Publications by authors named "Alisa M Goldstein"

212 Publications

A UVB-responsive common variant at chromosome band 7p21.1 confers tanning response and melanoma risk via regulation of the aryl hydrocarbon receptor, AHR.

Am J Hum Genet 2021 09 2;108(9):1611-1630. Epub 2021 Aug 2.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address:

Genome-wide association studies (GWASs) have identified a melanoma-associated locus on chromosome band 7p21.1 with rs117132860 as the lead SNP and a secondary independent signal marked by rs73069846. rs117132860 is also associated with tanning ability and cutaneous squamous cell carcinoma (cSCC). Because ultraviolet radiation (UVR) is a key environmental exposure for all three traits, we investigated the mechanisms by which this locus contributes to melanoma risk, focusing on cellular response to UVR. Fine-mapping of melanoma GWASs identified four independent sets of candidate causal variants. A GWAS region-focused Capture-C study of primary melanocytes identified physical interactions between two causal sets and the promoter of the aryl hydrocarbon receptor (AHR). Subsequent chromatin state annotation, eQTL, and luciferase assays identified rs117132860 as a functional variant and reinforced AHR as a likely causal gene. Because AHR plays critical roles in cellular response to dioxin and UVR, we explored links between this SNP and AHR expression after both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and ultraviolet B (UVB) exposure. Allele-specific AHR binding to rs117132860-G was enhanced following both, consistent with predicted weakened AHR binding to the risk/poor-tanning rs117132860-A allele, and allele-preferential AHR expression driven from the protective rs117132860-G allele was observed following UVB exposure. Small deletions surrounding rs117132860 introduced via CRISPR abrogates AHR binding, reduces melanocyte cell growth, and prolongs growth arrest following UVB exposure. These data suggest AHR is a melanoma susceptibility gene at the 7p21.1 risk locus and rs117132860 is a functional variant within a UVB-responsive element, leading to allelic AHR expression and altering melanocyte growth phenotypes upon exposure.
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http://dx.doi.org/10.1016/j.ajhg.2021.07.002DOI Listing
September 2021

Cancer patterns in nasopharyngeal carcinoma multiplex families over 15 years.

Cancer 2021 Jul 29. Epub 2021 Jul 29.

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

Background: Genetic and environmental factors are important determinants of nasopharyngeal carcinoma (NPC). NPC is associated with Epstein-Barr virus (EBV) infection. Studies have reported familial aggregation of NPC, but evidence has been mixed for elevated rates of cancers other than NPC.

Methods: The authors reassessed their previous evaluation of familial aggregation of cancer in 348 high-risk Taiwanese multiplex families with 2 or more NPC cases enrolled between 1980 and 2003. Participants were linked to the Taiwan National Cancer Registry and National Death Registry to identify cancers.

Results: In all, 2590 individuals contributed 37,959 person-years over an average of 15 years of follow-up; 314 incident cancers were identified. The authors computed multiple primary standardized incidence ratios (MP-SIRs) to evaluate the overall risk and the risk of infection-associated, EBV-associated, and individual cancers. The overall MP-SIR was 1.24 (95% confidence interval [CI], 1.10-1.38). The exclusion of excess NPC risk led to an overall MP-SIR of 1.11 (95% CI, 0.98-1.25). Similarly, the risk of cancers associated with infectious agents was driven by the excess in NPC, and its exclusion led to an MP-SIR of 1.22 (95% CI, 0.99-1.48) for infection-associated cancers and to an MP-SIR of 1.18 (95% CI, 0.72-1.82) for EBV-associated cancers. The authors observed a significant excess of second cancers among NPC cases (oral cancer, mouth cancer, tongue cancer, gum cancer, nasal cavity cancer, bone cancer, and non-Hodgkin lymphoma).

Conclusions: This reassessment of the largest NPC multiplex family study confirms the presence of NPC coaggregation within families in Taiwan but does not provide evidence for a broader familial syndrome involving NPC and other tumors. Among NPC cases, elevated rates of secondary cancers, mostly at the, head and neck and hematopoietic cancers suggest radiation treatment effects on subsequent cancer risk.
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http://dx.doi.org/10.1002/cncr.33799DOI Listing
July 2021

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

Cell-type-specific meQTLs extend melanoma GWAS annotation beyond eQTLs and inform melanocyte gene-regulatory mechanisms.

