Distinctive lower incidence rates of cutaneous melanoma on the hips and lower extremities of men.

BACKGROUND: Cutaneous melanomas (CMs) are more frequently found on the trunk in men, and on the hip and lower extremities (legs) in women. This discrepancy has been attributed to greater exposure to ultraviolet (UV) radiation of women's legs due to their dressing habits. OBJECTIVES: To understand the sex difference in the bodily distribution of CMs, especially those on the legs. METHODS: This was a cancer registry-based cohort study. CM incidences, relative tumour density and tumour mutational burdens (TMBs) were compared among different body sites in different sex and racial groups using the SEER (Surveillance, Epidemiology, and End Results) and TCGA SKCM (The Cancer Genome Atlas skin cutaneous melanoma) databases. RESULTS: White men had lower rates and lower relative tumour density (RTD) of CMs on their legs compared with the rest of their body sites, or compared with White women. Men classified by SEER into racial groups other than White did not show such a trend. White women had comparable RTDs among different body sites. The ratios between the 'White' and the 'other' groups were used to evaluate the approximate effect of sun exposure at different body sites, which further validated a distinct protective effect of men's legs in melanoma. TMB on leg melanomas was lower than on other sites in both sexes. CONCLUSIONS: The legs of both sexes in White patients show lower RTDs and lower levels of TMB, suggesting a weaker association with UV exposure. Furthermore, White men are especially protected against CM on their legs, suggesting an unknown intrinsic protective factor as compared with women.

Pediatric melanoma in the Hispanic population: An analysis of institutional and national data.

BACKGROUND/OBJECTIVES: Pediatric melanoma is rare and remains poorly characterized, especially in racial/ethnic minorities of whom Hispanics are the largest and fastest growing in the United States. The health care burden of melanoma in Hispanics, who often present with more advanced disease, is rising and has even been called an early epidemic in California. We sought to document key clinicopathologic features of melanoma in Hispanic pediatric patients and to compare these parameters to pediatric non-Hispanic whites (NHWs) under the a priori hypothesis that Spitzoid melanomas occur in greater proportions in Hispanics. METHODS: Single-institution cross-sectional study of pediatric melanoma cases (age < 20 years) with Hispanic stratification and comparison with matched Surveillance, Epidemiology, and End Results (SEER) data from the same time frame (1988-2016). RESULTS: Of our 61 institutional cases of pediatric melanoma, Hispanics (11), compared with NHWs (40), presented significantly younger (11.7 years, 95% CI: 2.77-8.00 years; P = .001), with lower limb predominance (46%; P < .05), mostly Spitzoid melanomas (82%; P < .05), and thicker tumors (2.34 mm, CI: 0.26-2.19 mm; P < .05). Similarly, SEER data (2499 cases) showed greater proportions of childhood/pre-pubertal adolescent melanomas (<15 years), lower limb involvement, Spitzoid subtype (36.5% vs 22.5% in NHWs; P = .001), and advanced (regional/distant) disease stages in Hispanics (212) compared with NHWs (2197). CONCLUSIONS: Pediatric melanomas may present differently in Hispanics, and heightened awareness/lower threshold to biopsy high-risk Spitzoid tumors on the lower limb may be warranted. Further investigations are needed to aid prevention and early detection in a vulnerable minority population less likely to seek outpatient dermatology specialty care.

Age-dependent interaction between sex and geographic ultraviolet index in melanoma risk.

