Unfolding the enigma of familial Hodgkin lymphoma: Current insights

Table 1 Candidate genes associated with Hodgkin lymphoma

Candidate gene	Full name/role in tumorigenesis	Ref.	Number of mutation-segregating families	Number of affected individuals/family relation/age of HL onset
KDR	Kinase insert domain receptor/encodes type III receptor tyrosine kinase of vascular endothelial growth factor; mutations cause uncontrolled cell survival and growth	Rotunno et al[43], 2016	2	5; family 1 (two brothers, 13 and 16 yo, and a first cousin, 18 yo M); family 2 (father, 40 yo, and daughter, 14 yo)
		Flerlage et al[21], 2023	3	7; family 1 (two brothers and a first cousin, M); family 2 (father and daughter) - previously reported by Rotunno et al[43]; family 3 (brother and sister, ages unknown)
DICER1	Ribonuclease type III/endoribonuclease required for microRNA biogenesis; microRNAs act as tumor suppressors by inhibiting oncogenic signaling pathways	Bandapalli et al[41], 2018	1	2; (mother, 34 yo, and daughter, 7 yo)
POT1	Protection of telomeres 1/mutations lead to excessive telomere lengthening and DNA fragility	McMaster et al[42], 2018	2	5; family 1 (mother, 29 yo, and 3 siblings: 18 yo F, 19 yo F, and 31 yo M); family 2 (two siblings, 16 yo F and 22 yo M)
		Flerlage et al[21], 2023	1	3; (mother, son, and daughter, ages unknown)
KLHDC8B	Kelch domain-containing protein B/tumor suppressor gene; mutations lead to errors in cytokinesis, binucleation, and chromosomal instability	Salipante et al[44], 2009	1	3; (two sisters, 39 yo, and 42 yo, and a brother, 28 yo - possibly also the mother as a fourth member; she died of a mediastinal tumor but declined further diagnosis)
		Flerlage et al[21], 2023	3	8; family 1 (brother and sister, ages unknown); family 2 (grandfather, his two grandsons – brothers - and one great grandson, ages unknown); family 3 (mother and daughter, ages unknown)
PAX5	Paired box protein 5/codes a protein crucial for the differentiation and maturation of lymphoid progenitor cells into B cells; mutations cause the loss of CD20 and formation of Reed-Sternberg cells	Flerlage et al[21], 2023	2	5; family 1 (mother and two daughters, ages unknown); family 2 (two brothers, ages unknown)
GATA3	GATA binding protein 3/tumor suppressor specifically in B-cell lymphomagenesis; deficiency promotes B-cell differentiation and proliferation	Flerlage et al[21], 2023	2	5; family 1 (brother and sister, ages unknown); family 2 (mother, son, and daughter, ages unknown)
IRF7	Interferon regulatory factor 7/encodes a protein engaged in antiviral response and immune system regulation; involved in the regulation of EBV latency	Flerlage et al[21], 2023	1	4; (sister and brother and the brother’s two sons, ages unknown)
EEF2KMT	Eukaryotic factor 2 lysine methyltransferase/role in lymphomagenesis is unclear	Flerlage et al[21], 2023	1	3 (brother, sister, and their first cousin, F, ages unknown)
POLR1A	RNA polymerase I subunit E/encodes a subunit of RNA polymerase I; responsible for transcribing ribosomal RNA; abnormal ribosomal biogenesis can lead to uncontrolled cell growth	Flerlage et al[21], 2023	2	4; family 1 (brother and sister, ages unknown); family 2 (mother and daughter, ages unknown)
ACAN	Aggrecan/encodes proteoglycan; alterations may promote the oncogenic effects of EBV	Ristolainen et al[45], 2015	1	3; (3 siblings: 5 yo M, 12 yo M, and 12 yo F)
PXR	Pregnane X receptor/member of the nuclear receptor superfamily; the role in lymphomagenesis is still uncertain	Khodzhaev et al[46], 2024	1	2; (2 sisters, 10 and 24 yo)

M: Male; F: Female; HL: Hodgkin lymphoma; yo: Years old.