Publications by authors named "Margaret A Tucker"

175 Publications

Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in the Childhood Cancer Survivor Study.

JNCI Cancer Spectr 2021 Apr 23;5(2):pkab007. Epub 2021 Jan 23.

Basic Research Subdirection, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico.

Background: Pediatric cancers are the leading cause of death by disease in children despite improved survival rates overall. The contribution of germline genetic susceptibility to pediatric cancer survivors has not been extensively characterized. We assessed the frequency of pathogenic or likely pathogenic (P/LP) variants in 5451 long-term pediatric cancer survivors from the Childhood Cancer Survivor Study.

Methods: Exome sequencing was conducted on germline DNA from 5451 pediatric cancer survivors (cases who survived ≥5 years from diagnosis; n = 5105 European) and 597 European cancer-free adults (controls). Analyses focused on comparing the frequency of rare P/LP variants in 237 cancer-susceptibility genes and a subset of 60 autosomal dominant high-to-moderate penetrance genes, for both case-case and case-control comparisons.

Results: Of European cases, 4.1% harbored a P/LP variant in high-to-moderate penetrance autosomal dominant genes compared with 1.3% in controls (2-sided  = 3 × 10). The highest frequency of P/LP variants was in genes typically associated with adult onset rather than pediatric cancers, including , , , , and . A statistically significant excess of P/LP variants, after correction for multiple tests, was detected in patients with central nervous system cancers (, , , ), Wilms tumor (, ), non-Hodgkin lymphoma (), and soft tissue sarcomas (, , , , ) compared with other pediatric cancers.

Conclusion: In long-term pediatric cancer survivors, we identified P/LP variants in cancer-susceptibility genes not previously associated with pediatric cancer as well as confirmed known associations. Further characterization of variants in these genes in pediatric cancer will be important to provide optimal genetic counseling for patients and their families.
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http://dx.doi.org/10.1093/jncics/pkab007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023430PMC
April 2021

Novel MAPK/AKT-impairing germline NRAS variant identified in a melanoma-prone family.

Fam Cancer 2021 Jul 3. Epub 2021 Jul 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, EPS 7106, Bethesda, MD, 20892, USA.

While several high-penetrance melanoma risk genes are known, variation in these genes fail to explain melanoma susceptibility in a large proportion of high-risk families. As part of a melanoma family sequencing study, including 435 families from Mediterranean populations we identified a novel NRAS variant (c.170A > C, p.D57A) in an Italian melanoma-prone family. This variant is absent in exomes in gnomAD, ESP, UKBiobank, and the 1000 Genomes Project, as well as in 11,273 Mediterranean individuals and 109 melanoma-prone families from the US and Australia. This variant occurs in the GTP-binding pocket of NRAS. Differently from other RAS activating alterations, NRAS D57A expression is unable to activate MAPK-pathway both constitutively and after stimulation but enhances EGF-induced PI3K-pathway signaling in serum starved conditions in vitro. Consistent with in vitro data demonstrating that NRAS D57A does not enrich GTP binding, molecular modeling suggests that the D57A substitution would be expected to impair Mg2 + binding and decrease nucleotide-binding and GTPase activity of NRAS. While we cannot firmly establish NRAS c.170A > C (p.D57A) as a melanoma susceptibility variant, further investigation of NRAS as a familial melanoma gene is warranted.
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http://dx.doi.org/10.1007/s10689-021-00267-9DOI Listing
July 2021

Increased risk of skin cancer in 1851 long-term retinoblastoma survivors.

J Invest Dermatol 2021 Jun 18. Epub 2021 Jun 18.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD.

Hereditary retinoblastoma patients are at risk for developing cutaneous melanoma, but little is known about the role of sun exposure or other factors, and incidence of non-melanoma skin cancer (NMSC) is poorly understood. We investigated the incidence of melanoma and NMSC in a cohort of 1851 white, long-term retinoblastoma survivors (1020 hereditary and 831 nonhereditary) diagnosed from 1914-2006. During follow-up through 2016, 33 hereditary and 7 nonhereditary survivors developed melanoma, and 26 hereditary and 9 nonhereditary survivors developed NMSC. Most NMSC were on the head/neck whereas melanomas were more broadly distributed with patterns similar to melanoma-prone families. For both outcomes, median age at diagnosis was ∼20 years younger among hereditary than nonhereditary survivors. Fifty years following retinoblastoma diagnosis, the cumulative incidence in hereditary survivors was 4.5% for melanoma and 3.7% for NMSC; for nonhereditary survivors, it was 0.7% and 1.5%, respectively. Sun sensitivity and phenotypic characteristics generally did not vary by skin cancer status. Hereditary retinoblastoma survivors have an increased risk for melanoma and NMSC that occurred earlier compared with nonhereditary survivors, likely reflecting genetic factors. These findings among white retinoblastoma survivors support consensus-based recommendations for skin cancer screening and sun protection starting at young ages and continuing long-term.
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http://dx.doi.org/10.1016/j.jid.2021.05.021DOI Listing
June 2021

Benign Tumors in Long-Term Survivors of Retinoblastoma.

Cancers (Basel) 2021 Apr 8;13(8). Epub 2021 Apr 8.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.

