MC1R Variation in a New Mexico Population.

BACKGROUND: The Melanocortin 1 Receptor (MC1R) contributes to pigmentation, an important risk factor for developing melanoma. Evaluating SNPs in MC1R and association with race/ethnicity, skin type, and perceived cancer risk in a New Mexico (NM) population will elucidate the role of MC1R in a multicultural population. METHODS: We genotyped MC1R in 191 NMs attending a primary care clinic in Albuquerque. We obtained individuals' self-identified race/ethnicity, skin type, and perceived cancer risk. We defined genetic risk as carriage of any one or more of the nine most common SNPs in MC1R. RESULTS: We found that one MC1R SNP, R163Q (rs885479), was identified in 47.6% of self-identified Hispanics and 12.9% of non-Hispanic whites (NHW), making Hispanics at higher "genetic risk" (as defined by carrying one of the MC1R common variants). When we deleted R163Q from analyses, Hispanics were no longer at higher genetic risk (33.3%) compared with NHW (48.3%), consistent with melanoma rates, tanning ability, and lower perceived risk. Hispanics had a perceived risk significantly lower than NHW and a nonsignificant better tanning ability than NHW. CONCLUSIONS: The R163Q variant in MC1R may not be a risk factor for melanoma among NM Hispanics. This suggestion points to the need to carefully interpret genetic risk factors among specific populations. IMPACT: Genetic risk cannot be extrapolated from Northern European populations directly to non-European populations.

Talking About Hepatitis C: FAQs From Young Adults Who Inject Drugs.

INTRODUCTION: Young adults who inject drugs and live in rural communities are at high risk for hepatitis C virus (HCV) infection. Recent changes in HCV treatment must be communicated within these communities to improve access to care and reduce HCV transmission. METHODS: Field workers in the ¡VÁLE! Hepatitis Treatment and Integrated Prevention Services study identified frequently asked questions (FAQs) posed by young-adult participants at high risk for HCV during screening and educational sessions. From 2016 to 2018, 183 young adults (44.3% women; 85.8% Latino/a) younger than 30 years who inject drugs and reside in Rio Arriba or Doña Ana counties in New Mexico were enrolled. The research team compiled deidentified questions during field enrollments. RESULTS: FAQs were reviewed and categorized into four major domains, including risk/prevention, screening, treatment, and reinfection. FAQs were addressed by a team of medical and public health professionals, using the most current research and recommendations. CONCLUSIONS: These FAQs address important gaps in HCV knowledge among young adults who are at high risk for infection. The FAQs also highlight the importance of risk reduction counseling provided by frontline public health providers as well as access to safe and effective HCV treatments for young adults who inject drugs.

Application of mutagen sensitivity assay in a glioma case-control study.

Few risk factors for glioma have been identified other than ionizing radiation. The alkylating agent acrylamide is a compound found in both occupational and the general environment and identified as one of the forty known or suspected neurocarcinogens in animal models. The mutagen sensitivity assay (MSA) has been used to indirectly show reduced DNA repair capacity upon exposure to ionizing radiation in those with glioma compared to controls. In this study, MSA was used to assess its applicability to a glioma case-control study and to test the hypothesis that subjects with glioma may have lower DNA repair capacity after exposure to selected potential human neurocarcinogens (i.e. acrylamide), compared to controls. Approximately 50 case and 50 control subjects were identified from a clinic-based study that investigated environmental risk factors for glioma, who completed an exposure survey, and had frozen immortalized lymphocytes available. A total of 50 metaphase spreads were read and reported for each participant. The association of case-control status with MSA for acrylamide, i.e. breaks per spread, was examined by multivariable logistic regression models. The mean number of breaks per slide was similar between hospital-based controls and cases. In addition, case-control status or exposure categories were not associated with the number of breaks per spread. Although the MSA has been shown as a useful molecular epidemiology tool for identifying individuals at higher risk for cancer, our data do not support the hypothesis that glioma patients have reduced DNA repair capacity in response to exposure to acrylamide. Further research is needed before the MSA is utilized in large-scale epidemiological investigations of alkylating agents.

Translation and adaptation of skin cancer genomic risk education materials for implementation in primary care.