Am J Hum Genet 2021 09 21;108(9):1631-1646. Epub 2021 Jul 21.

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

Although expression quantitative trait loci (eQTLs) have been powerful in identifying susceptibility genes from genome-wide association study (GWAS) findings, most trait-associated loci are not explained by eQTLs alone. Alternative QTLs, including DNA methylation QTLs (meQTLs), are emerging, but cell-type-specific meQTLs using cells of disease origin have been lacking. Here, we established an meQTL dataset by using primary melanocytes from 106 individuals and identified 1,497,502 significant cis-meQTLs. Multi-QTL colocalization with meQTLs, eQTLs, and mRNA splice-junction QTLs from the same individuals together with imputed methylome-wide and transcriptome-wide association studies identified candidate susceptibility genes at 63% of melanoma GWAS loci. Among the three molecular QTLs, meQTLs were the single largest contributor. To compare melanocyte meQTLs with those from malignant melanomas, we performed meQTL analysis on skin cutaneous melanomas from The Cancer Genome Atlas (n = 444). A substantial proportion of meQTL probes (45.9%) in primary melanocytes is preserved in melanomas, while a smaller fraction of eQTL genes is preserved (12.7%). Integration of melanocyte multi-QTLs and melanoma meQTLs identified candidate susceptibility genes at 72% of melanoma GWAS loci. Beyond GWAS annotation, meQTL-eQTL colocalization in melanocytes suggested that 841 unique genes potentially share a causal variant with a nearby methylation probe in melanocytes. Finally, melanocyte trans-meQTLs identified a hotspot for rs12203592, a cis-eQTL of a transcription factor, IRF4, with 131 candidate target CpGs. Motif enrichment and IRF4 ChIP-seq analysis demonstrated that these target CpGs are enriched in IRF4 binding sites, suggesting an IRF4-mediated regulatory network. Our study highlights the utility of cell-type-specific meQTLs.
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http://dx.doi.org/10.1016/j.ajhg.2021.06.018DOI Listing
September 2021

A systematic review of the prevalence of germline pathogenic variants in patients with pancreatic cancer.

J Gastroenterol 2021 Aug 13;56(8):713-721. Epub 2021 Jul 13.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Dr., Rockville, MD, 20850, USA.

The genetics of pancreatic ductal adenocarcinoma (PDAC) is complex with patients reported to harbor germline pathogenic variants (PVs) in many different genes. PDAC patients with familial pancreatic cancer (FPC) are more likely to carry germline PVs but there is no consensus main gene involved in FPC. We performed a systematic review of publications from PubMed and Scopus reporting PVs in patients with FPC, sporadic pancreatic cancer (SPC) and unselected cohorts of PDAC patients undergoing genetic testing and calculated a cumulative prevalence of PVs for each gene evaluated across these three groups of patients. When available, variants in the selected publications were reclassified according to the American College of Medical Genetics and Genomics classification system and used for prevalence calculations if classified as pathogenic or likely pathogenic. We observed an increased prevalence of PVs in FPC compared to SPC or unselected PDAC patients for most of the 41 genes reported. The genes with the highest prevalence of carriers of PVs in FPC were ATM, BRCA2, and CDKN2A. BRCA2 and ATM showed the highest prevalence of PVs in both SPC and unselected PDAC cohorts. Several genes with the highest prevalence of PVs are involved in breast and ovarian cancer suggesting strong overlap with underlying genetics in these disorders but no single gene was predominant. More research is needed to further understand the risk of PDAC associated with these many diverse genes.
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http://dx.doi.org/10.1007/s00535-021-01806-yDOI Listing
August 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

First international workshop of the ATM and cancer risk group (4-5 December 2019).

Fam Cancer 2021 Jun 14. Epub 2021 Jun 14.

Huntsman Cancer Institute, Salt Lake City, USA.

