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1.
Obstet Gynecol ; 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31503159

RESUMO

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.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31270100

RESUMO

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 CDKN2A/2B (P = 1.3 × 10-4), BRD2 (P = 1.6 × 10-3), TNFRSF19 (P = 4.0 × 10-3), and CLPTM1L/TERT (P = 5.4 × 10-3). 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 CDKN2A/2B, P = 4.6 × 10-4; for rare variants, P = 0.04). We also observed a suggestive association with rare variants in HNRNPU (P = 3.8 × 10-3) 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 CLPTM1L/TERT, BRD2, and HNRNPU, suggest a role for telomere length maintenance in NPC etiology.

3.
J Invest Dermatol ; 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31326397

RESUMO

CDKN2A and CDK4 are well-established melanoma susceptibility genes, but their effect on tumor location/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 non-carriers (104 patients, 157 melanomas) in U.S. 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/family correlations. Compared to having a truncal melanoma, CDK4 (vs. non-carriers: lower extremities OR=14.5, 95% CI, 5.02-42.0, P<.001; upper extremities OR=6.88, 95% CI, 2.37-19.9, P<.001; head/neck OR=18.6, 95% CI, 4.04-85.2, P<.001) and CDKN2A (vs. non-carriers: lower extremities OR=3.01, 95% CI, 1.56-5.82, P<.05; upper extremities OR=1.91, 95% CI, 1.03-3.52, P<.05; head/neck OR=5.40, 95% CI, 2.10-13.9, P<.001) carriers had higher odds of developing melanoma at all other sites. Similar findings were observed for analyses stratified by gender, age, and first vs. 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.

4.
Sci Rep ; 9(1): 9916, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31289279

RESUMO

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.

5.
J Am Acad Dermatol ; 81(2): 386-394, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30731170

RESUMO

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.

6.
JAMA Dermatol ; 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30516811

RESUMO

Importance: Wide use of genomic sequencing to diagnose disease has raised concern about the extent of genotype-phenotype correlations. Objective: To correlate disease-associated allele frequencies with expected and reported prevalence of clinical disease. Design, Setting, and Participants: Xeroderma pigmentosum (XP), a recessive, cancer-prone, neurocutaneous disorder, was used as a model for this study. From January 1, 2017, to May 4, 2018, the Human Gene Mutation Database and a cohort of patients at the National Institutes of Health were searched and screened to identify reported mutations associated with XP. The clinical phenotype of these patients was confirmed from reports in the literature and National Institutes of Health medical records. The genetically predicted prevalence of disease based on frequency of known pathogenic mutations was compared with the prevalence of patients clinically diagnosed with phenotypic XP. Exome sequencing of more than 200 000 alleles from the Genome Aggregation Database, the National Cancer Institute Division of Cancer Epidemiology and Genetics database of healthy controls, and an Inova Hospital Study database was used to investigate the frequencies of these mutations in the general population. Main Outcomes and Measures: Listing of all reported mutations associated with XP, their frequencies in 3 large exome sequence databases, determination of the number of patients in the United States with XP using modeling equations, and comparison of the observed and reported numbers of patients with XP with specific mutations. Results: A total of 156 pathogenic missense and nonsense mutations associated with XP were identified in the National Institutes of Health cohort and the Human Gene Mutation Database. The Genome Aggregation Database provided frequency data for 65 of these mutations, with a total allele frequency of 1.13%. The XPF (ERCC4) mutation, p.P379S, had an allele frequency of 0.4%, and the XPC mutation, p.P334H, had an allele frequency of 0.3%. With the Hardy-Weinberg equation, it was determined that there should be more than 8000 patients who are homozygous for these mutations in the United States. In contrast, only 3 patients with XP were reported as having the XPF mutation, and 1 patient was reported as having the XPC mutation. Conclusions and Relevance: The findings from this study suggest that clinicians should approach large genomic databases with caution when trying to correlate the clinical implications of genetic variants with the prevalence of disease risk. Unsuspected mutations in known genes with a predisposition for skin cancer may be responsible for some of the high frequency of skin cancers in the general population.