Genomic medicine has revolutionized disease risk identification and subsequent risk reduction interventions. Skin cancer risk genomic feedback is a promising vehicle to raise awareness and protective behaviors in the general population, including Hispanics who are largely unaware of their risks. Yet, personalized genomics currently has limited reach. This study is the initial phase of a randomized controlled trial investigating the personal utility and reach of genomic testing and feedback for melanoma. Semi-structured cognitive interviews (N = 28), stratified across education level, were conducted to assess the comprehension and acceptability of translated skin cancer genomic risk education materials with Spanish-speaking Hispanic primary care patients. Overall, materials were comprehensible and acceptable with 33 of 246 terms/concepts identified as difficult. Common problems included translation challenges (e.g., peeling from sunburn), ambiguous concepts (e.g., healthcare system), and problematic terms (e.g., risk version). Aiming to expand the reach of genomic medicine across subpopulations that may benefit from it, necessary modifications were made to education materials to improve comprehensibility, acceptability, and cultural relevance.

Variants in autophagy-related genes and clinical characteristics in melanoma: a population-based study.

Autophagy has been linked with melanoma risk and survival, but no polymorphisms in autophagy-related (ATG) genes have been investigated in relation to melanoma progression. We examined five single-nucleotide polymorphisms (SNPs) in three ATG genes (ATG5; ATG10; and ATG16L) with known or suspected impact on autophagic flux in an international population-based case-control study of melanoma. DNA from 911 melanoma patients was genotyped. An association was identified between (GG) (rs2241880) and earlier stage at diagnosis (OR 0.47; 95% Confidence Intervals (CI) = 0.27-0.81, P = 0.02) and a decrease in Breslow thickness (P = 0.03). The ATG16L heterozygous genotype (AG) (rs2241880) was associated with younger age at diagnosis (P = 0.02). Two SNPs in ATG5 were found to be associated with increased stage (rs2245214 CG, OR 1.47; 95% CI = 1.11-1.94, P = 0.03; rs510432 CC, OR 1.84; 95% CI = 1.12-3.02, P = 0.05). Finally, we identified inverse associations between ATG5 (GG rs2245214) and melanomas on the scalp or neck (OR 0.20, 95% CI = 0.05-0.86, P = 0.03); ATG10 (CC) (rs1864182) and brisk tumor infiltrating lymphocytes (TILs) (OR 0.42; 95% CI = 0.21-0.88, P = 0.02), and ATG5 (CC) (rs510432) with nonbrisk TILs (OR 0.55; 95% CI = 0.34-0.87, P = 0.01). Our data suggest that ATG SNPs might be differentially associated with specific host and tumor characteristics including age at diagnosis, TILs, and stage. These associations may be critical to understanding the role of autophagy in cancer, and further investigation will help characterize the contribution of these variants to melanoma progression.

Inherited variation at MC1R and ASIP and association with melanoma-specific survival.

Melanocortin-1 receptor (MC1R) is a marker of melanoma risk in populations of European ancestry. However, MC1R effects on survival are much less studied. We investigated associations between variation at MC1R and survival in an international, population-based series of single primary melanoma patients enrolled into the Genes, Environment, and Melanoma study. MC1R genotype data was available for 2,200 participants with a first incident primary melanoma diagnosis. We estimated the association of MC1R genotypes with melanoma-specific survival (i.e., death caused by melanoma) and overall survival using COX proportional hazards modeling, adjusting for established prognostic factors for melanoma. We also conducted stratified analyses by Breslow thickness, tumor site, phenotypic index, and age. In addition, we evaluated haplotypes involving polymorphisms near the Agouti signaling protein gene (ASIP) locus for their impacts on survival. Melanoma-specific survival was inversely associated with carriage of MC1R variants in the absence of consensus alleles compared to carriage of at least one consensus allele (hazard ratio (HR) = 0.60; 95% confidence interval (CI): 0.40, 0.90). MC1R results for overall survival were consistent with no association. We did not observe any statistical evidence of heterogeneity of effect estimates in stratified analyses. We observed increased hazard of melanoma-specific death among carriers of the risk haplotype TG near the ASIP locus (HR = 1.37; 95% CI: 0.91, 2.04) when compared to carriers of the most common GG haplotype. Similar results were noted for overall survival. Upon examining the ASIP TG/TG diplotype, we observed considerably increased hazard of melanoma-specific death (HR = 5.11; 95% CI: 1.88, 13.88) compared to carriers of the most common GG/GG diplotype. Our data suggest improved melanoma-specific survival among carriers of two inherited MC1R variants.

Cytokines and tumor metastasis gene variants in oral cancer and precancer in Puerto Rico.