Hereditary retinoblastoma survivors have substantially increased risk of subsequent malignant neoplasms (SMNs). The risk of benign neoplasms, a substantial cause of morbidity, is unclear. We calculated the cumulative incidence of developing benign tumors at 60 years following retinoblastoma diagnosis among 1128 hereditary (i.e., bilateral retinoblastoma or unilateral with family history, mutation testing was not available) and 924 nonhereditary retinoblastoma survivors diagnosed during 1914-2006 at two US medical centers with follow-up through 2016. Using Cox proportional hazards regression, we compared benign tumor risk by hereditary status and evaluated the association between benign tumors and SMNs. There were 100 benign tumors among 73 hereditary survivors (cumulative incidence = 17.6%; 95% confidence interval [CI] = 12.9-22.8%) and 22 benign tumors among 16 nonhereditary survivors (cumulative incidence = 3.9%; 95%CI = 2.2-6.4%), corresponding to 4.9-fold (95%CI = 2.8-8.4) increased risk for hereditary survivors. The cumulative incidence after hereditary retinoblastoma was highest for lipoma among males (14.0%; 95%CI = 7.7-22.1%) and leiomyoma among females (8.9%; 95%CI = 5.2-13.8%). Among hereditary survivors, having a prior SMN was associated with 3.5-fold (95%CI = 2.0-6.1) increased risk of developing a benign tumor; the reciprocal risk for developing an SMN after a benign tumor was 1.8 (95%CI = 1.1-2.9). These large-scale, long-term data demonstrate an increased risk for benign tumors after hereditary versus nonhereditary retinoblastoma. If confirmed, the association between benign tumors and SMNs among hereditary patients may have implications for long-term surveillance.
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http://dx.doi.org/10.3390/cancers13081773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068196PMC
April 2021

Genotypic vs Phenotypic Risk Assessment for Melanoma.

J Natl Cancer Inst 2021 Apr 10. Epub 2021 Apr 10.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD 20850.

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http://dx.doi.org/10.1093/jnci/djab077DOI Listing
April 2021

The Impact of Longitudinal Surveillance on Tumor Thickness for Melanoma-Prone Families with and without Pathogenic Germline Variants of and .

Cancer Epidemiol Biomarkers Prev 2021 Apr;30(4):676-681

Division of Cancer Epidemiology and Genetics, NCI, NIH, Rockville, Maryland.

Background: Skin cancer screening is routinely performed for members of melanoma-prone families, but longitudinal studies evaluating the efficacy of surveillance in this high-risk population are lacking.

Methods: We evaluated thickness for first primary melanomas diagnosed in melanoma-prone families (≥2 individuals with melanoma) enrolled in NCT00040352 (NCI familial melanoma study) from 1976 through 2014; enrolled patients received routine skin cancer screening and education about skin self-exams. We used linear and ordinal logistic regression models adjusted for gender and age with a generalized estimating equations approach to report changes in thickness and tumor (T) stage over time, comparing outcomes for NCI cases diagnosed before (pre-study) versus after study participation (prospective) and for NCI cases versus nonfamilial cases [Surveillance, Epidemiology, and End Results (SEER) 9 registries].

Results: Tumor thickness was evaluated for 293 NCI (pre-study = 246; prospective = 47) patients. Compared with NCI pre-study cases, NCI prospective melanomas were thinner (0.6 vs. 1.1 mm; < 0.001) and more likely to be T1 stage [39/47 (83%) vs. 98/246 (40%); < 0.001]. Similar findings ( < 0.05) were observed for familial cases with and without germline and mutations. Peters-Belson modeling suggested that calendar period effects of decreasing thickness in the general population (SEER 9) did not fully explain thickness trends in NCI families.

Conclusions: Participation in a longitudinal surveillance program providing skin cancer screening and education about skin self-exams was associated with thinner melanomas for members of melanoma-prone families.

Impact: The study findings support the clinical benefit of screening (physician and self) for this high-risk population.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049096PMC
April 2021

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Am J Hum Genet 2021 04 12;108(4):564-582. Epub 2021 Mar 12.

The Charles R. Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059339PMC
April 2021

Long-term risk of subsequent cancer incidence among hereditary and nonhereditary retinoblastoma survivors.

Br J Cancer 2021 Mar 21;124(7):1312-1319. Epub 2021 Jan 21.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Background: Increased sarcoma and melanoma risks after hereditary retinoblastoma are well established, whereas less is known about epithelial subsequent malignant neoplasms (SMNs) and risks for multiple (≥2) SMNs.

Methods: Leveraging long-term follow-up and detailed histologic information, we quantified incident SMN risk among 1128 hereditary and 924 nonhereditary retinoblastoma survivors (diagnosed 1914-2006; follow-up through 2016). Standardised incidence ratios (SIRs) compared cancer risk after retinoblastoma relative to the general population. We estimated cumulative incidence accounting for competing risk of death.

Results: Hereditary survivors had statistically significantly increased SMN risk (N = 239; SIR = 11.9; 95% confidence interval [CI] 10.4-13.5), with SIRs >80-fold for sarcomas, nasal cavity tumours and pineoblastoma. Significantly increased risks were also observed for melanoma and central nervous system, oral cavity and breast SMNs (SIRs = 3.1-17), but not the uterus, kidney, lung, bladder, pancreas or other types. Cumulative incidence 50 years following hereditary retinoblastoma was 33.1% (95% CI 29.0-37.2) for a first SMN and 6.0% (95% CI 3.8-8.2) for a second SMN. SMN risk was not increased after nonhereditary retinoblastoma (N = 25; SIR = 0.8; 95% CI 0.5-1.2).