7.
Genome Med ; 10(1): 99, 2018 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-30583724

RESUMO

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.


Assuntos
Genes Neoplásicos/genética , Predisposição Genética para Doença , Mutação , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Idoso , Estudos de Coortes , Análise Mutacional de DNA , Grupos Étnicos , Feminino , Humanos , Masculino
8.
Artigo em Inglês | MEDLINE | ID: mdl-30411536

RESUMO

BACKGROUND: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder with variable expression and nearly complete penetrance. PTCH1 is the major susceptibility locus and has no known hot spots or genotype-phenotype relationships. METHODS: We evaluated 18 NBCCS National Cancer Institute (NCI) families plus PTCH1 data on 333 NBCCS disease-causing mutations (DM) reported in the Human Gene Mutation Database (HGMD). National Cancer Institute families underwent comprehensive genomic evaluation, and clinical data were extracted from NCI and HGMD cases. Genotype-phenotype relationships were analyzed using Fisher's exact tests focusing on mutation type and PTCH1 domains. RESULTS: PTCH1 pathogenic mutations were identified in 16 of 18 NCI families, including three previously mutation-negative families. PTCH1 mutations were spread across the gene with no hot spot. After adjustment for multiple tests, a statistically significant genotype-phenotype association was observed for developmental delay and gross deletion-insertions (p = 9.0 × 10-6 ), and suggestive associations between falx cerebri calcification and all transmembrane domains (p = 0.002) and severe outcomes and gross deletion-insertions (p = 4.0 × 10-4 ). CONCLUSION: Overall, 89% of our NCI families had a pathogenic PTCH1 mutation. The identification of PTCH1 mutations in previously mutation-negative families underscores the importance of repeated testing when new technologies become available. Additional clinical information linked to mutation databases would enhance follow-up and future studies of genotype-phenotype relationships.

9.
Genome Res ; 28(11): 1621-1635, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30333196

RESUMO

Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type-specific regulatory landscape of human melanocytes, which give rise to melanoma but account for <5% of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335 cis-eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR < 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified trans-eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through cis-regulation of IRF4 Melanocyte eQTLs are enriched in cis-regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility loci, where imputed expression levels of five genes (ZFP90, HEBP1, MSC, CBWD1, and RP11-383H13.1) were associated with melanoma at genome-wide significant P-values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings, and present a robust database for genomic research of melanoma risk and melanocyte biology.

10.
Cancer ; 124(18): 3715-3723, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30207590

RESUMO

BACKGROUND: In the United States, only approximately 0.4% of all melanomas are diagnosed in patients aged <20 years. To the authors' knowledge, melanoma in pediatric members of melanoma-prone families has not been fully investigated to date. The objective of the current study was to evaluate pediatric patients with melanoma with extensive follow-up in melanoma-prone families with and without cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations. METHODS: For this non-population-based study, families were followed prospectively for up to 40 years. A total of 60 families with ≥ 3 patients with melanoma were included for analysis: 30 CDKN2A mutation-positive (CDKN2A+) and 30 CDKN2A mutation-negative (CDKN2A-) families. Age at the time of first melanoma and number of melanomas were obtained for each patient and summarized by family or sets (CDKN2A + vs CDKN2A-). For set comparisons and categorical variables (occurrence of melanoma in pediatric patients, number of melanomas, number of patients with single or multiple melanomas), the Pearson chi-square or Fisher exact test was used. RESULTS: Regardless of CDKN2A status, melanoma-prone families were found to have 6-fold to 28-fold higher percentages of patients with pediatric melanoma compared with the general population of patients with melanoma in the United States. Within CDKN2A + families, pediatric patients with melanoma were significantly more likely to have multiple melanomas compared with their relatives who were diagnosed at age >20 years (71% vs 38%, respectively; P = .004). CDKN2A + families had significantly higher percentages of pediatric patients with melanoma compared with CDKN2A- families (11.1% vs 2.5%; P = .004). CONCLUSIONS: These observations have implications for the prevention of melanoma as well as clinical care for its early detection. Children in melanoma-prone families should have careful sun protection from an early age and skin surveillance to reduce their risk of melanoma.

