Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis

Ramoz, Nicolás; Rueda, Luis-Alfredo; Bouadjar, B.; Montoya, Luz-Stella; Orth, Gérard; Favre, Michel

doi:10.1038/ng1044

Cited by 385 publications

(319 citation statements)

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“…2 Genome-wide linkage studies were performed to map two EV loci 3,4 and to identify the EVER genes (EVER1 or EVER2, also referred to as TMC6 and TMC8, respectively) in one of these loci. 5 The identification of EVER1 and EVER2 expressed sequence tags and cDNA from lymphoid tissue is consistent with a model in which EV mutations exert their direct effects in the immune system. It was recently discovered that 75% of EV patients studied have rare mutations in either of these adjacent, related, novel genes.…”

mentioning

confidence: 59%

Cutaneous human papillomavirus infection, the EVER2 gene and incidence of squamous cell carcinoma: A case‐control study

Patel¹,

Pawlita

Waterboer

et al. 2008

Intl Journal of Cancer

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The first evidence of an association between HPV and non-melanoma skin cancer comes from patients with epidermodysplasia verruciformis (EV). EV is a rare heritable disease characterized by cutaneous warts that display not only a high rate of progression to squamous cell carcinoma on sun-exposed sites, but also a strong predisposition to infection by b-HPVs, for which HPV 5 and 8 predominate. Two EV genes (EVER1 and EVER2) have been identified, and we tested the hypothesis that variation in the EVER2 gene (rs7208422) is related to seropositivity to HPV (of the genus b types) and risk of squamous cell carcinoma in a population-based casecontrol study of SCC (n 5 239 cases and 432 controls). Among controls, variant genotype was associated with b-HPV seropositvity (OR 5 2.3, 95%CI 5 1.2-4.3), specifically HPV5 or 8 seropositivity (OR 5 2.4, 95%CI 5 1.1-5.1) and seropositivity for multiple b-HPV types (OR 5 2.7, 95%CI 5 1.1-6.6). Furthermore, variant genotype was also related to SCC risk [adjusted OR for homozygous variant versus homozygous wild type for the EVER2 polymorphism 1.7, 95% CI 1.1-2.7]. These data provide evidence for a role of genetic variation in the EVER2 gene in b-HPV infection and risk of SCC, shedding light on the link between HPVs and skin cancers. ' 2008 Wiley-Liss, Inc.Key words: human papillomavirus; skin cancer; EVER2The initial link between HPV and skin cancers was a rare autosomal inherited disease called Epidermodysplasia Verruciformis (EV) first described nearly a century ago.1 The disease is characterized by cutaneous lesions that display a high rate of progression to squamous cell carcinomas (SCCs) beginning in the second decade of life. Furthermore, EV patients experience diminished cell-mediated immunity possibly resulting in an observed susceptibility to infection by specific HPV types falling into the genus b, with HPV5 and HPV8 the most prevalent infections in this patient population. Genome-wide linkage studies were performed to map two EV loci 3,4 and to identify the EVER genes (EVER1 or EVER2, also referred to as TMC6 and TMC8, respectively) in one of these loci. 5The identification of EVER1 and EVER2 expressed sequence tags and cDNA from lymphoid tissue is consistent with a model in which EV mutations exert their direct effects in the immune system. It was recently discovered that 75% of EV patients studied have rare mutations in either of these adjacent, related, novel genes. To date, 10 truncating, loss of function mutations have been identified, 4 in EVER1 and 6 in EVER2 and were identified in EV patients from Algeria, Columbia, Poland and Japan.5 More recently, 5 additional mutations have been detected in the EVER genes supporting the hypothesis that EVER1 and EVER2 are the molecular basis of EV. [6][7][8] b-HPV DNA has been detected in up to 50% of SCC tumors from immunocompetent individuals and in up to 90% of lesions from immunocompromised individuals, 9,10 further emphasizing the role of host susceptibility in infection with these viruses. Recently, we reported that the ...

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mentioning

confidence: 59%

Cutaneous human papillomavirus infection, the EVER2 gene and incidence of squamous cell carcinoma: A case‐control study

Patel¹,

Pawlita

Waterboer

et al. 2008

Intl Journal of Cancer

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“…One is that antibodies are a good marker of pathogenic skin infection, and variation in susceptibility to infection might therefore underpin the clustering. There are two main genes that are thought to determine such susceptibility, the EVER1 and EVER2 genes, which are mutated in patients with EV (Ramoz et al, 2002). A recent study showed that controls in a case-control study who carried a particular single-nucleotide polymorphism in the EVER2 gene were more likely to carry bPV antibodies and had a greater likelihood of having antibodies to multiple viruses (Patel et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

An analysis of clustering of betapapillomavirus antibodies

Mallitt

O’Rourke

Bavinck

et al. 2010

Journal of General Virology

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Betapapillomaviruses (βPVs) may contribute to the aetiology of cutaneous squamous cell carcinoma. However, no high-risk types have yet been identified, possibly because the high frequency of co-infection prevents a straightforward analysis of the independent effects of individual viruses. This study aimed to determine whether specific virus types were more likely to co-occur than others, thereby reducing the number of parameters needed in statistical models. Antibody data were analysed from controls who participated in case–control studies in The Netherlands, Italy and Australia and from participants in the German Nutrition Survey. Cluster analysis and two ordination techniques were used to identify patterns. Evidence of clustering was found only according to the number of viruses to which antibodies were detected. The lack of clustering of specific viral types identified suggests that if there are βPV types that are independently related to skin carcinogenesis, they are unlikely to be identified using standard epidemiological methods.

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“…Mutations in EVER1 and EVER2 genes result in susceptibility to beta-human papillomavirus (β-HPV) infection and a high risk of skin cancer -about 50% of the patients eventually develop cSCC (Ramoz et al, 2002). Onset of lesions usually appears within the first decade, with cSCCs appearing at an average age of 20 at sun-exposed areas (de Oliveira et al, 2003;Gul et al, 2007).…”

Section: Epidermodysplasia Verruciformismentioning

confidence: 99%