Conclusion: Beyond the established sarcoma and melanoma risks after hereditary retinoblastoma, we demonstrate increased risk for a more limited number of epithelial malignancies than previously suggested. Cumulative incidence estimates emphasise long-term SMN burden after hereditary retinoblastoma.
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http://dx.doi.org/10.1038/s41416-020-01248-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007574PMC
March 2021

Ambient Ultraviolet Radiation and Sebaceous Carcinoma Incidence in the United States, 2000-2016.

JNCI Cancer Spectr 2020 Apr 27;4(2):pkaa020. Epub 2020 Feb 27.

Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Sebaceous carcinoma (SC) is an aggressive skin tumor. Although ultraviolet radiation (UVR) is an important risk factor for some skin cancer types, no population-level study has evaluated for an association between UVR and SC risk. Herein, we examined satellite-based ambient UVR in relation to SC incidence using Surveillance, Epidemiology, and End Results 18 cancer registry data (2000-2016). There were 3503 microscopically confirmed cases of SC diagnosed during the study period. For non-Hispanic whites, there was an association between increasing ambient UVR and SC risk (incidence rate ratio [per UVR quartile] = 1.15, 95% confidence interval = 1.11 to 1.19; two-sided <.001) including among individuals with and without putative Muir-Torre syndrome. In contrast, there was no association between ambient UVR and SC risk for other race and ethnicities. Our findings support a role for UVR in SC tumorigenesis, which suggests that photoprotection may reduce SC risk, particularly for high-risk populations (eg, Muir-Torre syndrome).
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http://dx.doi.org/10.1093/jncics/pkaa020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190206PMC
April 2020

Sebaceous Carcinoma Incidence and Survival Among Solid Organ Transplant Recipients in the United States, 1987-2017.

JAMA Dermatol 2020 12;156(12):1307-1314

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

Importance: Risk of sebaceous carcinoma (SC), a rare skin cancer associated with Muir-Torre syndrome, is elevated among solid organ transplant recipients (SOTRs). However, population studies evaluating this association and assessing survival for posttransplant cases are lacking, and further understanding of SC epidemiology in this immunosuppressed population could provide etiologic and clinical insights.

Objective: To assess SC incidence and patient survival after solid organ transplantation.

Design, Setting, And Participants: This cohort study, conducted from January 1, 1987, to December 31, 2017, used data from the Transplant Cancer Match Study, which links transplant and cancer registry data for 17 states and 1 metropolitan area in the United States. Altogether, these registries account for approximately 46% of all US transplants. Data on demographic and transplant characteristics as well as induction and initial maintenance immunosuppressive therapies were obtained from the transplant registry. Standardized incidence ratios (SIRs) comparing SC incidence among SOTRs to the general population were calculated. Incidence rate ratios (IRRs) comparing SC risk between SOTR subgroups were calculated using multivariate Poisson regression. Cox regression was used to compare overall survival between SC cases in SOTRs and other individuals.

Main Outcomes And Measures: Sebaceous carcinoma incidence and overall patient survival after transplantation compared with the general population.

Results: A total of 326 282 transplant procedures were performed for 301 075 patients (No. [%] age at transplant, 126 550 [38.8%] aged 0-44 years; 82 394 [25.3%] aged 45-54 years; 82 082 [25.5%] aged 55-64 years; 35 256 [10.8%] aged ≥65 years; 201 354 male patients [61.7%]; 202 557 White patients [62.1%]). A total of 102 SCs were diagnosed in 301 075 SOTRs, corresponding to a 25-fold increased incidence (SIR, 24.8; 95% CI, 20.2-30.1). Incidence was especially elevated among lung recipients (SIR, 47.7; 95% CI, 20.6-94.0) and after a posttransplant diagnosis of cutaneous squamous cell carcinoma (SIR, 104.0; 95% CI, 62.8-163.0). Among SOTRs, factors independently associated with SC risk included male sex (IRR, 2.46; 95% CI, 1.48-4.07; P < .001), race/ethnicity (non-Hispanic Black vs non-Hispanic White, IRR, 0.28; 95% CI, 0.10-0.77; P = .01), older age (IRR, 7.85; 95% CI, 3.85-16.0; ≥65 vs 0-44 years; P < .001 for trend), use of thymoglobulin induction (IRR, 1.82; 95% CI, 1.16-2.86; P = .009), posttransplant cutaneous squamous cell carcinoma (IRR, 4.60; 95% CI, 2.67-7.94; P < .001), and longer time since transplant (IRR, 8.40; 95% CI, 3.94-17.90; ≥10 vs 0-1.9 years; P < .001 for trend). Muir-Torre syndrome-associated cancers were rare among both SOTRs and others with SC (3.3%-4.1%). Among patients with SC, prior transplantation was associated with increased overall mortality (adjusted hazard ratio, 2.09; 95% CI, 1.45-3.01), although few deaths were attributed to SC (4 of 92 SOTRs [4.3%]; 235 of 3585 non-SOTRs [6.6%]).