OBJECTIVES: A cross-sectional epidemiological study explored genetic susceptibility to oral precancer and cancer in Puerto Rico (PR). MATERIALS AND METHODS: Three hundred three individuals with a benign oral condition, oral precancer (oral epithelial hyperplasia/hyperkeratosis, oral epithelial dysplasia), or oral squamous cell carcinoma (SCCA) were identified via PR pathology laboratories. A standardized, structured questionnaire obtained information on epidemiological variables; buccal cells were collected for genetic analysis. Genotyping was performed using Taqman® assays. Allelic frequencies of single nucleotide polymorphisms (SNPs) were evaluated in cytokine genes and genes influencing tumor metastasis. Risk estimates for a diagnosis of oral precancer or SCCA while having a variant allele were generated using logistic regression. Adjusted models controlled for age, gender, ancestry, education, smoking and alcohol consumption. RESULTS: Relative to persons with a benign oral lesion, individuals with homozygous recessive allelic variants of tumor necrosis factor (TNF-α) -238 A/G SNP had a reduced odds of having an oral precancer (ORadjusted = 0.15; 95% CI 0.03-0.70). The transforming growth factor beta-1 (TGFß-1 -509 C/T) polymorphism was inversely associated with having an oral SCCA among persons homozygous for the recessive variant (ORcrude = 0.27; 95% CI 0.09-0.79). The matrix metalloproteinase gene (MMP-1) variant, rs5854, was associated with oral SCCA; participants with even one variant allele were more likely to have oral SCCA (ORadjusted = 2.62, 95% CI 1.05-6.53) compared to people with ancestral alleles. CONCLUSION: Our exploratory analyses suggest that genetic alterations in immune system genes and genes with metastatic potential are associated with oral precancer and SCCA risk in PR.

A pilot study of genetic variants in dopamine regulators with indoor tanning and melanoma.

Many people frequently tan indoors despite being aware of the increased risk of melanoma. Ultraviolet radiation is hypothesized to modify biological reward pathways, for example, through the dopamine neurotransmitter system, to reinforce tanning behaviour. In this pilot study, we relied on questionnaire and DNA data from a recently completed case-control study to examine 67 single-nucleotide polymorphisms (SNPs) and related haplotypes in five dopamine receptor and drug metabolism genes in relation to indoor tanning among controls. We also examined the association between individual SNPS and likelihood of melanoma, adjusting for or stratifying on indoor tanning status. In candidate and haplotype gene analyses, variants only in the DRD2 dopamine receptor and ANKK1 signalling genes were positively associated with indoor tanning use among controls; only associations for ANKK1 remained statistically significant (P < 0.05) after adjustment. Several SNPs in ANKK1 and DRD2 associated with indoor tanning among controls were also found to be associated with increased risk of melanoma. Upon stratifying for indoor tanning status, one ANKK1 SNP was positively associated with melanoma among non-tanners, while three DRD2 SNPS were positively associated with melanoma among tanners or non-tanners, depending on the SNP. These alleles represent important genomic regions to further explore addictive tanning behaviour.

DNA repair variants, indoor tanning, and risk of melanoma.

Although ultraviolet radiation (UV) exposure from indoor tanning has been linked to an increased risk of melanoma, the role of DNA repair genes in this process is unknown. We evaluated the association of 92 single nucleotide polymorphisms (SNPs) in 20 DNA repair genes with the risk of melanoma and indoor tanning among 929 patients with melanoma and 817 controls from the Minnesota Skin Health Study. Significant associations with melanoma risk were identified for SNPs in ERCC4, ERCC6, RFC1, XPC, MGMT, and FBRSL1 genes; with a cutoff of P < 0.05. ERCC6 and FBRSL1 gene variants and haplotypes interacted with indoor tanning. However, none of the 92 SNPs tested met the correction criteria for multiple comparisons. This study, based on an a priori interest in investigating the role of DNA repair capacity using variants in base excision and nucleotide excision repair, identified several genes that may play a role in resolving UV-induced DNA damage.

Self-reported ethnicity and genetic ancestry in relation to oral cancer and pre-cancer in Puerto Rico.