The first International Workshop of the ATM and Cancer Risk group focusing on the role of Ataxia-Telangiectasia Mutated (ATM) gene in cancer was held on December 4 and 5, 2019 at Institut Curie in Paris, France. It was motivated by the fact that germline ATM pathogenic variants have been found to be associated with different cancer types. However, due to the lack of precise age-, sex-, and site-specific risk estimates, no consensus on management guidelines for variant carriers exists, and the clinical utility of ATM variant testing is uncertain. The meeting brought together epidemiologists, geneticists, biologists and clinicians to review current knowledge and on-going challenges related to ATM and cancer risk. This report summarizes the meeting sessions content that covered the latest results in family-based and population-based studies, the importance of accurate variant classification, the effect of radiation exposures for ATM variant carriers, and the characteristics of ATM-deficient tumors. The report concludes that ATM variant carriers outside of the context of Ataxia-Telangiectasia may benefit from effective cancer risk management and therapeutic strategies and that efforts to set up large-scale studies in the international framework to achieve this goal are necessary.
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http://dx.doi.org/10.1007/s10689-021-00248-yDOI Listing
June 2021

Rare Germline Variants in Chordoma-Related Genes and Chordoma Susceptibility.

Cancers (Basel) 2021 May 30;13(11). Epub 2021 May 30.

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

Background: Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains largely unknown. In this study, we investigated rare germline genetic variants in genes involved in TBXT/chordoma-related signaling pathways and other biological processes in chordoma patients from North America and China.

Methods: We identified variants that were very rare in general population and internal control datasets and showed evidence for pathogenicity in 265 genes in a whole exome sequencing (WES) dataset of 138 chordoma patients of European ancestry and in a whole genome sequencing (WGS) dataset of 80 Chinese patients with skull base chordoma.

Results: Rare and likely pathogenic variants were identified in 32 of 138 European ancestry patients (23%), including genes that are part of notochord development, PI3K/AKT/mTOR, Sonic Hedgehog, SWI/SNF complex and mesoderm development pathways. Rare pathogenic variants in COL2A1, EXT1, PDK1, LRP2, TBXT and TSC2, among others, were also observed in Chinese patients.

Conclusion: We identified several rare loss-of-function and predicted deleterious missense variants in germline DNA from patients with chordoma, which may influence chordoma predisposition and reflect a complex susceptibility, warranting further investigation in large studies.
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http://dx.doi.org/10.3390/cancers13112704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197919PMC
May 2021

ABO genotypes and the risk of esophageal and gastric cancers.

BMC Cancer 2021 May 22;21(1):589. Epub 2021 May 22.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Dr. 6E3280, Rockville, MD, 20850, USA.

Background: Blood type has been associated with the risk of gastric cancer, but few studies have examined the association with esophageal squamous cell carcinoma (ESCC).

Methods: We conducted a case-control study using genotyping data of Chinese individuals, including cases of 2022 ESCC, 1189 gastric cardia adenocarcinoma, 1161 gastric noncardia adenocarcinoma, and 2696 controls. Genetic blood type was imputed using three single nucleotide polymorphisms. We used logistic regression to examine the association between blood type and the risk of each cancer.

Results: Compared to blood type O, the risk of ESCC was significantly elevated for blood type B and AB, with the highest risk for type AB (OR, 95%CI: 1.34, 1.07-1.67). Analysis of genotype suggested that the association of ESCC was from carrying the B allele. Similarly, blood type was significantly associated with gastric noncardia adenocarcinoma (P < 0.001) with risk significantly elevated in type A (1.37, 1.14-1.65) and AB (1.44, 1.10-1.89) compared to type O. Blood type was not associated with gastric cardia adenocarcinoma (P = 0.13).

Conclusions: This study provides novel insights into the association between blood type and the risk of ESCC and restricted previously observed association to only gastric noncardia cancer, providing important evidence to clarify the pattern of association and suggesting mechanisms of action.
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http://dx.doi.org/10.1186/s12885-021-08334-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141232PMC
May 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 04;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

Whole genome sequencing of skull-base chordoma reveals genomic alterations associated with recurrence and chordoma-specific survival.

Nat Commun 2021 02 3;12(1):757. Epub 2021 Feb 3.