Conclusions And Relevance: Among SOTRs, results of this large cohort study suggest that SC was associated with measures of immunosuppression, and overall survival was worse than for other patients with SC. Findings also suggest a possible role for UV radiation in carcinogenesis.
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http://dx.doi.org/10.1001/jamadermatol.2020.3111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643042PMC
December 2020

Role of radiotherapy and chemotherapy in the risk of leukemia after childhood cancer: An international pooled analysis.

Int J Cancer 2021 May 9;148(9):2079-2089. Epub 2020 Nov 9.

Radiation Epidemiology Group, Unit 1018 INSERM-CESP, Villejuif, France.

Childhood cancer survivors are at increased risk for second primary leukemia (SPL), but there is little consensus on the magnitude of some risk factors because of the small size of previous studies. We performed a pooled analysis of all published studies with detailed treatment data, including estimated active bone marrow (ABM) dose received during radiation therapy and doses of specific chemotherapeutic agents for childhood cancer diagnosed from 1930 through 2000, in order to more thoroughly investigate treatment-related risks of SPL. A total of 147 SPL cases (of which 69% were acute myeloid leukemia [AML]) were individually matched to 522 controls, all from four case-control studies including patients from six countries (France, United Kingdom, United States, Canada, Italy and Netherlands). Odds ratios (OR) and corresponding 95% confidence intervals (CIs) were calculated using conditional logistic regression, and the excess OR per Gray (EOR/Gy) was also calculated. After accounting for the other therapies received, topoisomerase II inhibitor was associated with an increased SPL risk (highest tertile vs none: OR = 10.0, 95% CI: 3.7-27.3). Radiation dose to the ABM was also associated with increased SPL risk among those not receiving chemotherapy (EOR/Gy = 1.6, 95% CI: 0.1-14.3), but not among those who received chemotherapy (CT). SPL were most likely to occur in the first decade following cancer treatment. Results were similar when analyses were restricted to AML. The evidence of interaction between radiation and CT has implications for leukemogenic mechanism. The results for topoisomerase II inhibitors are particularly important given their increasing use to treat childhood cancer.
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http://dx.doi.org/10.1002/ijc.33361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174089PMC
May 2021

Using whole-exome sequencing and protein interaction networks to prioritize candidate genes for germline cutaneous melanoma susceptibility.

Sci Rep 2020 10 14;10(1):17198. Epub 2020 Oct 14.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Although next-generation sequencing has demonstrated great potential for novel gene discovery, confirming disease-causing genes after initial discovery remains challenging. Here, we applied a network analysis approach to prioritize candidate genes identified from whole-exome sequencing analysis of 98 cutaneous melanoma patients from 27 families. Using a network propagation method, we ranked candidate genes by their similarity to known disease genes in protein-protein interaction networks and identified gene clusters with functional connectivity. Using this approach, we identified several new candidate susceptibility genes that warrant future investigations such as NGLY1, IL1RN, FABP2, PRKDC, and PROSER2. The propagated network analysis also allowed us to link families that did not have common underlying genes but that carried variants in genes that interact on protein-protein interaction networks. In conclusion, our study provided an analysis perspective for gene prioritization in the context of genetic heterogeneity across families and prioritized top potential candidate susceptibility genes in our dataset.
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http://dx.doi.org/10.1038/s41598-020-74293-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560829PMC
October 2020

Subsequent Neoplasm Risk Associated With Rare Variants in DNA Damage Response and Clinical Radiation Sensitivity Syndrome Genes in the Childhood Cancer Survivor Study.

JCO Precis Oncol 2020 21;4. Epub 2020 Aug 21.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Purpose: Radiotherapy for childhood cancer is associated with elevated subsequent neoplasm (SN) risk, but the contribution of rare variants in DNA damage response and radiation sensitivity genes to SN risk is unknown.

Patients And Methods: We conducted whole-exome sequencing in a cohort of childhood cancer survivors originally diagnosed during 1970 to 1986 (mean follow-up, 32.7 years), with reconstruction of doses to body regions from radiotherapy records. We identified patients who developed SN types previously reported to be related to radiotherapy (RT-SNs; eg, basal cell carcinoma [BCC], breast cancer, meningioma, thyroid cancer, sarcoma) and matched controls (sex, childhood cancer type/diagnosis, age, SN location, radiation dose, survival). Conditional logistic regression assessed SN risk associated with potentially protein-damaging rare variants (SnpEff, ClinVar) in 476 DNA damage response or radiation sensitivity genes with exact permutation-based values using a Bonferroni-corrected significance threshold of < 8.06 × 10.

Results: Among 5,105 childhood cancer survivors of European descent, 1,108 (21.7%) developed at least 1 RT-SN. Out-of-field RT-SN risk, excluding BCC, was associated with homologous recombination repair (HRR) gene variants (patient cases, 23.2%; controls, 10.8%; odds ratio [OR], 2.6; 95% CI, 1.7 to 3.9; = 4.79 × 10), most notably but nonsignificantly for (patient cases, 4.0%; matched controls, 0.6%; = 9.64 × 10). HRR variants were not associated with likely in/near-field RT-SNs, excluding BCC (patient cases, 12.7%; matched controls, 12.9%; = .92). Irrespective of radiation dose, risk for RT-SNs was also associated with variants (patient cases, 1.8%; controls, 0.4%; = 3.31 × 10), another gene implicated in DNA double-strand break repair.

