Frequent basal cell cancer development is a clinical marker for inherited cancer susceptibility

Cho, Hyunje G.; Kuo, Karen Y.; Li, Shufeng; Bailey-Healy, Irene; Aasi, Sumaira Z.; Chang, Anne Lynn S.; Oro, Anthony E.; Tang, Jean Y.; Sarin, Kavita Y.

doi:10.1172/jci.insight.122744

Cited by 29 publications

(21 citation statements)

References 23 publications

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“…Furthermore, basal cell carcinoma, which in most cases can be cured with surgical excision ( 26 ), associated with the diagnosis of an alternative type of cancer in CVID. Independently of the diagnosis of CVID or an alternative PID, germline mutations have been shown to play an important role in case of early-onset and/or recurrent basal cell carcinomas and to associate with increased risk for other forms of cancer ( 63 , 64 ). The identification of such cancer-associated manifestations together with the integration of tools/questionnaires ( 65 ) and/or relevant information from high-throughput genetic data (i.e., WES or WGS), which are becoming all the more available in daily clinical practice of PID, could aid the development of cost-effective screening programs, which may improve patients’ outcome and reduce cancer-associated mortality in CVID.…”

Section: Discussionmentioning

confidence: 99%

Common Variable Immunodeficiency-Associated Cancers: The Role of Clinical Phenotypes, Immunological and Genetic Factors

et al. 2022

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ObjectiveThe aim of this study was to investigate the prevalence of cancer and associating clinical, immunological, and genetic factors in a German cohort of patients with common variable immunodeficiency (CVID).MethodsIn this retrospective monocenter cohort study, we estimated the standardized incidence ratio (SIR) for different forms of cancer diagnosed in CVID patients. Furthermore, we evaluated the likely association of infectious and non-infectious CVID-related phenotypes with the diagnosis of cancer by calculation of the odds ratio. The genetic background of CVID in patients with cancer was evaluated with sequential targeted next-generation sequencing (tNGS) and whole-exome sequencing (WES). Patients’ family history and WES data were evaluated for genetic predisposition to cancer.ResultsA total of 27/219 patients (12.3%) were diagnosed with at least one type of cancer. Most common types of cancer were gastric cancer (SIR: 16.5), non-melanoma skin cancer (NMSC) (SIR: 12.7), and non-Hodgkin lymphoma (NHL) (SIR: 12.2). Immune dysregulation manifesting as arthritis, atrophic gastritis, or interstitial lung disease (ILD) was associated with the diagnosis of cancer. Furthermore, diagnosis of NMSC associated with the diagnosis of an alternative type of cancer. Studied immunological parameters did not display any significant difference between patients with cancer and those without. tNGS and/or WES yielded a definite or likely genetic diagnosis in 11.1% of CVID patients with cancer. Based on identified variants in cancer-associated genes, the types of diagnosed cancers, and family history data, 14.3% of studied patients may have a likely genetic susceptibility to cancer, falling under a known hereditary cancer syndrome.ConclusionsGastric cancer, NMSC, and NHL are the most frequent CVID-associated types of cancer. Manifestations of immune dysregulation, such as arthritis and ILD, were identified as risk factors of malignancy in CVID, whereas studied immunological parameters or the identification of a monogenic form of CVID appears to have a limited role in the evaluation of cancer risk in CVID.

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Section: Discussionmentioning

confidence: 99%

Common Variable Immunodeficiency-Associated Cancers: The Role of Clinical Phenotypes, Immunological and Genetic Factors

et al. 2022

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“…We speculate that these patients may carry germline variants in the DNA repair genes rendering them more susceptible to develop recurrent tumors. Indeed, Cho H. et al have shown that germline variants in DNA repair genes-such as APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN and PALB2-are implicated in recurrent BCCs [35]. Another possibility is that the different variants in PTCH1 and / or SMO may have occurred accidentally and contributed independently to BCC pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Molecular profiling of basal cell carcinomas in young patients