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

Chordoma is a rare bone tumor with an unknown etiology and high recurrence rate. Here we conduct whole genome sequencing of 80 skull-base chordomas and identify PBRM1, a SWI/SNF (SWItch/Sucrose Non-Fermentable) complex subunit gene, as a significantly mutated driver gene. Genomic alterations in PBRM1 (12.5%) and homozygous deletions of the CDKN2A/2B locus are the most prevalent events. The combination of PBRM1 alterations and the chromosome 22q deletion, which involves another SWI/SNF gene (SMARCB1), shows strong associations with poor chordoma-specific survival (Hazard ratio [HR] = 10.55, 95% confidence interval [CI] = 2.81-39.64, p = 0.001) and recurrence-free survival (HR = 4.30, 95% CI = 2.34-7.91, p = 2.77 × 10). Despite the low mutation rate, extensive somatic copy number alterations frequently occur, most of which are clonal and showed highly concordant profiles between paired primary and recurrence/metastasis samples, indicating their importance in chordoma initiation. In this work, our findings provide important biological and clinical insights into skull-base chordoma.
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http://dx.doi.org/10.1038/s41467-021-21026-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859411PMC
February 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

Integrative molecular characterisation of gallbladder cancer reveals micro-environment-associated subtypes.

J Hepatol 2021 05 1;74(5):1132-1144. Epub 2020 Dec 1.

Division of Cancer Epidemiology and Genetics, NIH, Rockville, MD, USA. Electronic address:

Background & Aims: Gallbladder cancer (GBC) is the most common type of biliary tract cancer, but the molecular mechanisms involved in gallbladder carcinogenesis remain poorly understood. In this study, we applied integrative genomics approaches to characterise GBC and explore molecular subtypes associated with patient survival.

Methods: We profiled the mutational landscape of GBC tumours (whole-exome sequencing on 92, targeted sequencing on 98, in total 190 patients). In a subset (n = 45), we interrogated the matched transcriptomes, DNA methylomes, and somatic copy number alterations. We explored molecular subtypes identified through clustering tumours by genes whose expression was associated with survival in 47 tumours and validated subtypes on 34 publicly available GBC cases.

Results: Exome analysis revealed TP53 was the most mutated gene. The overall mutation rate was low (median 0.82 Mut/Mb). APOBEC-mediated mutational signatures were more common in tumours with higher mutational burden. Aflatoxin-related signatures tended to be highly clonal (present in ≥50% of cancer cells). Transcriptome-wide survival association analysis revealed a 95-gene signature that stratified all GBC patients into 3 subtypes that suggested an association with overall survival post-resection. The 2 poor-survival subtypes were associated with adverse clinicopathologic features (advanced stage, pN1, pM1), immunosuppressive micro-environments (myeloid-derived suppressor cell accumulation, extensive desmoplasia, hypoxia) and T cell dysfunction, whereas the good-survival subtype showed the opposite features.

Conclusion: These data suggest that the tumour micro-environment and immune profiles could play an important role in gallbladder carcinogenesis and should be evaluated in future clinical studies, along with mutational profiles.

Lay Summary: Gallbladder cancer is highly fatal, and its causes are poorly understood. We evaluated gallbladder tumours to see if there were differences between tumours in genetic information such as DNA and RNA. We found evidence of aflatoxin exposure in these tumours, and immune cells surrounding the tumours were associated with survival.
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http://dx.doi.org/10.1016/j.jhep.2020.11.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058239PMC
May 2021

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

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

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

Clin Cancer Res 2021 01 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

Clinical findings in families with chordoma with and without T gene duplications and in patients with sporadic chordoma reported to the Surveillance, Epidemiology, and End Results program.

J Neurosurg 2020 Jun 19;134(5):1399-1408. Epub 2020 Jun 19.

1Division of Cancer Epidemiology & Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda.

Objective: To gain insight into the role of germline genetics in the development of chordoma, the authors evaluated data from 2 sets of patients with familial chordoma, those with and without a germline duplication of the T gene (T-dup+ vs T-dup-), which was previously identified as a susceptibility mechanism in some families. The authors then compared the patients with familial tumors to patients with sporadic chordoma in the US general population reported to the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program through 2015.

Methods: Evaluation of family members included review of personal and family medical history, physical and neurological examination, and pre- and postcontrast MRI of the skull base and spine. Sixteen patients from 6 white families with chordoma had a chordoma diagnosis at family referral. Screening MR images of 35 relatives revealed clival lesions in 6, 4 of which were excised and confirmed to be chordoma. Thus, data were available for 20 patients with histologically confirmed familial chordoma. There were 1759 patients with histologically confirmed chordoma in SEER whose race was known.

