Involvement of INF-ꝩ functional single

nucleotide polymorphism +874 T/A (rs2430561)

in breast cancer risk

Dr. Sherif Refaat , MSc, MD

Lecturer of medical Oncology, OCMU
Faculty of Medicine
Mansoura University
Background
• According Global Cancer Statistics 2020 GLOBOCAN estimates female breast cancer was found as the most commonly
diagnosed cancer in females , with an estimated 2.3 million new cases (11.7%), and the fourth leading cause (6.9%) of cancer
death among women worldwide.
• From the INF family ( 3 members) , INF-ꝩ is the only type which can orchestrate both innate and adaptive immune responses
against viruses, bacteria, and tumors.
• INF-ꝩ may be produced in perverse manner which is associated with disease pathology, even in cancers and chronic autoimmune
diseases
• INF-ꝩ producing cells are restricted to T lymphocytes and natural killer (NK) cells representing innate immune responses.
• The production of INF is correlated to the functional SNPs INF- ꝩ T + 874A, presenting the T allele contributing to the high INF

production, and the A allele responsible for the low INF production .
- At First INF-ꝩ was known to posses exclusively an antitumor anti-proliferative effects by different mechanisms , But In
tumor cells and host cells, INF-ꝩ was found to induce paradoxical responses that facilitate tumor outgrowth leading
to initiation of immunosuppressive tumor microenvironment and adaptive resistance which result in tumor-specific T
cells suppression
- The effect of different cytokines gene polymorphisms in breast cancer have been documented in several studies
confirming its association to BC involvement

-Aim of the study :

to investigate in depth the involvement of the INF- ꝩ + 874 T/A gene polymorphism in the pathogenesis and
its relation to different breast cancer characteristic.
-Patients and methods :
• 3 groups were recruited : breast cancer (BC) : 163 patients , inflammatory breast conditions (ICB) 79 patients ,
healthy controls (C) 144 patients
• DNA extraction and INF- ꝩ gene + 874 T/A (rs2430561) genotyping: by ARMS / PCR “amplification refractory
mutational system “
Results:
1- Distribution of INF- ꝩ + 874 T/A (rs2430561) genotype in different studied groups:
strong significant association of INF- ꝩ + 874 genotype with BC patients with both codominant models (AA vs. AT)
and (AA vs. TT), dominant model (TT + AT versus AA), recessive model (TT versus AA + AT) as well as and allelic
frequency of INF-c + 874 (T versus A).
These results support a potential role of INF-c + 874 T/A in the pathogenesis of breast cancer among the studied
Egyptian population.
Results:
2- Distribution of INF- ꝩ + 874 T/A (rs2430561) genotype in different variant of BC Group: By comparing the different
models of INF-c + 874 T/A (rs2430561) genotype as a risk estimate with different variables of tumor in BC group, results
revealed
- No association with ER, PR, metastasis or operation type
- significant association in the host INF- ꝩ + 874 T/A genotype with Her2/neu expression in the codominant model (AA
vs. TT, P = 0.03) as well as recessive model (TT versus AA + AT P = 0.03) with the positive Her2/neu.
- No significant difference between TNBC and HER-2 enriched when compared to luminal A
- Significant difference between Luminal HER-2 pattern (ER, PR +VE, HER2 +VE” when compared to luminal A in the
codominant and recessive models.
Results:
3- Distribution of INF- ꝩ + 874 T/A (rs2430561) genotype according Nottigham prognostic index (NPI) in BC Group :
No significant differences have been noted within different groups
No significant differences when different genotypes is tested within the different NPI groups ( GPI, MPI,PPI).

4- Distribution of INF- ꝩ + 874 T/A (rs2430561) genotype according metastasis in BC Group:

- Mets was detected in 24 patients, where 4 patients show AA genotype, 12 patient show AT genotype and 8 with
TT genotype
- Bone mets were the most common
Discussion:
- Our study showed strong significant association of INF- ꝩ + 874 genotype with BC patients with both codominant
models (AA vs. AT) and (AA vs. TT), dominant model (TT + AT versus AA), recessive model (TT versus AA + AT) as well
as and allelic frequency of INF- ꝩ + 874 (T versus A).
- Our findings seem not to be reported before, where the INF- ꝩ + 874 TT genotype and T allele were found to be
associated with high transcription of INF-c gene in BC, in which they are involved in the higher production of INF- ꝩ
- Many previous studies “ on different disorders “ and Asian BC supports our findings (Szkup et al., 2019; Cameron et al., 2021).
-. In contrast to these results, a lack of association between INF ꝩ + 874 T/A gene Polymorphism and cancer risk was
reported by Ge and coworkers (2014), this may be as they included 38 studies with different cancer types and
pooled all these types’ results together while each cancer type has different response to INF ꝩ + 874 T/A gene
Polymorphism
- The ICB group “was used as another control” : no association to the INF-c + 874 T/A SNP in codominant model (AA
vs. TT), recessive model (TT versus AA + AT) as well as and allelic frequency of INF-c + 874 (T versus A) when
comparing to healthy control group.
Discussion:
- No existed data to compare our results with, but the results confirm the strong involvement of INF- ꝩ + 874 T/A SNP in BC
patients’ carcinogenesis and not ICB patients.
- No significant association was found between different genotypes and ER, PR, or metastasis but significant association with HER-
2 in the codominant (AA vs TT) and recessive models (TT vs AA+ AT) confirming the association of TT genotype with
aggressiveness of BC
- Significant association of the codominant and recessive model to the luminal HER-2 type when compared to lumonal A ,
confirming again association of TT with aggressiveness of breast cancer.
- Metastasis: TT genotype had more metastatic cases > AA and TT was the only genotype presenting with mets in TNBC and HER-2
enriched types.
- INFGR1 : potential therapeutic target especially in TNBC in the metastatic setting.
Conclusion:

The study demonstrated strong association between INF- ꝩ 874 A/T polymorphism with the

aggressiveness and carcinogenesis of BC, suggesting its role in the pathogenesis of BC especially

TT genotype and T allele involvements.

. It may be used as practical biomarker to guide the BC carcinogenesis and risk assessment
Thank
you