BACKGROUND: Ultraviolet (UV) exposure may not affect melanoma development equally in different sexes and ages. Whether and how these factors interact with each other in relation to melanoma risk is unknown. OBJECTIVE: This study attempts to estimate interactions among UV index (UVI), sex, and age in melanoma risk. METHODS: Melanoma incidence data were collected from 42 cancer registries. Geographic UVI was collected from local satellite stations. Negative binomial regression models were used to estimate the impact of each risk factor and their interactions. RESULTS: Sex, UVI, and age, as well as interactions between any 2 of these factors, were significantly associated with melanoma risk. In younger age groups, female sex is an independent risk factor for melanoma that is not affected by ambient UV exposure. In older age groups, however, female sex interacts with UV exposure as a risk factor, exhibiting a protective effect. The switching age category is 45 to 49, which correlates with dramatic hormonal changes. LIMITATIONS: The interaction between sex and UVI is measured at an ecologic level. CONCLUSIONS: The interaction between sex and UVI is age dependent. Female sex is an independent risk factor for early-onset melanoma, but female sex also protects against UV-associated melanoma in older age groups.

A Possible Link of Genetic Variations in ER/IGF1R Pathway and Risk of Melanoma.

The mechanism of gender disparity in cutaneous melanoma incidence remains unclear. Steroid hormones including estrogens have long been implicated in the course of melanoma, but the conclusion is controversial. Estrogen receptors (ERs) and insulin-like growth factor 1 receptor (IGF1R) show extensive crosstalk in cancer development, but how the ER/IGF1R network impacts melanoma is currently unclear. Here we studied the melanoma associations of selected SNPs from the ER/IGF1R network. Part of the International Genes, Environment, and Melanoma (GEM) cohort was used as a discovery set, and the Gene Environment Association Studies Initiative (GENEVA) dataset served as a validation set. Based on the associations with other malignant disease conditions, thirteen single nucleotide polymorphism (SNP) variants in ESR1, ESR2, IGF1, and IGF1R were selected for candidate gene association analyses. The rs1520220 in IGF1 and rs2229765 in IGF1R variants were significantly associated with melanoma risk in the GEM dataset after Benjamini-Hochberg multiple comparison correction, although they were not validated in the GENEVA set. The discrepancy may be caused by the multiple melanoma characteristics in the GEM patients. Further analysis of gender disparity was carried out for IGF1 and IGF1R SNPs in the GEM dataset. The GG phenotype in IGF1 rs1520220 (recessive model) presented an increased risk of melanoma (OR = 8.11, 95% CI: 2.20, 52.5, p = 0.006) in men but a significant opposite effect in women (OR = 0.15, 95% CI: 0.018, 0.86, p = 0.045). The AA genotype in IGF1R rs2229765 (recessive model) showed a significant protective effect in men (OR = 0.24, 95% CI: 0.07, 0.64, p = 0.008) and no effect in women. Results from the current study are warranted for further validation.

Oxidative stress and antioxidants in the pathophysiology of malignant melanoma.

The high number of somatic mutations in the melanoma genome associated with cumulative ultra violet (UV) exposure has rendered it one of the most difficult of cancers to treat. With new treatment approaches based on targeted and immune therapies, drug resistance has appeared as a consistent problem. Redox biology, including reactive oxygen and nitrogen species (ROS and RNS), plays a central role in all aspects of melanoma pathophysiology, from initiation to progression and to metastatic cells. The involvement of melanin production and UV radiation in ROS/RNS generation has rendered the melanocytic lineage a unique system for studying redox biology. Overall, an elevated oxidative status has been associated with melanoma, thus much effort has been expended to prevent or treat melanoma using antioxidants which are expected to counteract oxidative stress. The consequence of this redox-rebalance seems to be two-fold: on the one hand, cells may behave less aggressively or even undergo apoptosis; on the other hand, cells may survive better after being disseminated into the circulating system or after drug treatment, thus resulting in metastasis promotion or further drug resistance. In this review we summarize the current understanding of redox signaling in melanoma at cellular and systemic levels and discuss the experimental and potential clinic use of antioxidants and new epigenetic redox modifiers.

A cancer registry-based analysis on the non-white populations reveals a critical role of the female sex in early-onset melanoma.