11.
J Gen Virol ; 99(9): 1268-1273, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29975184

RESUMO

Epstein-Barr virus (EBV) is an obligatory factor in the development of nasopharyngeal carcinoma (NPC), and anti-EBV IgA antibodies are elevated many years prior to the development of NPC. Nearly all adults are infected with EBV, but only a few develop cancer, suggesting that additional co-factors, including genetic susceptibility, must be required for the disease to manifest. Individuals were selected from the Taiwan Family Study, a cohort of 3389 individuals from NPC multiplex families. Primary analyses were conducted among 671 individuals from 69 pedigrees with the strongest family history of disease (>3 NPC-affected family members). The likelihood that a given family member carried a NPC susceptibility variant was estimated using Mendelian segregation rules, assuming a dominant mode of inheritance. We compared anti-EBV IgA antibody seropositivity between family members predicted to be carriers of NPC-linked genetic variants and those with a lower likelihood of carrying such variants. Obligate carriers of NPC susceptibility variants (100 % predicted probability of harbouring the genetic mutation) were nine-fold more likely to be anti-EBV IgA positive compared to family members predicted not to carry disease-causing variants (OR=9.2; P-trend<0.001). This elevated risk was confirmed in analyses restricted to both unaffected individuals and pedigrees with EBV-related pathway variants identified through exome sequencing. Our data indicate that family members who are more likely to carry NPC susceptibility variants are also more likely to be anti-EBNA1 IgA seropositive. Genetic susceptibility associated with control over this common herpes virus is likely a co-factor in determining which EBV-infected adults develop NPC.

12.
J Invest Dermatol ; 138(12): 2617-2624, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29890168

RESUMO

It is unclear to what degree genomic and traditional (phenotypic and environmental) risk factors overlap in their prediction of melanoma risk. We evaluated the incremental contribution of common genomic variants (in pigmentation, nevus, and other pathways) and their overlap with traditional risk factors, using data from two population-based case-control studies from Australia (n = 1,035) and the United Kingdom (n = 1,460) that used the same questionnaires. Polygenic risk scores were derived from 21 gene regions associated with melanoma and odds ratios from published meta-analyses. Logistic regression models were adjusted for age, sex, center, and ancestry. Adding the polygenic risk score to a model with traditional risk factors increased the area under the receiver operating characteristic curve (AUC) by 2.3% (P = 0.003) for Australia and by 2.8% (P = 0.002) for Leeds. Gene variants in the pigmentation pathway, particularly MC1R, were responsible for most of the incremental improvement. In a cross-tabulation of polygenic by traditional tertile risk scores, 59% (Australia) and 49% (Leeds) of participants were categorized in the same (concordant) tertile. Of participants with low traditional risk, 9% (Australia) and 21% (Leeds) had high polygenic risk. Testing of genomic variants can identify people who are susceptible to melanoma despite not having a traditional phenotypic risk profile.

13.
Br J Haematol ; 181(3): 372-377, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29693246

RESUMO

In a previous whole exome sequencing of patients from 41 families with Hodgkin lymphoma, we identified two families with distinct heterozygous rare coding variants in POT1 (D224N and Y36H), both in a highly conserved region of the gene. POT1 D224N mutant did not bind to a single-stranded telomere oligonucleotide in vitro suggesting the mutation perturbs POT1's ability to bind to the telomeric G-rich overhang. Human HT1080 cells expressing POT1 D224N and lymphoblastoid cells carrying Y36H both showed increased telomere length and fragility in comparison to wild type cells. This strongly suggests that mutant POT1 causes chromosome instability and may play a role in lymphomagenesis in these families.