Conclusion: In this large-scale discovery study, we identified novel associations between RT-SN risk after childhood cancer and potentially protein-damaging rare variants in genes involved in DNA double-strand break repair, particularly HRR. With replication, these results could affect screening recommendations for childhood cancer survivors and risk-benefit assessments of treatment approaches.
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http://dx.doi.org/10.1200/PO.20.00141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469586PMC
August 2020

Sebaceous Carcinoma Epidemiology and Genetics: Emerging Concepts and Clinical Implications for Screening, Prevention, and Treatment.

Clin Cancer Res 2021 Jan 9;27(2):389-393. Epub 2020 Sep 9.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, NCI, Rockville, Maryland.

Sebaceous carcinoma is an aggressive skin cancer with a 5-year overall survival rate of 78% for localized/regional disease and 50% for metastatic disease. The incidence of this cancer has been increasing in the United States for several decades, but the underlying reasons for this increase are unclear. In this article, we review the epidemiology and genetics of sebaceous carcinoma, including recent population data and tumor genomic analyses that provide new insights into underlying tumor biology. We further discuss emerging evidence of a possible viral etiology for this cancer. Finally, we review the clinical implications of recent advances in sebaceous carcinoma research for screening, prevention, and treatment.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854832PMC
January 2021

Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma.

PLoS One 2020 3;15(9):e0237792. Epub 2020 Sep 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America.

Background: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor.

Methods: We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry).

Results: We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5×10-8) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84×10-8).

Conclusions: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk.

Impact: Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237792PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470401PMC
October 2020

Risk of Second Primary Bone and Soft-Tissue Sarcomas Among Young Adulthood Cancer Survivors.

JNCI Cancer Spectr 2019 Sep 20;3(3):pkz043. Epub 2019 Jun 20.

Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.

Excess sarcoma risks after childhood cancer are well established, but risks among young adulthood cancer survivors are poorly understood. Using US population-based cancer registry data, we compared bone and soft-tissue sarcoma risk vs the general population among 186 351 individuals who were diagnosed with nonsarcoma first primary malignancies at ages 20-39 years from 1975 to 2014 (follow-up through 2015) and survived at least 1 year. Bone sarcomas were rare (n = 50), but risk was statistically significantly elevated overall (2.9-fold) and greater than fivefold after Hodgkin lymphoma, non-Hodgkin lymphoma, and central nervous system tumors. Soft-tissue sarcomas were more common (n = 284) and risks were statistically significantly elevated approximately twofold overall and after melanoma and carcinomas of the breast, thyroid, and testis, and greater than fourfold after Hodgkin lymphoma and central nervous system tumors. Risks varied markedly by subtype, with the highest risks (greater than fourfold) for osteosarcoma and the soft-tissue subtypes of rhabdomyosarcoma and blood vessel and nerve sheath sarcomas. These data demonstrate elevated risk for sarcoma after a range of young adulthood cancers.
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http://dx.doi.org/10.1093/jncics/pkz043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049991PMC
September 2019

Recommendations for Long-Term Follow-up of Adults with Heritable Retinoblastoma.

Ophthalmology 2020 11 15;127(11):1549-1557. Epub 2020 May 15.

Memorial Sloan Kettering Cancer Center, New York, New York; Weill Cornell Medical College, New York, New York.

Purpose: To generate recommendations for long-term follow-up of adult survivors of heritable retinoblastoma.

Design: We convened a meeting of providers from retinoblastoma centers around the world to review the state of the science and to evaluate the published evidence.

Participants: Retinoblastoma is a rare childhood cancer of the retina. Approximately 40% of retinoblastoma cases are heritable, resulting from a germline mutation in RB1. Dramatic improvements in treatment and supportive care have resulted in a growing adult survivor population. However, survivors of heritable retinoblastoma have a significantly increased risk of subsequent malignant neoplasms, particularly bone and soft tissue sarcomas, uterine leiomyosarcoma, melanomas, and radiotherapy-related central nervous system tumors, which are associated with excess morbidity and mortality. Despite these risks, no surveillance recommendations for this population currently are in place, and surveillance practices vary widely by center.

Methods: Following the Institute of Medicine procedure for clinical practice guideline development, a PubMed, EMBASE, and Web of Science search was performed, resulting in 139 articles; after abstract and full-text review, 37 articles underwent detailed data abstraction to quantify risk and evidence regarding surveillance, if available. During an in-person meeting, evidence was presented and discussed, resulting in consensus recommendations.

Main Outcome Measures: Diagnosis and mortality from subsequent neoplasm.

Results: Although evidence for risk of subsequent neoplasm, especially sarcoma and melanoma, was significant, evidence supporting routine testing of asymptomatic survivors was not identified. Skin examination for melanoma and prompt evaluation of signs and symptoms of head and neck disease were determined to be prudent.

Conclusions: This review of the literature confirmed some of the common second cancers in retinoblastoma survivors but found little evidence for a benefit from currently available surveillance for these malignancies. Future research should incorporate international partners, patients, and family members.
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http://dx.doi.org/10.1016/j.ophtha.2020.05.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606265PMC
November 2020

Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility.

Nat Genet 2020 05 27;52(5):494-504. Epub 2020 Apr 27.

Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain.

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.
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http://dx.doi.org/10.1038/s41588-020-0611-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255059PMC
May 2020

Histologic features of melanoma associated with germline mutations of CDKN2A, CDK4, and POT1 in melanoma-prone families from the United States, Italy, and Spain.

J Am Acad Dermatol 2020 Sep 10;83(3):860-869. Epub 2020 Apr 10.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.

Background: CDKN2A, CDK4, and POT1 are well-established melanoma-susceptibility genes.

Objective: We evaluated melanoma histopathology for individuals with germline mutations of CDKN2A, CDK4, and POT1.

Methods: We assessed histopathology for melanomas diagnosed in melanoma-prone families (≥2 individuals with melanoma) from the United States, Italy, and Spain. Comparisons between mutation carriers and noncarriers (no mutation) were adjusted for age, sex, Breslow depth, and correlations among individuals within the same family.

Results: Histologic slides were evaluated for 290 melanomas (139 from 132 noncarriers, 122 from 68 CDKN2A carriers, 10 from 6 CDK4 carriers, and 19 from 16 POT1 carriers). Superficial spreading was the predominant subtype for all groups. Spitzoid morphology (>25% of tumor) was observed in 10 of 15 invasive melanomas (67%) from POT1 carriers (P < .0001 vs noncarriers). This finding was independently confirmed by 3 expert melanoma dermatopathologists in 9 of 15 invasive melanomas (60%). In situ and invasive melanomas from CDKN2A and CDK4 carriers were histologically similar to melanomas from noncarriers.

Limitations: Limited sample sizes for rare melanoma-susceptibility syndromes (CDK4, POT1).

Conclusion: Spitzoid morphology was associated with POT1 mutations suggesting that telomere dysfunction (POT1 mutations) may contribute to spitzoid differentiation in melanocytic tumors.
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http://dx.doi.org/10.1016/j.jaad.2020.03.100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505133PMC
September 2020

Ambient ultraviolet radiation and major salivary gland cancer in the United States.

J Am Acad Dermatol 2020 Dec 1;83(6):1775-1777. Epub 2020 Apr 1.

Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland.

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http://dx.doi.org/10.1016/j.jaad.2020.03.077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648631PMC
December 2020

Comparison of Radiation Dose Reconstruction Methods to Investigate Late Adverse Effects of Radiotherapy for Childhood Cancer: A Report from the Childhood Cancer Survivor Study.

Radiat Res 2020 02 3;193(2):95-106. Epub 2019 Dec 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.

Quantification of radiation dose to normal tissue during radiotherapy is critical for assessing risk for radiotherapy-related late effects, including subsequent neoplasms (SNs). Case-control studies of SNs typically reconstruct absorbed radiation dose to the specific SN location using individual treatment parameters. A simplified method estimates the maximum prescribed target dose to the body region in which the SN arises. We compared doses and risk estimates from these methods using data from case-control studies of subsequent brain tumors (64 cases, 244 controls) and breast cancer (94 cases, 358 controls) nested within the Childhood Cancer Survivor Study (≥5-year survivors of childhood cancer diagnosed 1970-1986). The weighted kappa statistic [95% confidence interval (CI)] evaluating agreement between categorical (>0-9.9/10-19.9/20-29.9/≥30 Gy) body-region and tumor location-specific doses was 0.95 (0.91-0.98) for brain and 0.76 (0.69-0.82) for breast. The body-region and location-specific doses were assigned to the same dose category for a smaller proportion of patients treated with fields delivering a heterogeneous dose across the tissue of interest (e.g., partial brain field = 57.1%; mantle field = 61.3%) than patients treated with fields delivering a more homogeneous dose (e.g., whole brain field = 100%). Excess odds ratios per Gy (95% CI) from conditional logistic regression were 1.25 (0.33-6.33) and 1.20 (0.31-6.14) for brain tumors and 0.21 (0.05-0.77) and 0.10 (0.02-0.44) for breast cancer, using location-specific and body-region doses, respectively. We observed that body-region doses can approximate location-specific doses when the tissue of interest is clearly in the radiation field or outside the treated body region. Agreement is lower when there is greater ambiguity of SN location relative to the treatment field.
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http://dx.doi.org/10.1667/RR15308.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063664PMC
February 2020

Risk factors for the development of cutaneous melanoma after allogeneic hematopoietic cell transplantation.

J Am Acad Dermatol 2020 Sep 22;83(3):762-772. Epub 2019 Oct 22.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland. Electronic address:

Background: Melanoma risk is increased after allogeneic hematopoietic cell transplantation (HCT), but specific risk factors are unknown.

Objective: Investigate risk factors for melanoma after allogeneic hematopoietic cell transplantation.

Methods: We conducted a nested case-control study of 140 melanoma cases and 557 controls (matched by age at HCT, sex, primary disease, survival time) through the Center for International Blood and Marrow Transplant Research.