PURPOSE: Most melanoma studies have been performed in the white population who exhibits the highest incidence rate due to their skin sensitivity to UV radiation. Previous publications have shown that young women (approximately under the menopausal age) exhibit higher incidence rates than men of the same age, and the causes are mostly attributed to their sun behavior or indoor tanning. In our recent publications, we suggested that higher risk in younger women was due to pathophysiological factors, such as hormonal impact, and thus this higher risk in young women should be shared across ethnicities regardless of their skin color or UV behavior. METHODS: A total of 13,208 non-white melanoma patients from SEER and 15,226 from WHO CI5-Plus were extracted for analysis. Age-specific incidence rates, female-to-male incidence rate ratios, and p values were calculated. RESULTS: As observed in the white population, younger women and older men showed higher melanoma incidence rates than their peers of the other gender in all ethnic groups. The highest female-to-male incidence rate ratios were observed in the pubescent and reproductive ages. Previously this gender discrepancy in the white population was attributed to the preference of skin tanning in young females. There is no evidence to show that darker-skinned young females adopt a similar tanning preference. Thus the age-dependent gender difference in the risk of melanoma is shared across ethnic groups and is perhaps independent of UV behavior. CONCLUSIONS: Our results highlight the importance of gender as one of the melanoma risk factors beyond traditional UV radiation, which warrants further investigation and may provide a base for an improved prevention strategy.

A Case-Control Study of the Genetic Variability in Reactive Oxygen Species-Metabolizing Enzymes in Melanoma Risk.

Recent studies have shown that ultraviolet (UV)-induced chemiexcitation of melanin fragments leads to DNA damage; and chemiexcitation of melanin fragments requires reactive oxygen species (ROS), as ROS excite an electron in the melanin fragments. In addition, ROS also cause DNA damages on their own. We hypothesized that ROS producing and metabolizing enzymes were major contributors in UV-driven melanomas. In this case-control study of 349 participants, we genotyped 23 prioritized single nucleotide polymorphisms (SNPs) in nicotinamide adenine dinucleotide phosphate (NADPH) oxidases 1 and 4 (NOX1 and NOX4, respectively), CYBA, RAC1, superoxide dismutases (SOD1, SOD2, and SOD3) and catalase (CAT), and analyzed their associated melanoma risk. Five SNPs, namely rs1049255 (CYBA), rs4673 (CYBA), rs10951982 (RAC1), rs8031 (SOD2), and rs2536512 (SOD3), exhibited significant genotypic frequency differences between melanoma cases and healthy controls. In simple logistic regression, RAC1 rs10951982 (odds ratio (OR) 8.98, 95% confidence interval (CI): 5.08 to 16.44; p < 0.001) reached universal significance (p = 0.002) and the minor alleles were associated with increased risk of melanoma. In contrast, minor alleles in SOD2 rs8031 (OR 0.16, 95% CI: 0.06 to 0.39; p < 0.001) and SOD3 rs2536512 (OR 0.08, 95% CI: 0.01 to 0.31; p = 0.001) were associated with reduced risk of melanoma. In multivariate logistic regression, RAC1 rs10951982 (OR 6.15, 95% CI: 2.98 to 13.41; p < 0.001) remained significantly associated with increased risk of melanoma. Our results highlighted the importance of RAC1, SOD2, and SOD3 variants in the risk of melanoma.

Sex differences in the association of cutaneous melanoma incidence rates and geographic ultraviolet light exposure.

BACKGROUND: Cutaneous melanoma (CM) incidence rates continue to increase, and the reasons are unknown. Previously, we reported a unique age-specific sex difference in melanoma that suggested additional causes other than solar ultraviolet (UV) radiation. OBJECTIVE: This study attempted to understand whether and how UV radiation differentially impacts the CM incidence in men and women. METHODS: CM data and daily UV index (UVI) from 31 cancer registries were collected for association analysis. A second dataset from 42 US states was used for validation. RESULTS: There was no association between log-transformed female CM rates and levels of UVI, but there was a significant association between male rates and UVI and a significant association between overall rates and UVI. The 5-year age-specific rate-UVI association levels (represented by Pearson's coefficient ρ) increased with age in men, but age-specific ρ levels remained low and unchanged in women. The significant rate-UVI association in men and nonassociation in women was validated in a population of white residents of the United States. LIMITATIONS: Confounders, including temperature and latitude, are difficult to separate from UVI. CONCLUSIONS: Ambient UVI appears to be associated with melanoma incidence in males but not in females.

