Microsoft Excel.

How we chose our patients? What is the treatment outcome?

Column1 Arg/Arg Arg/Gln Gln/GlnNo.patients (%) 49 (52.12) 32 (34.04) 13 (13.82)Sex (men/women) 21/28 12/20 5/8Age, median (range) 57.51 57.46 56.28Disease, no. (%)

Stage 3,4 18 (36.73) 13 (40.62) 6 (46.15)Elevated LDH 34 (69.38) 19 (59.37) 6 (46.15)Extranodal sites 12 (24.48) 11 (34.37) 3 (23.03)

ECOG, no. (%)1,2 35(72.91) 20(64.51) 9 (75)3,4 13(27.08) 11(35.48) 3 (25)

Response, no (%)Resistent 21 (53.84) 9 (36) 1 (8.33)Partial remission 12 (30.76) 11 (44) 7 (58.33)Complete remission 6 (15.39) 5 (20) 4 (33.33)

Survival, no (%)Survival 38 (77.55) 27 (84.37) 13 (100)Death 11 (22.44) 5 (15.62) 0 (0)

Is there an association between Lymphoma and XRCC1 Arg399Gln polymorphisms?

Negative association, statistically significant

between the XRCC1 Arg399Gln and

Lymphoma in men

PROTECTIVE ACTION

Genotype P OR IC

AG/AA 0.13 0.61 0.33-1.11

GG/AA 0.67 0.77 0.33-1.79

MenAG/AA 0.03 0.38 0.16-0.92

GG/AA 0.38 0.49 0.15-1.63

WomenAG/AA 0.82 1.20 0.49-2.29

GG/AA 0.74 1.57 0.41-5.90

Adjusted ORs with 95% CI and P value for XRCC1 Arg399Gln polymorphism according to sex.

Where is the mutation more frequent: in men or women?

Hodgkin or Non-Hodgking? Lymphoma classification

What is Ann Arbor staging? What influences it?

What Ann Arbour stage changes in lymphomas evolution?

How does the genotype increase or decrease the probability of survival?

How does the genotype increase or decrease the probability of survival?

What therapy changes in the survival chances?

What do other studies say?

a. No significant evidence was found supporting the hypothesis that lymphoma risk is affected by DNA base excision repair gene XRCC1 Arg399Gln[1]

b. The variants of 399Gln were shown to be associated with favorable outcomes and decreased relape risk [4]

c. XRCC1 399Gln(A) variant allele had no effect on the risk for either NHL overall or any subtype in a Japanese population[1]

d. Among heavy smokers, individuals with at least one Arg399Gln variant allele have a threefold increase in follicular lymphoma risk compared to individuals with wild type genotype[2]

Our conclusions are…

1. XRCC1 Arg399Gln has a protective action against lymphoma in men

2. the presence of the mutant allele brings a decreasing resistance of lymphomas for treatment

3. Gln399Gln genotype has the best survival probability

4. Chemotherapy only treatment has better results then chemotherapy combined with radiotherapy

5. the frequencies of the XRCC1 399Gln alleles among healty controls were similar to the frequencies reported to other studies

Limitations

1. interaction with environmental factors should be considered

2. to date, only a few studies have adressed the association between alterations in the XRCC1 gene and lymphoid tumors

References• [1] K. Matsuo et al. Lack of association between DNA base excision repair gene

XRCC1 Gln399Arg polymorphism and risk of malignant lymphoma in Japan. Cancer Genetics and Cytogenetics 149 (2004) 77-80

• [2] J. Liu et al. DNA repair gene XRCC1 polymorphisms and non-Hodgkin lymphoma risk in a Chinese population. Cancer Genetics and Cytogenetics 191 (2009) 67-72

• [3] D.A. Eichenauer et al. Hodgkin's lymphoma:ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 22 (2011) 55-58

• [4] I.S. Kim et al. DNA repair gene XRCC1 polymorphisms and halotypes in diffuse large B-cell lymphoma in a Korean population. Cancer Genetics and Cytogenetics 196 (2010) 31-37

• [5] E.J. Duell. Polymorphisms in DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells. Carcinogenesis vol.21 no.5 965-971, 2000.