Results: Melanoma risk was significantly increased among HCT survivors who received total body irradiation-based myeloablative conditioning (multivariable adjusted odds ratio [OR] = 1.77; 95% confidence interval [CI] = 1.00-3.15) or reduced-intensity conditioning containing melphalan (OR = 2.60; 95% CI = 1.13-6.02) or fludarabine (OR = 2.72; 95% CI = 1.02-7.30) versus busulfan-based myeloablative regimens; were diagnosed with acute graft-versus-host disease (GVHD) with stage 2+ skin involvement (OR = 1.92; 95% CI = 1.19-3.10), chronic GvHD without skin involvement (OR = 1.91; 95% CI = 1.03-3.57), or keratinocytic carcinoma (OR = 2.37; 95% CI = 1.16-4.83); and resided in areas with higher ambient ultraviolet radiation (ORtertile3 = 1.64; 95% CI = 1.01-2.67).

Limitations: Data on individual-level ultraviolet radiation exposure and clinical data on melanoma characteristics were lacking. Additionally, misclassification of melanoma is possible as not all pathology reports were available for review.

Conclusion: These results emphasize the importance of adherence to current surveillance guidelines (routine skin examination, photoprotection recommendations), particularly for HCT survivors at highest risk.
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http://dx.doi.org/10.1016/j.jaad.2019.10.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206613PMC
September 2020

Bone and Soft-Tissue Sarcoma Risk in Long-Term Survivors of Hereditary Retinoblastoma Treated With Radiation.

J Clin Oncol 2019 12 17;37(35):3436-3445. Epub 2019 Oct 17.

National Cancer Institute, Bethesda, MD.

Purpose: Survivors of hereditary retinoblastoma have excellent survival but substantially increased risks of subsequent bone and soft-tissue sarcomas, particularly after radiotherapy. Comprehensive investigation of sarcoma risk patterns would inform clinical surveillance for survivors.

Patients And Methods: In a cohort of 952 irradiated survivors of hereditary retinoblastoma who were originally diagnosed during 1914 to 2006, we quantified sarcoma risk with standardized incidence ratios (SIRs) and cumulative incidence analyses. We conducted analyses separately for bone and soft-tissue sarcomas occurring in the head and neck (in/near the radiotherapy field) versus body and extremities (out of field).

Results: Of 105 bone and 124 soft-tissue sarcomas, more than one half occurred in the head and neck (bone, 53.3%; soft tissue, 51.6%), one quarter in the body and extremities (bone, 29.5%; soft tissue, 25.0%), and approximately one fifth in unknown/unspecified locations (bone, 17.1%; soft tissue, 23.4%). We noted substantially higher risks compared with the general population for head and neck versus body and extremity tumors for both bone (SIR, 2,213; 95% CI, 1,671 to 2,873 SIR, 169; 95% CI, 115 to 239) and soft-tissue sarcomas (SIR, 542; 95% CI, 418 to 692 SIR, 45.7; 95% CI, 31.1 to 64.9). Head and neck bone and soft-tissue sarcomas were diagnosed beginning in early childhood and continued well into adulthood, reaching a 60-year cumulative incidence of 6.8% (95% CI, 5.0% to 8.7%) and 9.3% (95% CI, 7.0% to 11.7%), respectively. In contrast, body and extremity bone sarcoma incidence flattened after adolescence (3.5%; 95% CI, 2.3% to 4.8%), whereas body and extremity soft-tissue sarcoma incidence was rare until age 30, when incidence rose steeply (60-year cumulative incidence, 6.6%; 95% CI, 4.1% to 9.2%), particularly for females (9.4%; 95% CI, 5.1% to 13.8%).

Conclusion: Strikingly elevated bone and soft-tissue sarcoma risks differ by age, location, and sex, highlighting important contributions of both radiotherapy and genetic susceptibility. These data provide guidance for the development of a risk-based screening protocol that focuses on the highest sarcoma risks by age, location, and sex.
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http://dx.doi.org/10.1200/JCO.19.01096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001778PMC
December 2019

Risk of therapy-related myelodysplastic syndrome/acute myeloid leukemia after childhood cancer: a population-based study.

Leukemia 2019 12 24;33(12):2947-2978. Epub 2019 Jul 24.

Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.

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http://dx.doi.org/10.1038/s41375-019-0520-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884663PMC
December 2019

Variation in Cutaneous Patterns of Melanomagenesis According to Germline CDKN2A/CDK4 Status in Melanoma-Prone Families.

J Invest Dermatol 2020 01 18;140(1):174-181.e3. Epub 2019 Jul 18.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

CDKN2A and CDK4 are well-established melanoma susceptibility genes, but their effect on tumor location and distribution is unknown. We used a case-case study design to assess for differences in tumor location between mutation carriers (CDKN2A = 141 patients, 348 melanomas; CDK4 = 15 patients, 54 melanomas) and noncarriers (104 patients, 157 melanomas) in US melanoma-prone families. Associations between groups were assessed with chi-square tests. Odds ratios (ORs) for tumor location were adjusted for diagnosis age, gender, and superficial spreading subtype. Models included random effects to account for within individual and family correlations. Compared with having a truncal melanoma, CDK4 (vs. noncarriers: lower extremities OR = 14.5, 95% confidence interval [CI] = 5.02-42.0, P < 0.001; upper extremities OR = 6.88, 95% CI = 2.37-19.9, P < 0.001; head and neck OR = 18.6, 95% CI = 4.04-85.2, P < 0.001) and CDKN2A (vs. noncarriers: lower extremities OR = 3.01, 95% CI = 1.56-5.82, P < 0.05; upper extremities OR = 1.91, 95% CI = 1.03-3.52, P < 0.05; head and neck OR = 5.40, 95% CI = 2.10-13.9, P < 0.001) carriers had higher odds of developing melanoma at all other sites. Similar findings were observed for analyses stratified by gender, age, and first versus subsequent melanoma diagnoses. Further studies are needed to understand the biology underlying these genotype-associated patterns of tumor development, which could provide new insights into melanoma treatment and prevention.
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http://dx.doi.org/10.1016/j.jid.2019.06.138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926144PMC
January 2020

Risk for malignancies of infectious etiology among adult survivors of specific non-Hodgkin lymphoma subtypes.

