Distinctive Genomic Features of Hydroa Vacciniforme Lymphoproliferative Disorder in Latin American Patients: A Multicenter Multi-Omics Study

Hydroa vacciniforme lymphoproliferative disorder (HV-LPD) is a chronic EBV-driven disease with variable clinical behavior. While indolent in Western populations, HV-LPD in Latin America and Mexico is often aggressive, with systemic involvement and high mortality¹. To investigate this disparity, we conducted a comprehensive genomic profiling of 43 Latin American HV-LPD patients (Mendeley Supplemental (MS) Figure 1)—the largest such cohort to date—through whole-exome sequencing (WES), RNA-seq, and copy number variation (CNV) analysis. All cases met 2022 WHO and ICC diagnostic criteria. The cohort included 31 pediatric and 12 adult patients (median age 15 years). Most presented with papulovesicular skin lesions on sun-exposed areas and systemic symptoms, including fever (78%), anemia (20%), and hepatosplenomegaly (17%) (Table 1, MS Table 1). Histologically, lesions showed vesiculo-ulcerative features (MS Figure 2). All cases demonstrated EBV-positive, cytotoxic T- or NK-cell infiltrates with variable loss of pan–T-cell markers (MS Table 2). Most cases (60%) showed a CD8+ T-cell phenotype, but NK-cell and “silent” phenotypes were also observed (MS Figure 3). Genomic profiling (MS Table 3; MS Figure 4) via WES and RNA-seq revealed frequent mutations in epigenetic regulators—KMT2D (28%), CREBBP (21%), BCOR (14.3%)—and loss of function mutations in tumor suppressors ATM (14.3%), BARD1 (10.7%), MLH1 (10.7%) (Figure 1; MS Table 4; MS Figure 5). Chromatin-modifier (CM) mutations comprised 41.5% of driver events, underscoring epigenetic dysregulation in HV-LPD. KMT2D alterations showed a non-significant trend toward poorer prognosis (p = 0.2) (MS Figure 6).

Table 1.

Clinical Summary of the patient population with Hydroa vacciniforme lymphoproliferative disorder

	(%)
Sex (n=43)
-Male	20 (47)
-Female	23 (53)
Age median (range)	15 (3–30)
Site of lesion
Head alone	5 (12)
Head and extremities	19 (45)
Generalized	10 (23)
Extremities alone	7 (16)
Abdomen	1 (2)
Neck	1 (2)
Type of skin lesion
Papulovessicles, crusts and ulceration	38 (88)
Papulovessicles and crusts	4 (10)
Erythema	6 (14)
Edema	3 (7)
N/A	1 (2)
Number of lesions
Multiple	38(88)
Solitary	5 (12)
Systemic Presentation
Yes	32 (74)
No	7 (16)
N/A	4 (10)
Serum EBV
EBV DNA (>1000 copies/ml)	32 (74)
Positive antibody titers	4 (10)
N/A	7 (16)
Treatment of HV-LPD
Chemotherapy	16 (37)
Chemotherapy and Radiotherapy	2 (5)
Thalidomide	7 (16)
Thalidomide +Methotrexate	3 (7)
Corticosteroid	16 (37)
Outcome
Alive	15 (36)
Dead	27 (64)

Age, years; EBV; Epstein Barr virus; N/A, not available

Figure 1.

Distribution of copy number variants and somatic mutations in HV-LPD. Each column represents an HV-LPD case, which is shown in different colors according to the platform used or the country of origin of the patients. Each row represents a gene in the indicated gene ontology. The upper-level row represents copy number variants (CNV), and the three CNV types are distinguished by different colors. The lower-level rows represent single-nucleotide variants. The four mutation types are also differentiated by different colors. Bars (left) represent the mutation rates in 28 patients, including 3 patients with 2 biopsies

CNV profiling demonstrated frequent deletions in key regulatory genes: MAP2K4 (50%), SMARCB1 (36%), FANCA (36%) and PRDM1 (14.2%) (MS Table 5–6, MS Figure 7). Recurrent homozygous deletions in KMT2D and ARID1A further implicate chromatin disruption in disease development. Analysis of serial biopsies in three patients revealed increased EBV RNA and progressive accumulation of mutations, particularly in CM genes (MS Figure 8). Differential gene expression in select HV-LPD patients with KMT2D and BCOR alterations confirmed significant overexpression of genes involved in cytokine signaling, EBV response, NK/T-cell function, and JAK/STAT signaling (MSTable 7–8, MS Figure 9). JAK3 was upregulated in all samples, though activating STAT3 or JAK3 mutations were rare (MS Figure 10). Clinically, 64% of patients died of disease, with an overall median survival of 60 months. While multilesional presentation correlated with poorer outcomes (p=0.009), survival did not significantly differ by age, sex, or treatment (MS Figure 11). The high prevalence of CM gene alterations parallels findings in aggressive NK/T-cell lymphomas ^{2, 3}and chronic active EBV infection^{4, 5}. Notably, the genomic features of this Latin American HV-LPD cohort were not identified in Western populations⁵, highlighting possible regional or ethnic determinants of disease biology (see MS discussion).

In conclusion, our study defines a unique mutational and transcriptomic profile for HV-LPD in Latin American patients. The high frequency of CM gene mutations and deletions supports a model of epigenetically driven oncogenesis, likely compounded by EBV infection (MS Figure 12). These findings provide novel insights into HV-LPD pathogenesis and underscore the potential for molecular classification and therapeutic targeting in this rare disorder.

Abbreviations

HV

Hydroa vacciniforme

HV-LPD

lymphoproliferative disorder

EBV

Epstein-Barr virus

CAEBV

chronic active EBV

NK

natural killer

WHO

World Health Organization

ICC

International Consensus

WES

whole-exome sequencing

CNV

copy number variation

ENKTCL

Extranodal NK/T cell lymphoma

ANKL

aggressive NK cell leukemia

OS

Overall survival

IHC

immunohistochemical

TSGs

tumor suppressor genes

LOF

loss-of-function

MS

Mendeley supplemental

CM

chromatin modification