Family History of Cancer and Risk of Lymphoma: Influence of IL8RB, GGH IVS7 and IL10 Polymorphisms.
Authors: Domingo-Domènech Eva , Benavente Yolanda , Montalbán Carlos , Bosch Ramon , Gumà Josep , Wang Sophia , Rothman Nathaniel , Gonzalez-Barca Eva , de Sanjose Silvia 
Published: April 2020

Abstract
Background and aims: Family history of cancer in lymphoma patients has largely been described. On the other hand, genetic susceptibility associated to lymphoma risk is being investigated at the present time. However, single nucleotide polymorphisms (SNPs) associated to the entity among those reporting family history of cancer have yet not been identified. In a previous study of our group, we identified that the probability of having a first-degree relative with cancer was significantly higher among the patients with lymphoid neoplasm than among the control subjects (43% vs 35%, p&lt;0.05). When analysing by lymphoma subtypes, B-cell lymphoma, chronic lymphocytic leukaemia (CLL) and multiple myeloma (MM) patients were significantly more likely to report a first-degree relative with any cancer, with a risk increase ranging from 1.4 up to 2.1 among CLL patients. Thus, a 2-to 4-fold increased risk of lymphoma has been identified in patients with a family history of hematologic disease or lymphoma in first-degree relatives, with CLL, MM and Hodgkin’s lymphoma (HL) being the three entities more consistently reported. The purpose of this study was to evaluate the role of genetic variants of several polymorphisms in the risk of developing a lymphoid neoplasm among subjects with family history of cancer in the case-control study Epilymph.
Material and methods: Newly diagnosed cases of lymphoma were recruited between 1998–2002 in 4 Spanish centers. Controls were hospitalized patients matched to the cases by age, gender and study center. Personal interviews were conducted in order to collect data on demographics, environmental exposure, medical and family history, including cancer. The site of cancer, age at diagnosis, and status of any affected relatives with cancer were requested. In this analysis, we only included those subjects who reported a family history of cancer. 72 SNPs in 47 genes were included in the analysis. DNA of 503 cases and 569 controls were genotyped using the TaqmanTM platform. Odds Ratios (OR) and 95% confidence intervals (CI) for the association of the variants with the risk of lymphoma were calculated using unconditional logistic regression analysis, under the log additive inheritance model.
Results: Family history of cancer was reported by 421 subjects (196 controls and 225 cases, p-value=0.001). Among those, 41 had an hematological origin. The two SNP genotyped in IL8RB gene were associated to an increase in risk of lymphoma for every extra variant allele (IL8RB +1235C&gt;T OR=1.68, 95%CI=1.25–2.27 and IL8RB -1010A&gt;G OR=1.59, 95%CI=1.17–2.17). The OR associated to an additional variant allele of Ggh IVS7-3001 polymorphism was 1.82 (95%CI=1.06–3.14). IL-1082 A&gt;G was observed to decrease the risk of lymphoma (OR=0.72, 95%CI=0.54–0.96).Restricting the analysis to those with a familial cancer of hematological origin under a log-additive inheritance model, a statistical increase in the risk was found for every extra variant allele MTHFR +429A&gt;C in the genotype (OR=21.52, 95%CI=2.42–191.08), whereas presenting at least one variant allele of IL10 -1082 A&gt;G decreased the risk of lymphoma (OR=0.05, 95%CI=0.01–0.38). In order to evaluate the association between SNPs and lymphoma subtypes in subjects with family history of cancer, we explored the relation between all statistically significant SNPs reported above and non-Hodgkin lymphomas (NHL), Chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and Hodgkin lymphoma (HL). We observe that the association of SNPs and all lymphoma is similar after stratifying by subtypes, although these results are based on few subjects. Interestingly, those SNPs related to low risk of lymphoma, were observed to have the lowest risk among HL cases (IL10 -1082 A&gt;G OR=0.28, 95%CI=0.09– 0.82), whereas HL and MM seems to be at higher risk for those SNPs related to increased risk of lymphoma (IL8RB+1235 OR=2.29, 95%CI=1.29–4.05 and IL8RB-1010 OR=2.45, 95%CI=1.33–4.51 for MM and Ggh IVS7-3001 OR=5.47, 95%CI=1.33–22.52 for HL).
Conclusions: These results suggest a potential role of IL8RB, GGH IVS7 and IL10 SNPs in the risk of lymphoid neoplasms among subjects with family history of cancer. HL and MM seem to be those entities in which these associations appear to be stronger, although the number of cases included is small.