14.
J Invest Dermatol ; 138(7): 1620-1626, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29408205

RESUMO

Since 1976, melanoma-prone families have been followed at the National Cancer Institute to identify etiologic factors for melanoma. We compared risks of melanoma and other cancers in 1,226 members of 56 families followed for up to 4 decades with population rates in the Surveillance, Epidemiology, and End Results program. All families were tested for mutations in CDKN2A and CDK4; 29 were mutation-positive and 27 mutation-negative. We compared rates of invasive melanomas, both first and second, by family mutation status, with Surveillance, Epidemiology, and End Results program. Comparing three calendar periods of the study, risk of first primary melanoma decreased slightly. Risks of melanoma after first examination, however, were approximately one-third the risks prior to the first examination in both mutation-positive and mutation-negative families. Among patients with melanoma, risk of a second melanoma was increased 10-fold in all families; risk was somewhat higher in mutation-positive families. Risks of other second cancers were increased only for pancreatic cancer after melanoma in mutation-positive families. Over 4 decades, prospective risk of melanoma has decreased substantially in both mutation-positive and mutation-negative families, when melanoma has greatly increased in the general population. TRIAL REGISTRATION: NCI 02-C-0211, ClinicalTrials.gov ID NCT00040352.

15.
Genet Med ; 20(9): 1087-1090, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29215650

RESUMO

PURPOSE: Carriers of CDKN2A mutations have high risks of melanoma and certain other cancers. In this study we examined the occurrence of tumors among CDKN2A wild type (wt) members of melanoma-prone families with CDKN2A mutations. METHODS: Swedish and US melanoma-prone families with CDKN2A mutations were included. Data was collected on tumors diagnosed among family members. Among the CDKN2A mutated families, members with CDKN2A wt status who were diagnosed with melanoma were designated phenocopies. RESULTS: Of patients with melanoma in the CDKN2A mutated families (n = 266), 7.1%, were seen among members with CDKN2A wt status (phenocopy rate). Among the CDKN2A wt family members of the CDKN2A mutated families (n = 256), 7.4% were diagnosed with melanoma. The prospective relative risk for melanomas was significantly higher among the CDKN2A wt subjects compared with population-based controls (7.4 (95% confidence interval 1.7-33.2)), while no elevated risks of nonmelanoma cancers were seen and their offspring did not have significantly elevated risks of melanoma or other cancers. CONCLUSION: Members of CDKN2A mutation carrying families who test negative for their family's mutation have moderately increased risk for melanoma and should, in addition to being considered for continuing dermatologic surveillance, be encouraged to follow sun safety recommendations and practice skin self-exams.

16.
Hum Mol Genet ; 26(24): 4886-4895, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29036293

RESUMO

Known high-risk cutaneous malignant melanoma (CMM) genes account for melanoma risk in <40% of melanoma-prone families, suggesting the existence of additional high-risk genes or perhaps a polygenic mechanism involving multiple genetic modifiers. The goal of this study was to systematically characterize rare germline variants in 42 established melanoma genes among 144 CMM patients in 76 American CMM families without known mutations using data from whole-exome sequencing. We identified 68 rare (<0.1% in public and in-house control datasets) nonsynonymous variants in 25 genes. We technically validated all loss-of-function, inframe insertion/deletion, and missense variants predicted as deleterious, and followed them up in 1, 559 population-based CMM cases and 1, 633 controls. Several of these variants showed disease co-segregation within families. Of particular interest, a stopgain variant in TYR was present in five of six CMM cases/obligate gene carriers in one family and a single population-based CMM case. A start gain variant in the 5'UTR region of PLA2G6 and a missense variant in ATM were each seen in all three affected people in a single family, respectively. Results from rare variant burden tests showed that familial and population-based CMM patients tended to have higher frequencies of rare germline variants in albinism genes such as TYR, TYRP1, and OCA2 (P < 0.05). Our results suggest that rare nonsynonymous variants in low- or intermediate-risk CMM genes may influence familial CMM predisposition, warranting further investigation of both common and rare variants in genes affecting functionally important pathways (such as melanogenesis) in melanoma risk assessment.