UV-Induced Molecular Signaling Differences in Melanoma and Non-melanoma Skin Cancer.

There are three major types of skin cancer: melanoma, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BCC and SCC are often referred to as non-melanoma skin cancer (NMSC). NMSCs are relatively non-lethal and curable by surgery, hence are not reportable in most cancer registries all over the world. Melanoma is the deadliest skin cancer. Its incidence rate (case number) is about 1/10th of that for NMSC, yet its death toll is ~8 fold higher than NMSC.Melanomas arise from melanocytes which are normally located on the basement membrane with dendrites extending into the epidermal keratinocytes. A major known function of melanocytes is to produce pigments which are enclosed by lipid membrane (termed melanosomes) and distribute them into keratinocytes, thus give different shade of skin colors. BCCs arise from basal cells, which are a layer of cells located at the deepest part of epidermis. Basal cells are recently considered to be skin stem cells as they are constantly proliferating and generating keratinocytes which are continuously pushed to the surface and eventually become a dead layer of stratum corneum. Squamous cells are the keratinocytes which resembles fish scale shape, ie, those initiated from basal cells and differentiated into squamous cells. Both basal cells and squamous cells belong to keratinocytes, therefore sometimes BCC and SCC are termed keratinocyte cancer.These three types of cancer share many characteristics, yet they are very different from etiology to progression. One shared characteristic of skin cancer is that, according to the current views, they all are caused by solar or artificial ultraviolet radiation (UVR). UVA and UVB from solar UVR are the major UV bands reaching the earth surface. Both UV types cause DNA damage and immune suppression which play crucial roles in skin carcinogenesis. UVB can be directly absorbed by DNA molecules and thus causes UV-signature DNA damages; UVA, on the other hand, may function through inducing cellular ROS which then causes oxidative DNA damages [1-4]. This chapter will discuss the molecular signaling differences of UVR in melanoma and NMSC.

Amyloids, melanins and oxidative stress in melanomagenesis.

Melanoma has traditionally been viewed as an ultraviolet (UV) radiation-induced malignancy. While UV is a common inducing factor, other endogenous stresses such as metal ion accumulation or the melanin pigment itself may provide alternative pathways to melanoma progression. Eumelanosomes within melanoma often exhibit disrupted membranes and fragmented pigment which may be due to alterations in their amyloid-based striated matrix. The melanosomal amyloid can itself be toxic, especially in combination with reactive oxygen species (ROS) and reactive nitrogen species (RNS) generated by endogenous NADPH oxidase (NOX) and nitric oxide synthase (NOS) enzymes, a toxic mix that may initiate melanomagenesis. Further understanding of the loss of the melanosomal organization, the behaviour of the exposed melanin and the induction of ROS/RNS in melanomas may provide critical insights into this deadly disease.

Updates of reactive oxygen species in melanoma etiology and progression.

Reactive oxygen species (ROS) play crucial roles in all aspects of melanoma development, however, the source of ROS is not well defined. In this review we summarize recent advancement in this rapidly developing field. The cellular ROS pool in melanocytes can be derived from mitochondria, melanosomes, NADPH oxidase (NOX) family enzymes, and uncoupling of nitric oxide synthase (NOS). Current evidence suggests that Nox1, Nox4 and Nox5 are expressed in melanocytic lineage. While there is no difference in Nox1 expression levels in primary and metastatic melanoma tissues, Nox4 expression is significantly higher in a subset of metastatic melanoma tumors as compared to the primary tumors; suggesting distinct and specific signals and effects for NOX family enzymes in melanoma. Targeting these NOX enzymes using specific NOX inhibitors may be effective for a subset of certain tumors. ROS also play important roles in BRAF inhibitor induced drug resistance; hence identification and blockade of the source of this ROS may be an effective way to enhance efficacy and overcome resistance. Furthermore, ROS from different sources may interact with each other and interact with reactive nitrogen species (RNS) and drive the melanomagenesis process at all stages of disease. Further understanding ROS and RNS in melanoma etiology and progression is necessary for developing new prevention and therapeutic approaches.