Results: The median age at chordoma diagnosis differed across the groups: it was lowest in T-dup+ familial patients (26.8 years, range 5.3-68.4 years); intermediate in T-dup- patients (46.2 years, range 11.8-60.1 years); and highest in SEER patients (57 years, range 0-98 years). There was a marked preponderance of skull base tumors in patients with familial chordoma (93% in T-dup+ and 83% in T-dup-) versus 38% in the SEER program (37% in white, 53% in black, and 48.5% in Asian/Pacific Islander/American Indian/Alaska Native patients). Furthermore, 29% of white and 16%-17% of nonwhite SEER patients had mobile-spine chordoma, versus no patients in the familial group. Several T-dup+ familial chordoma patients had putative second/multiple primary chordomas.

Conclusions: The occurrence of young age at diagnosis, skull base presentation, or multiple primary chordomas should encourage careful review of family history for patients diagnosed with chordoma as well as screening of at-risk family members by MRI for early detection of chordoma. Furthermore, given genetic predisposition in some patients with familial chordoma, identification of a specific mutation in a family will permit surveillance to be limited to mutation carriers-and consideration should be given for imaging the entire neuraxis in any chordoma patient presenting at an early age or with a blood relative with chordoma. Finally, future studies should explore racial differences in age at diagnosis and presenting site in chordoma.
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http://dx.doi.org/10.3171/2020.4.JNS193505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188573PMC
June 2020

A Systematic Literature Review of Whole Exome and Genome Sequencing Population Studies of Genetic Susceptibility to Cancer.

Cancer Epidemiol Biomarkers Prev 2020 08 28;29(8):1519-1534. Epub 2020 May 28.

National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland.

The application of next-generation sequencing (NGS) technologies in cancer research has accelerated the discovery of somatic mutations; however, progress in the identification of germline variation associated with cancer risk is less clear. We conducted a systematic literature review of cancer genetic susceptibility studies that used NGS technologies at an exome/genome-wide scale to obtain a fuller understanding of the research landscape to date and to inform future studies. The variability across studies on methodologies and reporting was considerable. Most studies sequenced few high-risk (mainly European) families, used a candidate analysis approach, and identified potential cancer-related germline variants or genes in a small fraction of the sequenced cancer cases. This review highlights the importance of establishing consensus on standards for the application and reporting of variants filtering strategies. It also describes the progress in the identification of cancer-related germline variation to date. These findings point to the untapped potential in conducting studies with appropriately sized and racially diverse families and populations, combining results across studies and expanding beyond a candidate analysis approach to advance the discovery of genetic variation that accounts for the unexplained cancer heritability.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279039PMC
August 2020

Integrated analysis of genome-wide miRNAs and targeted gene expression in esophageal squamous cell carcinoma (ESCC) and relation to prognosis.

BMC Cancer 2020 May 6;20(1):388. Epub 2020 May 6.

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

Background: Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer death worldwide and in China. We know miRNAs influence gene expression in tumorigenesis, but it is unclear how miRNAs affect gene expression or influence survival at the genome-wide level in ESCC.

Methods: We performed miRNA and mRNA expression arrays in 113 ESCC cases with tumor/normal matched tissues to identify dysregulated miRNAs, to correlate miRNA and mRNA expressions, and to relate miRNA and mRNA expression changes to survival and clinical characteristics.

Results: Thirty-nine miRNAs were identified whose tumor/normal tissue expression ratios showed dysregulation (28 down- and 11 up-regulated by at least two-fold with P < 1.92E-04), including several not previously reported in ESCC (miR-885-5p, miR-140-3p, miR-708, miR-639, miR-596). Expressions of 16 miRNAs were highly correlated with expressions of 195 genes (P < 8.42E-09; absolute rho values 0.51-0.64). Increased expressions of miRNA in tumor tissue for both miR-30e* and miR-124 were associated with increased survival (P < 0.05). Similarly, nine probes in eight of 818 dysregulated genes had RNA expression levels that were nominally associated with survival, including NF1, ASXL1, HSPA4, TGOLN2, BAIAP2, EZH2, CHAF1A, SUPT7L.

Conclusions: Our characterization and integrated analysis of genome-wide miRNA and gene expression in ESCC provides insights into the expression of miRNAs and their relation to regulation of RNA targets in ESCC tumorigenesis, and suggest opportunities for the future development of miRs and mRNAs as biomarkers for early detection, diagnosis, and prognosis in ESCC.
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http://dx.doi.org/10.1186/s12885-020-06901-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201714PMC
May 2020

Low Epstein-Barr Virus Prevalence in Cardia Gastric Cancer Among a High-Incidence Chinese Population.

