Abstract
Objective
Hodgkin lymphoma (HL) is a lymphoproliferative malignancy of B-cell origin and one of the common tumors in adolescent and young adults. Less than one percent of HL patients have a family history and siblings of the affected individual may have an increased risk of developing the disease. HL risk is associated with immunodeficiency syndromes. Clustering of cases of HL within families may also suggest a genetic predisposition. In cases with familial clustering, recognition of genetic predisposition genes in the pathogenesis of HL may offer therapeutic benefits, and provide genetic counseling and surveillance for the family members for early diagnosis. We had previously reported CD70 signaling defect in an extended family with multiple consanguineous marriages and individuals affected with Hodgkin lymphoma and/or immune deficiency (J Clin Immunol.2020, 40(6):883-892). The aim of this study is to investigate for a cancer predisposition gene/condition in two siblings with HL, whose parents had a consanguineous marriage.
Material and Methods
A 10 year-old girl with progressive HL was referred for further evaluation and treatment. She had been diagnosed with stage IIIBs HL, nodular sclerosing subtype and had received chemotherapy (ABVD) where she was reported to have partial response, followed by progressive disease. The tumor was CD30 positive. At admission, the patient had a massive enlarged mediastinum due to conglomerate lymph nodes, nodules in the lung, lymph adenomegalies in the cervical, supraclavicular, axillary regions. She was treated with ifosfamide+mesna, etoposide, carboplatinum (ICE) and brentuximab and achieved a complete metabolic response in PET-CT evaluation after six courses. She is transferred to receive stem cell transplantation. Her 24 year-old sister was also diagnosed with early stage HL during pregnancy, had a healthy delivery, was treated with chemotherapy and was in remission.
In this study, we performed exome sequencing of the index case (IV-7). The elder sister who was diagnosed with HL and the parents, whose informed consents were taken. There were five children in the family; two of the girls were (IV-7 and IV-11) diagnosed with HL, a boy (IV-8) with inflammatory skin findings, a sister (IV-9) and a cousin (IV-13) with suspected lymphoma, and a healthy girl (IV-10) (Figure 1). After quality control and alignment steps, variants were annotated using ANNOVAR, dbSNP, and ExAC. Variant evaluation was performed by in-house filtering steps based on MAF<0.1%, CADD score >10, SIFT, PolyPhen, MutationTaster, FATHMM scores. We also used Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE) tool for identification and classification of the variants.
Results
A germline homozygous missense gene variation (c.928 G>A, p.D310N, rs144833620) was identified on the ligand binding domain of the Pregnane X Receptor Gene (PXR or NR1I2) gene. Sanger sequencing confirmed the familial segregation; IV-7 and IV-11 HL cases were homozygous and parents (III-13 and III-14) were heterozygous. The index case did not have elevated EBV-DNA PCR levels. Index case had increased CD3, CD2 and CD8 and reduced CD4 levels.
(Conclusion)
The PXR encodes a member of the nuclear receptor (NR) superfamily and functions in the metabolism and elimination of xenobiotics and several commonly used drugs. Heterodimerization of PXR and RXR (functional partner) lead to conformational changes upon ligand binding, functions as the transcriptional regulator of PXR target genes including metabolizing enzymes, drug transporters, inflammation and cell cycle associated genes. Previously reported Pxr-/- animal model showed that mice lacking the steroid and xenobiotic receptor develop B cell lymphoma. However, there is no case of HL published linked to variation in PXR gene. Clustering of cases of HL within families, especially in families with consanguineous marriages should suggest a genetic predisposition. The PXR seems to be a novel candidate gene for predisposition of HL.
Funding: This study was funded by Scientific Research Projects Coordination Unit of Istanbul University with a project number TDK-2020-37127.
No relevant conflicts of interest to declare.
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