BACKGROUND: Hispanics are known to be an extremely diverse and genetically admixed ethnic group. The lack of methodologies to control for ethnicity and the unknown admixture in complex study populations of Hispanics has left a gap in understanding certain cancer disparity issues. Incidence rates for oral and pharyngeal cancer (OPC) in Puerto Rico are among the highest in the Western Hemisphere. We conducted an epidemiological study to examine risk and protective factors, in addition to possible genetic susceptibility components, for oral cancer and precancer in Puerto Rico. METHODOLOGY/PRINCIPAL FINDINGS: We recruited 310 Puerto Rico residents who had been diagnosed with either an incident oral squamous cell carcinoma, oral precancer, or benign oral condition. Participants completed an in-person interview and contributed buccal cells for DNA extraction. ABI Biosystem Taqman™ primer sets were used for genotyping 12 ancestry informative markers (AIMs). Ancestral group estimates were generated using maximum likelihood estimation software (LEADMIX), and additional principal component analysis was carried out to detect population substructures. We used unconditional logistic regression to assess the contribution of ancestry to the risk of being diagnosed with either an oral cancer or precancer while controlling for other potential confounders. The maximum likelihood estimates showed that study participants had a group average ancestry contribution of 69.9% European, 24.5% African, and 5.7% detectable Native American. The African and Indigenous American group estimates were significantly higher than anticipated. Neither self-identified ethnicity nor ancestry markers showed any significant associations with oral cancer/precancer risk in our study. CONCLUSIONS/SIGNIFICANCE: The application of ancestry informative markers (AIMs), specifically designed for Hispanics, suggests no hidden population substructure is present based on our sampling and provides a viable approach for the evaluation and control of ancestry in future studies involving Hispanic populations.

Identification and characterization of novel SNPs in CHEK2 in Ashkenazi Jewish men with prostate cancer.

Checkpoint kinase 2 (CHEK2) is a protein involved in arresting cell cycle in response to DNA damage. To investigate whether it plays an important role in the development of prostate cancer (PRCA) in the Ashkenazi Jewish (AJ) population, we sequenced CHEK2 in 75 AJ individuals with prostate, breast, or no cancer (n=25 each). We identified seven coding SNPs (five are novel) that changed the amino-acid sequence, resulting in R3W, E394F, Y424H, S428F, D438Y, P509S, and P509L. We determined the frequency of each variant in 76 AJ families collected by members of the International Consortium for Prostate Cancer Genetics (ICPCG) where >or=2 men were affected by PRCA. Only one variant, Y424H in exon 11, was identified in more than two families. Exon 11 was then screened in nine additional AJ ICPCG families (a total of 85 families). The Y424H variant occurred in nine affected cases from four different families; however, it did not completely segregate with the disease. We performed bioinformatics analysis, which showed that Y424H is a non-conservative missense substitution that falls at a position that is invariant in vertebrate CHEK2 orthologs. Both SIFT and Align-GVGD predict that Y424H is a loss of function mutation. However, the frequency of Y424H was not significantly different between unselected AJ cases from Montreal/Memorial Sloan Kettering Cancer Centre (MSKCC) and AJ controls from Israel/MSKCC (OR 1.18, 95%CI: 0.34-4.61, p=.99). Moreover, functional assays using Saccharomyces cerevisiae revealed that the Y424H substitution did not alter function of CHEK2 protein. Although we cannot rule out a subtle influence of the CHEK2 variants on PRCA risk, these results suggest that germline CHEK2 mutations have a minor role in, if any, PRCA susceptibility in AJ men.

Fine-mapping the putative chromosome 17q21-22 prostate cancer susceptibility gene to a 10 cM region based on linkage analysis.

Prostate cancer linkage studies have suggested the existence of a prostate cancer susceptibility gene on chromosome 17q21-22. We now report the results of an extended linkage analysis including 95 new multiplex prostate cancer families and 9 additional microsatellite markers resulting in a maximum LOD score of 2.99 at approximately 81-82 cM for all 453 pedigrees. Results from these 95 new pedigrees provide additional support for a chromosome 17q21-22 prostate cancer susceptibility gene. Inclusion of the 9 additional markers significantly reduced the size of the candidate region, as defined using a 1-LOD support interval, especially when focusing analyses on subsets of pedigrees with four or more confirmed affecteds or average age of diagnosis less than or equal to 65 years. A novel subset analysis of only those families (n = 147) that had four or more prostate cancer cases and an average age of prostate cancer diagnosis < or = 65 years results in a maximum LOD score of 5.49 at 78 cM with a 1-LOD support interval of 10 cM. This large set of pedigrees with four more prostate cancer cases characterized by early-onset disease will serve as a useful resource for identifying the putative 17q21-22 prostate cancer susceptibility gene.

Role of the Nijmegen breakage syndrome 1 gene in familial and sporadic prostate cancer.