Dig Dis Sci 2021 04 4;66(4):1220-1226. Epub 2020 May 4.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Room 6E110, 9609 Medical Center Drive, Rockville, MD, 20892-9776, USA.

Background: Epstein-Barr virus (EBV) positivity is associated with better gastric cancer prognosis and is found in a relatively fixed 9% of tumors worldwide.

Aim: We aimed to examine the EBV status of gastric adenocarcinomas in a very high-incidence population and to compare prevalence between cardia and non-cardia anatomic subsites.

Methods: We evaluated 1035 adult gastric adenocarcinoma cases presenting during 1997-2005 to the Shanxi Cancer Hospital in Taiyuan, Shanxi Province, China. EBV-encoded RNA was detected in alcohol-fixed paraffin-embedded tumor specimens by in situ hybridization. Associations were assessed in case-case comparisons using the Chi-squared test for categorical variables and the Mann-Whitney U test for continuous variables, with p values < 0.05 considered statistically significant. Adjusted odds ratios were calculated using logistic regression, and mortality hazard ratios (HRs) were estimated by Cox proportional hazards regression.

Results: Sixty-four percent of the evaluated cancers were found in the cardia. Cardia tumor localization was associated with male sex, advanced primary tumor stage, better differentiated histology, and intestinal-type Lauren classification. Four percent of the non-cardia and only 0.9% of cardia cancers were EBV-positive. EBV positivity was associated with better overall survival (adjusted HR 0.30, 95% CI 0.14-0.63).

Conclusions: Our study highlights unusually low EBV prevalence in gastric adenocarcinoma among a high-incidence population, particularly for cardia cancers. These findings suggest a unique risk factor profile for the high incidence of gastric cancer in this population.
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http://dx.doi.org/10.1007/s10620-020-06288-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685001PMC
April 2021

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

Insights into Genetic Susceptibility to Melanoma by Gene Panel Testing: Potential Pathogenic Variants in ACD, and .

Cancers (Basel) 2020 04 19;12(4). Epub 2020 Apr 19.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, MD 20892, USA.

The contribution of recently established or candidate susceptibility genes to melanoma missing heritability has yet to be determined. Multigene panel testing could increase diagnostic yield and better define the role of candidate genes. We characterized 273 and negative probands through a custom-designed targeted gene panel that included and Co-segregation, loss of heterozygosity (LOH)/protein expression analysis, and splicing characterization were performed to improve variant classification. We identified 16 (5.9%) pathogenic and likely pathogenic variants in established high/medium penetrance cutaneous melanoma susceptibility genes ( and ), including two novel variants in and 4 in . We also found four deleterious and five likely deleterious variants in (3.3%). Thus, including potentially deleterious variants in increased the diagnostic yield to about 9%. Inclusion of rare variants of uncertain significance would increase the overall detection yield to 14%. At least 10% of melanoma missing heritability may be explained through panel testing in our population. To our knowledge, this is the highest frequency of putative deleterious variants reported in melanoma families, suggesting a possible role in melanoma susceptibility, which needs further investigation.
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http://dx.doi.org/10.3390/cancers12041007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226507PMC
April 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

Body mass index and height and risk of cutaneous melanoma: Mendelian randomization analyses.

Int J Epidemiol 2020 08;49(4):1236-1245

Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

Background: Height and body mass index (BMI) have both been positively associated with melanoma risk, although findings for BMI have been less consistent than height. It remains unclear, however, whether these associations reflect causality or are due to residual confounding by environmental and lifestyle risk factors. We re-evaluated these associations using a two-sample Mendelian randomization (MR) approach.

Methods: We identified single nucleotide polymorphisms (SNPs) for BMI and height from separate genome-wide association study (GWAS) meta-analyses. We obtained melanoma SNPs from the most recent melanoma GWAS meta-analysis comprising 12 874 cases and 23 203 controls. We used the inverse variance-weighted estimator to derive separate causal risk estimates across all SNP instruments for BMI and height.