Assuntos
Mutação em Linhagem Germinativa , Melanoma/genética , Neoplasias Cutâneas/genética , Adulto , Feminino , Predisposição Genética para Doença , Genótipo , Fosfolipases A2 do Grupo VI/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Risco , Sequenciamento Completo do Exoma/métodos
17.
Carcinogenesis ; 38(11): 1119-1128, 2017 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-29028942

RESUMO

Eleven high-evidence single-nucleotide polymorphisms (SNPs) at nine loci for gastric cancer (GC) risk were reported, but their associations with survival remain unknown. In this study, we examined associations between SNP and GC survival by anatomic location and histology among 1147 incident cases from the Shanxi Upper Gastrointestinal Genetics Project. We further examined whether SNPs were expression quantitative trait loci in normal and tumor gastric tissues, and whether tumor versus normal somatic mRNA differences in 126 cases were associated with survival. No SNPs were associated with GC survival overall. However, subtype-specific associations were observed for gastric cardia adenocarcinomas at MUC1/TRIM46/1q22 rs2070803 [HRAA versus GA+GG = 2.16; 95% confidence interval (CI) = 1.24-3.78; P = 0.0068] and LTA/TNF/6p21.33 rs1799724 (HRTT+CT versus CC = 1.30; 95% CI = 1.07-1.57; P = 0.0077), and for diffuse-type GC at PSCA/8q24.3 rs2294008 (HRTT versus CT+CC = 1.99; 95% CI = 1.33-2.97; P = 7.8E-04). Rs2294008T was a cis-expression quantitative trait loci for PSCA, upregulating mRNA in normal gastric (ß = 0.60; P = 5.7E-21) and GC (ß = 0.30; P = 0.0089) tissues. Cases in the highest quartile (the smallest downregulation of tumor PSCA) had shortest survival than cases with the most downregulated PSCA (median survival of 0.47 years in the highest quartile versus 3.73 years in the lowest quartile; hazard ratio = 9.70; 95% CI = 2.46-38.4; P = 0.0012). Less striking effects for mRNA levels were observed for MTX1 at 1q22 in gastric cardia adenocarcinoma and for JRK at 8q24.3 in diffuse GC. Our results suggest three high-evidence GC risk loci have prognostic importance in GC subtypes. Future studies in well-characterized independent populations are warranted to validate our findings and further investigate the clinical utility of these variants in predicting GC prognosis.


Assuntos
Expressão Gênica/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/genética , Adenocarcinoma/etiologia , Adenocarcinoma/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Regulação para Baixo/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/genética , Fatores de Risco , Regulação para Cima/genética
18.
J Invest Dermatol ; 137(12): 2606-2612, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28830827

RESUMO

Germline mutations in CDKN2A are frequently identified among melanoma kindreds and are associated with increased atypical nevus counts. However, a clear relationship between pathogenic CDKN2A mutation carriage and other nevus phenotypes including counts of common acquired nevi has not yet been established. Using data from GenoMEL, we investigated the relationships between CDKN2A mutation carriage and 2-mm, 5-mm, and atypical nevus counts among blood-related members of melanoma families. Compared with individuals without a pathogenic mutation, those who carried one had an overall higher prevalence of atypical (odds ratio = 1.64; 95% confidence interval = 1.18-2.28) nevi but not 2-mm nevi (odds ratio = 1.06; 95% confidence interval = 0.92-1.21) or 5-mm nevi (odds ratio = 1.26; 95% confidence interval = 0.94-1.70). Stratification by case status showed more pronounced positive associations among non-case family members, who were nearly three times (odds ratio = 2.91; 95% confidence interval = 1.75-4.82) as likely to exhibit nevus counts at or above the median in all three nevus categories simultaneously when harboring a pathogenic mutation (vs. not harboring one). Our results support the hypothesis that unidentified nevogenic genes are co-inherited with CDKN2A and may influence carcinogenesis.