The Nijmegen breakage syndrome 1 (NBS1) gene, which participates in DNA double strand break repair, has been postulated to be a susceptibility factor for a number of cancers, including prostate cancer. Numerous mutations have been identified in NBS1, including the founder mutation 657del5. In this study, a number of analyses were done to determine whether mutations in NBS1 are associated with an increased risk for prostate cancer. The frequency of the 657del5 mutation in both familial prostate cancer cases (1,819 affected men among 909 families) and sporadic prostate cancer cases (1,218 affected men) collected from five centers participating in the International Consortium for Prostate Cancer Genetics were compared with that found in 697 normal controls. Seven individuals were identified to carry the mutation among the 3,037 cases screened: four in the familial group (three from one family and one from another) and three in the sporadic cases. The carrier frequency was 0.22% (2 of 909) for the probands and 0.25% (3 of 1,218) for the sporadic cases of prostate cancer. The 657del5 mutation was not detected in either the 293 unaffected members of the prostate cancer families or in the 697 control samples tested. The entire NBS1 gene was also sequenced in 20 of the youngest affected individuals from the Finnish group of familial cases to identify the presence of possible mutations in this high-risk group. One rare (D95N) and one common (E185Q) missense alteration was identified. More detailed analyses of the E185Q polymorphism, along with a third rare variant (R215W), failed to show an association with prostate cancer. Because the 657del5 mutation was absent from the control population, we are unable to determine if this alteration predisposes to prostate cancer. However, our data does suggest that mutations within NBS1, and in particular, 657del5, do not significantly contribute to the overall prostate cancer burden within our patient samples.

APC I1307K and the risk of prostate cancer.

The kin-cohort design has been proposed as an alternative to traditional case-control and cohort measures to evaluate inherited susceptibility to cancer in population-based studies. Here, we used this design to evaluate inherited susceptibility to prostate cancer associated with APC I1307K using data from the Molecular Epidemiology of Colorectal Cancer study. Two techniques were used to compare the incidence of prostate cancer in APC I1307K carriers. First, we compared the incidence of prostate cancer in relatives of mutation carriers and noncarriers using standard techniques for survival analysis. Second, we used the marginal maximum likelihood method for kin-cohort analysis to infer the genotypes in the relatives. We also evaluated APC I1307K in 75 Ashkenazi Jewish individuals with prostate cancer from 27 families enrolled in the University of Michigan Prostate Cancer Genetic Study. We observed a slightly increased risk of prostate cancer in relatives of APC I1307K carriers, however, this difference was not statistically significant (hazard ratio, 1.6; 95% confidence intervals, 0.7-3.4). Similar conclusions were drawn using both techniques for kin-cohort analysis. APC I1307K was found in 7.4% of families genotyped, which is slightly higher than the allele prevalence reported in Ashkenazi Jews in the general population. In addition, we did not observe loss of heterozygosity at APC or a somatic mutation near APC I1307K using microdissected tumor DNA from mutation carriers enrolled in the Prostate Cancer Genetic Study. Overall, the evidence for an association between APC I1307K and prostate cancer is not compelling. APC I1307K is unlikely to play a clinically meaningful role in susceptibility to prostate cancer.

Truncating BRCA1 mutations are uncommon in a cohort of hereditary prostate cancer families with evidence of linkage to 17q markers.

PURPOSE: A genome-wide scan of 175 hereditary prostate cancer families from the University of Michigan Prostate Cancer Genetics Project provided evidence of prostate cancer linkage to 17q markers near the BRCA1 gene. To examine the possibility that germ-line BRCA1 mutations were associated with hereditary prostate cancer, individuals from 93 families with evidence of linkage to chromosome 17q were screened for germ-line BRCA1 mutations. EXPERIMENTAL DESIGN: One individual from each of the 93 families, the majority with three or more cases of prostate cancer, were screened for BRCA1 mutations with denaturing high-performance liquid chromatography (HPLC). Fragments exhibiting denaturing HPLC variant patterns were additionally analyzed by direct sequencing. RESULTS: Sixty-five of the individuals selected for sequencing from 65 unrelated families were determined to have wild-type BRCA1 sequence by denaturing HPLC. One individual from a family with both prostate and ovarian cancer was found to have a truncating BRCA1 mutation (3829delT). An additional 27 germ-line variants were identified, including 15 missense variants. CONCLUSIONS: These sequencing results suggest that BRCA1 truncating mutations do not account for the linkage evidence on chromosome 17 observed in University of Michigan Prostate Cancer Genetics Project families. A recently completed combined genome scan has also detected linkage to 17q22, and studies are ongoing to identify the relevant prostate cancer susceptibility gene in this region.