Results: Based on the combined estimate derived from 730 SNPs for BMI, we found no evidence of an association between genetically predicted BMI and melanoma [odds ratio (OR) per one standard deviation (1 SD) (4.6 kg/m2) increase in BMI 1.00, 95% confidence interval (CI): 0.91-1.11]. In contrast, we observed a positive association between genetically-predicted height (derived from a pooled estimate of 3290 SNPs) and melanoma risk [OR 1.08, 95% CI: 1.02-1.13, per 1 SD (9.27 cm) increase in height]. Sensitivity analyses using two alternative MR methods yielded similar results.

Conclusions: These findings provide no evidence for a causal association between higher BMI and melanoma, but support the notion that height is causally associated with melanoma risk. Mechanisms through which height influences melanoma risk remain unclear, and it remains possible that the effect could be mediated through diverse pathways including growth factors and even socioeconomic status.
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http://dx.doi.org/10.1093/ije/dyaa009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778056PMC
August 2020

Reproductive Health in Xeroderma Pigmentosum: Features of Premature Aging.

Obstet Gynecol 2019 10;134(4):814-819

National Human Genome Research Institute, National Institutes of Health, and the Laboratory of Cancer Biology and Genetics, Center for Cancer Research, and the Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and Howard University Medical Center, Washington, DC.

Objective: To assess the age at menarche and menopause of women with xeroderma pigmentosum, a DNA repair disease with premature aging, in a longitudinal natural history study.

Methods: We conducted a natural history study that reviewed medical records for gynecologic and reproductive health of all female patients with xeroderma pigmentosum aged older than 9 years examined at the National Institutes of Health (NIH). We performed gynecologic and laboratory examinations on a subset of the patients. Women in a second subset, who could not be examined, were interviewed using a questionnaire. Women who were deceased or lost to follow-up formed a third subset.

Results: Sixty females with xeroderma pigmentosum aged older than 9 years (median 29 years, range 10-61 years) were evaluated at the NIH from 1971 to 2018. Of these 60, 31 had history, questionnaire, record review, and gynecologic evaluation; 14 had record review and questionnaire interview by telephone; and 15 had only NIH record review. Menarche in females with xeroderma pigmentosum occurred at a median age of 12.0 years (range 9-17 years), which was comparable with the U.S. general population. Among the 18 patients with menopause, the median age at menopause of 29.5 years (range 18-49.5 years) was more than 20 years younger than in the U.S. general population (52.9 years). Premature menopause (before age 40 years) occurred in 14 of the 45 (31%) women aged 18 years or older, and primary ovarian insufficiency was documented in nine of them. There were 32 live births among 21 of the women, five of whom subsequently developed premature menopause.

Conclusion: Females with xeroderma pigmentosum in our study had a normal age at menarche and were fertile but had increased incidence of premature menopause. Premature menopause, a symptom of premature aging, should be considered for gynecologic and reproductive health as well as implicating DNA repair in maintaining normal ovarian function.

Clinical Trial Registration: ClinicalTrials.gov, NCT00001813.
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http://dx.doi.org/10.1097/AOG.0000000000003490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768713PMC
October 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

Whole-Exome Sequencing of Nasopharyngeal Carcinoma Families Reveals Novel Variants Potentially Involved in Nasopharyngeal Carcinoma.

Sci Rep 2019 07 9;9(1):9916. Epub 2019 Jul 9.

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

Genetic susceptibility is likely involved in nasopharyngeal carcinoma (NPC), a cancer caused by Epstein-Barr virus (EBV) infection. Understanding of genetic factors involved in NPC and how they contribute to EBV-induced carcinogenesis is limited. We conducted whole-exome capture/sequencing among 251 individuals from 97 multiplex families from Taiwan (205 affected, 21 obligate carriers, and 25 unaffected) using SeqCap EZ Human Exome Library v3.0 and Illumina HiSeq. Aligned sequences were filtered to identify likely-to-be-functional deleterious variants that co-segregated with disease. Ingenuity Pathway analysis was performed. Circulating magnesium levels were measured in 13 individuals in 2 families with NIPAL1 mutations and in 197 sporadic NPC cases and 237 controls. We identified variants in 12 genes likely involved in cancer pathogenesis, viral infection or immune responses to infection. These included genes postulated to be involved in magnesium transport (NIPAL1), EBV cell entry (ITGB6), modulation of EBV infection (BCL2L12, NEDD4L), telomere biology (CLPTM1L, BRD2, HNRNPU), modulation of cAMP signaling (RAPGEF3), DNA repair (PRKDC, MLH1), and Notch signaling (NOTCH1, DLL3). Pathway based analysis demonstrated enrichment for Notch signaling genes (p-value = 0.0006). Evaluation of individuals within NIPAL1 families suggested lower serum magnesium in NPC compared to unaffected members. A significant reduction in serum magnesium levels was observed among sporadic NPC cases compared to controls (7.1% NPC/1.7% controls below normal range; OR = 4.5; 95% CI = 1.4,14) and is consistent with findings demonstrating a role for magnesium channeling in T-cell responses to EBV. We identified novel genes associated with NPC that point to new areas of inquiry to better understand genetic factors that determine the fate of viral infections and/or otherwise predisposes to NPC.
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http://dx.doi.org/10.1038/s41598-019-46137-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617453PMC
July 2019

