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Identification of Genetic Risk Factors for Keratinocyte Cancer in Immunosuppressed Solid Organ Transplant Recipients: A Case-Control Study.

ABSTRACT: Because of long-term immunosuppression, solid organ transplant recipients are at increased risk for keratinocyte cancer. We matched solid organ transplant patients (n = 150), cases with keratinocyte cancers and tumor-free controls, considering the most important risk factors for keratinocyte cancer in solid organ transplant recipients. Using whole exome data of germline DNA from this patient cohort, we identified several genetic loci associated with the occurrence of multiple keratinocyte cancers. We found one genome-wide significant association of a common single nucleotide polymorphism located in EXOC3 (rs72698504). In addition, we found several variants with a p-value of less than 10^-5 associated with the number of keratinocyte cancers. These variants were located in the genes CYB561, WASHC1, PITRM1-AS1, MUC8, ABI3BP, and THBS2-AS1. Using whole exome sequencing data, we performed groupwise tests for rare missense variants in our dataset and found robust associations (p < 10^-6, Burden Zeggini test) between MC1R, EPHA8, EPO, MYCT1, ADGRG3, and MGME1 and keratinocyte cancer. Thus, overall, we detected genes involved in pigmentation/UV protection, tumor suppression, immunomodulation, intracellular traffic, and response to UV as genetic risk factors for multiple keratinocyte cancers in solid organ transplant recipients. We also grouped selected genes to pathways and found a selection of genes involved in the "cellular response to UV" to be significantly associated with multiple keratinocyte cancers.

SUBMITTER: Sunder-Plassmann R

PROVIDER: S-EPMC10340609 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Identification of Genetic Risk Factors for Keratinocyte Cancer in Immunosuppressed Solid Organ Transplant Recipients: A Case-Control Study.

Sunder-Plassmann Raute R Geusau Alexandra A Endler Georg G Weninger Wolfgang W Wielscher Matthias M

Cancers 20230626 13

Because of long-term immunosuppression, solid organ transplant recipients are at increased risk for keratinocyte cancer. We matched solid organ transplant patients (<i>n</i> = 150), cases with keratinocyte cancers and tumor-free controls, considering the most important risk factors for keratinocyte cancer in solid organ transplant recipients. Using whole exome data of germline DNA from this patient cohort, we identified several genetic loci associated with the occurrence of multiple keratinocyte ...[more]

PMID: 37444464

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Project description:BackgroundImmunosuppressed solid organ transplant recipients (SOTRs) have elevated rates of certain rare cancers caused by viruses. Evaluating risk of rare cancers among SOTRs may provide etiological clues for additional cancers linked to poor immunity and viral infections.MethodsWe performed a cohort study of 262 455 SOTRs (1987-2014) from the US SOTR registry linked to 17 population-based cancer registries. First cancers in SOTRs were categorized using an established classification scheme based on site and histology. Standardized incidence ratios (SIRs) compared risk in SOTRs with the general population. We used Poisson regression to calculate incidence rate ratios according to immune-related SOTR characteristics, including time since transplant (ie, duration of immunosuppression). All statistical tests were 2-sided.ResultsWe examined 694 distinct cancer subtypes, with 33 manifesting statistically significantly elevated SIRs (Bonferroni P < 7.2 × 10-5). All 33 are rare (incidence <6 per 100 000 person-years) and several have known viral etiology (eg, Merkel cell carcinoma: SIR = 24.7, 95% confidence interval [CI] = 20.8 to 29.1). Additional cancers that were increased include squamous cell carcinomas of the lip (SIR range = 18.3-19.8), eye and adnexa (SIR = 13.8, 95% CI = 7.9 to 22.3), salivary gland (SIR = 9.3, 95% CI = 6.1 to 13.5), and nasal cavity and sinuses (SIR = 4.5, 95% CI = 2.8 to 6.8); sebaceous adenocarcinoma (SIR = 34.3, 95% CI = 26.3 to 44.0); malignant fibrous histiocytoma (15.4); and subtypes of bladder, kidney, lung, and colon cancer (SIR range = 3.2-13.3). Incidence of several cancers increased over time since transplant (Ptrend < .05), including squamous cell carcinomas of the lip, salivary gland, and anogenital sites.ConclusionsSOTRs experience elevated rates of several rare cancers. Because some of these cancers exhibit aggressive behavior with poor outcomes, it is important to further characterize the role of immunity and the potential involvement of oncogenic viruses to improve prevention and treatment.

Dataset Information

Identification of Genetic Risk Factors for Keratinocyte Cancer in Immunosuppressed Solid Organ Transplant Recipients: A Case-Control Study.

Publications

Identification of Genetic Risk Factors for Keratinocyte Cancer in Immunosuppressed Solid Organ Transplant Recipients: A Case-Control Study.

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