Immune dysfunction in inborn errors of immunity causing malignancies

Figures & data

Figure 1. Inadequate functioning of the immune mechanisms prevents effective immunosurveillance facilitating malignancy development in IEI. Created with BioRender.com

Table 1. Types of IEI and reported malignancies

Type of IEI	Genes	Frequency	Types of Malignancy
CVID	CD19, CD20, CD21, CD81, NFKB1/2, IKZF1, TNFRSF13B, TNFRSF13C	8.2–21%	Lymphoma (NHL and MALT mostly), leukemia, gastric carcinoma
IgA deficiency	Unknown	Rare	Lymphoma, gastric carcinoma
X-linked agammaglobulinemia	BTK	4.1–6%	Gastric adenocarcinoma, intestinal carcinoma
SCID	ADA, AK2, JAK3, IL2RG	1.5%	Lymphoma, leukemia, EBV-related SMTs
SCID with defective DNA repair	RAG1/2, NHEJ1, PRKCD, DCLRE1C, LIG4	Unknown	Lymphoma, leukemia
CID	STAT3-GOF, ZAP70, RHOH, ITK, CARD11, MALT1, ORAI1, STIM1, STK4, PIK3CD, PIK3R1, OX40, W1PF1, CTLA4, LRBA, CTPS1, ADA, PNP	Unknown	Lymphoma, leukemia
AT	ATM	25–40%	Lymphoma (NHL, HL), leukemia
NBS	NBN	40%	Lymphoma (NHL, HL), medulloblastoma, neuroblastoma, dysgerminoma, thyroid cancer
Bloom syndrome	BLM	33%	Lymphoma, Leukemia, colorectal carcinoma, breast cancer, skin cancers (BCC, SCC), Wilms’ tumor
Wiskott-Aldrich syndrome	WAS	13–23%	Lymphoma, leukemia, myelodysplastic syndrome
DOCK8 deficiency	DOCK8	16.3%	Squamous cell carcinomas (skin, mucosa), NHL
ALPS	TNFRSF6, TNFSF6	25%	Lymphoma (NHL, HL), myelodysplastic syndrome, ALL
CD40L deficiency (X-linked Hyper IgM syndrome)	CD40LG	Unknown	Liver, biliary tract, pancreatic carcinomas
DiGeorge Syndrome	22q11.2 deletion, TBX1	0.9%	Thyroid cancer, hepatoblastoma, neuroblastoma, ALL, lymphoma, Wilms’ tumor, teratoid/rhabdoid tumor
Myeloid development defects (Severe Congenital Neutropenia)	ELANE, HAX1, GF11, G6PC3	21–31%	Myelodysplastic syndrome, AML
Stem cell development defects	GATA2, RMRP, SBDS	Unknown	HPV-related carcinoma, EBV-related SMTs, leukemia (AML), myelodysplastic syndrome
Diseases of Immune Dysregulation-EBV susceptibility	SH2DIA, XIAP, CD27, CD70, CD137, CARMIL2, GATA2, MAGT1, PRKCD, RASGRP1, CTPS1	Unknown	Lymphoma (NHL, HL), EBV-related SMTs
Diseases of immune dysregulation with colitis	IL10RA, IL10RB	Unknown	Lymphoma
Chronic mucocutaneous candidiasis	AIRE, IL17RA, IL17RC, IL17F, STAT1-GOF, TRAF3IP2	Unknown	Oral and esophageal SCC
WHIM	CXCR4	30%	B-cell lymphoma, AML, genital and squamous cell carcinoma

Abbreviations: AT: Ataxia-telangiectasia, ALL: Acute lymphocytic leukemia, ALPS: Autoimmune lymphoproliferative syndrome, AML: Acute myelocytic leukemia, BCC: Basal cell carcinoma, CID: Combined immunodeficiency, CVID: Common variable immunodeficiency, GOF: Gain-of-function, IEI: Inborn error of immunity, HL: Hodgkin’s lymphoma, MALT: Mucosa associated lymphoid tissue, NBS: Nijmegen breakage syndrome, NHL: Non-Hodgkin’s lymphoma, SCC: Squamous cell carcinoma, SCID: Severe combined immunodeficiency, SMT: Smooth muscle tumor, WHIM: Warts, hypogammaglobulinemia, infections, myelokathexis syndrome, XLP: X-linked lymphoproliferative syndrome.