Evaluation of Rare and Common Variants from Suspected Familial or Sporadic Nasopharyngeal Carcinoma (NPC) Susceptibility Genes in Sporadic NPC.

Cancer Epidemiol Biomarkers Prev 2019 10 3;28(10):1682-1686. Epub 2019 Jul 3.

Genomics Research Center, Academia Sinica, Taipei, Taiwan.

Background: Genetic susceptibility is associated with nasopharyngeal carcinoma (NPC). We previously identified rare variants potentially involved in familial NPC and common variants significantly associated with sporadic NPC.

Methods: We conducted targeted gene sequencing of 20 genes [16 identified from the study of multiplex families, three identified from a pooled analysis of NPC genome-wide association study (GWAS), and one identified from both studies] among 819 NPC cases and 938 controls from two case-control studies in Taiwan (independent from previous studies). A targeted, multiplex PCR primer panel was designed using the custom Ion AmpliSeq Designer v4.2 targeting the regions of the selected genes. Gene-based and single-variant tests were conducted.

Results: We found that NPC was associated with combined common and rare variants in ( = 1.3 × 10), ( = 1.6 × 10), ( = 4.0 × 10), and ( = 5.4 × 10). Such associations were likely driven by common variants within these genes, based on gene-based analyses evaluating common variants and rare variants separately (e.g., for common variants of = 4.6 × 10; for rare variants, = 0.04). We also observed a suggestive association with rare variants in ( = 3.8 × 10) for NPC risk. In addition, we validated four previously reported NPC risk-associated SNPs.

Conclusions: Our findings confirm previously reported associated variants and suggest that some common variants in genes previously linked to familial NPC are associated with the development of sporadic NPC.

Impact: NPC-associated genes, including , and , suggest a role for telomere length maintenance in NPC etiology.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774819PMC
October 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

Prevalence of pathogenic/likely pathogenic variants in the 24 cancer genes of the ACMG Secondary Findings v2.0 list in a large cancer cohort and ethnicity-matched controls.

Genome Med 2018 12 24;10(1):99. Epub 2018 Dec 24.

Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.

Background: Prior research has established that the prevalence of pathogenic/likely pathogenic (P/LP) variants across all of the American College of Medical Genetics (ACMG) Secondary Findings (SF) genes is approximately 0.8-5%. We investigated the prevalence of P/LP variants in the 24 ACMG SF v2.0 cancer genes in a family-based cancer research cohort (n = 1173) and in cancer-free ethnicity-matched controls (n = 982).

Methods: We used InterVar to classify variants and subsequently conducted a manual review to further examine variants of unknown significance (VUS).

Results: In the 24 genes on the ACMG SF v2.0 list associated with a cancer phenotype, we observed 8 P/LP unique variants (8 individuals; 0.8%) in controls and 11 P/LP unique variants (14 individuals; 1.2%) in cases, a non-significant difference. We reviewed 115 VUS. The median estimated per-variant review time required was 30 min; the first variant within a gene took significantly (p = 0.0009) longer to review (median = 60 min) compared with subsequent variants (median = 30 min). The concordance rate was 83.3% for the variants examined by two reviewers.

Conclusion: The 115 VUS required database and literature review, a time- and labor-intensive process hampered by the difficulty in interpreting conflicting P/LP determinations. By rigorously investigating the 24 ACMG SF v2.0 cancer genes, our work establishes a benchmark P/LP variant prevalence rate in a familial cancer cohort and controls.
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http://dx.doi.org/10.1186/s13073-018-0607-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305568PMC
December 2018
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