Assuntos
Inibidor de Quinase Dependente de Ciclina p18/genética , Mutação em Linhagem Germinativa , Melanoma/genética , Nevo/genética , Neoplasias Cutâneas/genética , Análise Mutacional de DNA , Saúde da Família , Feminino , Genótipo , Humanos , Masculino , Nevo Pigmentado/genética , Razão de Chances , Fenótipo , Sistema de Registros
19.
Artigo em Inglês | MEDLINE | ID: mdl-28730144

RESUMO

Helicobacter pylori (Hp) is the primary cause of gastric cancer but we know little of its relative abundance and other microbes in the stomach, especially at the time of gastric cancer diagnosis. Here we characterized the taxonomic and derived functional profiles of gastric microbiota in two different sets of gastric cancer patients, and compared them with microbial profiles in other body sites. Paired non-malignant and tumor tissues were sampled from 160 gastric cancer patients with 80 from China and 80 from Mexico. The 16S rRNA gene V3-V4 region was sequenced using MiSeq platform for taxonomic profiles. PICRUSt was used to predict functional profiles. Human Microbiome Project was used for comparison. We showed that Hp is the most abundant member of gastric microbiota in both Chinese and Mexican samples (51 and 24%, respectively), followed by oral-associated bacteria. Taxonomic (phylum-level) profiles of stomach microbiota resembled oral microbiota, especially when the Helicobacter reads were removed. The functional profiles of stomach microbiota, however, were distinct from those found in other body sites and had higher inter-subject dissimilarity. Gastric microbiota composition did not differ by Hp colonization status or stomach anatomic sites, but did differ between paired non-malignant and tumor tissues in either Chinese or Mexican samples. Our study showed that Hp is the dominant member of the non-malignant gastric tissue microbiota in many gastric cancer patients. Our results provide insights on the gastric microbiota composition and function in gastric cancer patients, which may have important clinical implications.


Assuntos
Bactérias/isolamento & purificação , Microbioma Gastrointestinal , Neoplasias Gástricas/microbiologia , Estômago/microbiologia , Adulto , Idoso , Bactérias/classificação , Bactérias/genética , China , Feminino , Helicobacter pylori/classificação , Helicobacter pylori/genética , Helicobacter pylori/isolamento & purificação , Humanos , Masculino , México , Pessoa de Meia-Idade , Adulto Jovem
20.
Sci Rep ; 7(1): 4642, 2017 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-28680059

RESUMO

Based on our initial genome-wide association study (GWAS) on esophageal squamous cell carcinoma (ESCC) in Han Chinese, we conducted a follow-up study to examine the single nucleotide polymorphisms (SNPs) associated with family history (FH) of upper gastrointestinal cancer (UGI) cancer in cases with ESCC. We evaluated the association between SNPs and FH of UGI cancer among ESCC cases in a stage-1 case-only analysis of the National Cancer Institute (NCI, 541 cases with FH and 1399 without FH) and Henan GWAS (493 cases with FH and 869 without FH) data (discovery phase). The top SNPs (or their surrogates) from discovery were advanced to a stage-2 evaluation in additional Henan subjects (2801 cases with FH and 3136 without FH, replication phase). A total of 19 SNPs were associated with FH of UGI cancer in ESCC cases with P < 10-5 in the stage-1 meta-analysis of NCI and Henan GWAS data. In stage-2, the association for rs79747906 (located at 18p11.31, P = 5.79 × 10-6 in discovery) was replicated (P = 0.006), with a pooled-OR of 1.59 (95%CI: 1.11-2.28). We identified potential genetic variants associated with FH of UGI cancer. Our findings may provide important insights into new low-penetrance susceptibility regions involved in the susceptibility of families with multiple UGI cancer cases.

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