et al. 2021

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Background Basal cell carcinoma (BCC) represents by far the most common non-melanoma skin cancer (NMSC) in the world with an increasing incidence of 3% to 10% per year, especially in patients under the age of 40. While variants in the sonic Hedgehog and cell cycle regulation pathways account for the majority of BCC cases in adults, the molecular etiology of BCC in young patients is unelucidated yet. This study aims to investigate the molecular profile of BCC in the young population. Methods 28 tumors belonging to 25 Lebanese patients under the age of 40, presenting different stages of BCC and diagnosed at Hôtel Dieu de France—Saint Joseph University Medical Center were included in this study. A selected panel of 150 genes involved in cancer was analyzed by Next Generation Sequencing (NGS) in the 28 included tumors. Results Genetic variants detected in more than 5% of the reads, with a sequencing depth ≥ 50x, were selected. Two hundred and two genetic variants in 48 different genes were detected, with an overall average sequencing depth of 1069x. Among the 28 studied tumors, 18 (64.3%) show variations in the PTCH1 gene, 6 (21.4%) in TP53 and 3 (10.7%) in SMO. Conclusions This is the first study reporting NGS-based analysis of BCC in a cohort of young patients. Our results highlight the involvement of the hedgehog and cell cycle regulation pathways in the genesis of BCC in the general population. The inclusion of a larger cohort of young patients is needed to confirm our findings.

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“…2) Non-melanoma skin cancers (NMSC), most of which are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), account for over 98% of total skin cancers. Patients with BCC and/or SCC may have an increased risk for developing melanoma [104][105][106][107][108] and certainly have the highest possibility of early melanoma diagnosis because their skin is clinically assessed multiple times during BCC and SCC treatments.…”

Section: Discussionmentioning

confidence: 99%

Evolved adaptation to low ultraviolet radiation may be the main cause of malignant melanoma independent of high ultraviolet radiation levels

You

Henneberg

Coventry

et al. 2020

Preprint

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Abstract Background: The low melanin production (depigmentation) evolved in response to low ultraviolet radiation may be the principal determinant of malignant melanoma of skin (C43). Methods: Worldwide country-speciﬁc estimates of melanoma incidence, daily UVR levels, skin colour (EEL), socioeconomic status (GDP PPP), magnitude of reduced natural selection (Ibs), ageing, urbanization, percentage of European descendants (Eu%), and depigmentation measured by blonde hair colour, were subjected to statistical analyses. Data for 182 individual countries were derived from WHO, United Nations, World Bank databases and the literature. Parametric and non-parametric correlations, partial correlation analyses keeping confounders statistically constant, multivariate regressions and analyses of variance were used. Results: Worldwide, UVR levels were in negative correlation with melanoma (C43) incidence (“rho” = -0.515, p<0.001). This relationship remained significant and negative in parametric partial correlation (r = -0.513, p<0.001) when GDP PPP, Ibs, ageing and urbanization were statistically kept constant. In stepwise linear regression analysis, UVR was the variable having greatest negative influence on melanoma incidence (R2=0.301). Melanoma incidence was in strong correlation with Eu% (r = 0.711, p<0.001). The negative relationship between melanoma and UVR levels (r = -0.498, r<0.001) and positive relationship of melanoma with Eu% (r = 0.477, p<0.001) remained significant in partial correlation analyses.When melanoma incidence rate was standardised on Eu% it did not correlate at all with UVR (“rho”=0.004, p=0.967, n=127). The country-specific depigmentation level strongly correlated with melanoma incidence (r = 0.705, p<0.001, n= 48) remaining significant in partial correlation (r=0.315, p<0.01). However, UVR showed nil no correlation with melanoma when depigmentation, together with the other four potential confounders was included as the controlled variable. Conclusions: Low melanin production, genetically determined, that has adaptively evolved over generations represents the principal risk factor for melanoma, while UVR has a secondary role.

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Frequent basal cell cancer development is a clinical marker for inherited cancer susceptibility

Cited by 29 publications

References 23 publications

Common Variable Immunodeficiency-Associated Cancers: The Role of Clinical Phenotypes, Immunological and Genetic Factors

Common Variable Immunodeficiency-Associated Cancers: The Role of Clinical Phenotypes, Immunological and Genetic Factors

Molecular profiling of basal cell carcinomas in young patients

Evolved adaptation to low ultraviolet radiation may be the main cause of malignant melanoma independent of high ultraviolet radiation levels

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