Blood Adv 2019 07;3(13):1961-1969

Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD.

Infectious agents have been identified in the etiology of certain non-Hodgkin lymphoma (NHL) subtypes and solid tumors. The impact of this shared etiology on risk for second cancers in NHL survivors has not been comprehensively studied. We used US population-based cancer registry data to quantify risk of solid malignancies associated with infectious etiology among 127 044 adult 1-year survivors of the 4 most common NHL subtypes diagnosed during 2000 to 2014 (mean follow-up, 4.5-5.2 years). Compared with the general population, elevated risks for liver, stomach, and anal cancers were observed among diffuse large B-cell lymphoma (DLBCL) survivors (standardized incidence ratio [SIR], 1.85; 95% confidence interval [CI], 1.46-2.31; SIR, 1.51; 95% CI, 1.16-1.94; SIR, 3.71; 95% CI, 2.52-5.27, respectively) and marginal zone lymphoma (MZL; SIR, 1.98; 95% CI, 1.34-2.83; SIR, 2.78; 95% CI, 2.02-3.74; SIR, 2.36; 95% CI, 1.02-4.64, respectively) but not follicular lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma. Anal cancer risk was particularly elevated among DLBCL survivors with HIV (SIR, 68.34; 95% CI, 37.36-114.66) vs those without (SIR, 2.09; 95% CI, 1.22-3.34). The observed patterns are consistent with shared associations between these cancers and hepatitis C virus, , and HIV, respectively. In contrast, risks for cervical and oropharyngeal/tonsil cancers were not elevated among survivors of any NHL subtype, possibly because of the lack of NHL association with human papillomavirus or population-wide screening practices (for cervical cancer). In summary, patterns of elevated second cancer risk differed by NHL subtype. Our results suggest shared infectious etiology has implications for subsequent cancer risks among DLBCL and MZL survivors, which may help inform surveillance for these survivors.
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http://dx.doi.org/10.1182/bloodadvances.2019030924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616262PMC
July 2019

Reproductive factors, exogenous hormone use and incidence of melanoma among women in the United States.

Br J Cancer 2019 04 28;120(7):754-760. Epub 2019 Feb 28.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services, Rockville, MD, USA.

Background: Although the photosensitising effects of oestrogens may increase the impact of ultraviolet radiation (UVR) on melanoma risk, few prospective studies have comprehensively assessed the association between oestrogen-related factors and melanoma.

Methods: We examined the associations between reproductive factors, exogenous oestrogen use and first primary invasive melanoma among 167 503 non-Hispanic white, postmenopausal women in the NIH-AARP Diet and Health Study. Satellite-based ambient UVR estimates were linked to geocoded residential locations of participants at study baseline.

Results: Increased risk of melanoma was associated with early age at menarche (≤10 vs ≥15 years: HR = 1.25, 95% CI: 0.92, 1.71; P for trend = 0.04) and late age at menopause (≥50 vs <45 years: HR = 1.34, 95% CI: 1.13, 1.59; P for trend = 0.001). The relationship between ambient UVR and melanoma risk was highest among women with age at menarche ≤10 years (HR per UVR quartile increase = 1.29; 95% CI: 1.05, 1.58; P-interaction = 0.02). Melanoma risk was not associated with parity, age at first birth, use of oral contraceptives or use of menopausal hormone therapy.

Conclusions: Our findings suggest that increased melanoma risk is associated with early age at menarche and late age at menopause. Effect modification findings support the hypothesis that endogenous oestrogen exposure in childhood increases photocarcinogenicity. Future studies should include information on personal UVR exposure and sun sensitivity.
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http://dx.doi.org/10.1038/s41416-019-0411-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461881PMC
April 2019

Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT.

J Am Acad Dermatol 2019 Aug 5;81(2):386-394. Epub 2019 Feb 5.

Department of Clinical Sciences, Lund University Hospital Lund, Sweden; Department of Surgery, Lund University Hospital, Lund, Sweden.

Background: Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of families with melanoma and whether performance improvements can be achieved.

Methods: In total, 2116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CIs) along with net reclassification indices (NRIs) as performance metrics.

Results: MELPREDICT performed well (AUC 0.752, 95% CI 0.730-0.775), and GenoMELPREDICT performance was similar (AUC 0.748, 95% CI 0.726-0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (P < .0001) in GenoMELPREDICT (AUC 0.772, 95% CI 0.750-0.793, NRI 0.40). Including phenotypic risk factors did not improve performance.

Conclusion: The MELPREDICT model functioned well in a global data set of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in directing these patients to receive genetic testing or cancer risk counseling.
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http://dx.doi.org/10.1016/j.jaad.2019.01.079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634996PMC
August 2019
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