Unsupervised Analysis Reveals the Involvement of Key Immune Response Genes and the Matrisome in Resistance to BRAF and MEK Inhibitors in Melanoma.

Melanoma tumors exhibit a wide range of heterogeneity in genomics even with shared mutations in the MAPK pathway, including BRAF mutations. Consistently, adaptive drug resistance to BRAF inhibitors and/or BRAF plus MEK inhibitors also exhibits a wide range of heterogeneous responses, which poses an obstacle for discovering common genes and pathways that can be used in clinic for overcoming drug resistance. This study objectively analyzed two sets of previously published tumor genomics data comparing pre-treated melanoma tumors and BRAFi- and/or MEKi-resistant tumors. Heterogeneity in response to BRAFi and BRAFi/MEKi was evident because the pre-treated tumors and resistant tumors did not exhibit a tendency of clustering together. Differentially expressed gene (DEG) analysis revealed eight genes and two related enriched signature gene sets (matrisome and matrisome-associated signature gene sets) shared by both sets of data. The matrisome was closely related to the tumor microenvironment and immune response, and five out of the eight shared genes were also related to immune response. The PLXNC1 gene links the shared gene set and the enriched signature gene sets as it presented in all analysis results. As the PLXNC1 gene was up-regulated in the resistant tumors, we validated the up-regulation of this gene in a laboratory using vemurafenib-resistant cell lines. Given its role in promoting inflammation, this study suggests that resistant tumors exhibit an inflammatory tumor microenvironment. The involvement of the matrisome and the specific set of immune genes identified in this study may provide new opportunities for developing future therapeutic methods.

Comparing maternal substance use and perinatal outcomes before and during the COVID-19 pandemic.

OBJECTIVE: To examine the effect of the COVID-19 pandemic on maternal substance abuse and neonatal outcomes. STUDY DESIGN: Cross-sectional observational study of neonates admitted to the NICU and born to mothers with evidence of substance abuse pre-pandemic compared to during the COVID-19 pandemic. RESULT: We noted a significant increase in fentanyl (12% vs. 0.6%, p < 0.001) and tobacco use (64% vs. 33%, p < 0.001) during the pandemic compared to pre-pandemic, including an increase in fentanyl use among mothers enrolled in opioid maintenance therapy (OMT) during the pandemic (32.3% vs. 1.5%, p < 0.001). There was a significant increase in preterm births (58% vs. 48%, p = 0.022) and lower birth weight (2315 ± 815 vs. 2455 ± 861 g, p = 0.049) during pandemic. CONCLUSION: There was a significant increase in maternal fentanyl use during the pandemic, even with OMT enrollment, with an increase in preterm births and lower birth weights among infants born to mothers with substance use.

Tumor Androgen Receptor Protein Level Is Positively Associated with a Better Overall Survival in Melanoma Patients.

Androgen receptor (AR) is expressed in numerous tissues and serves important biologic functions in skin, prostate, immune, cardiovascular, and neural systems, alongside sexual development. Several studies have associated AR expression and patient survival in various cancers, yet there are limited studies examining the relationship between AR expression and cutaneous melanoma. This study used genomics and proteomics data from The Cancer Proteome Atlas (TCPA) and The Cancer Genome Atlas (TCGA), with 470 cutaneous melanoma patient data points. Cox regression analyses evaluated the association between AR protein level with overall survival and revealed that a higher level of AR protein was positively associated with a better overall survival (OS) (p = 0.003). When stratified by sex, the AR association with OS was only significant for both sexes. The multivariate Cox models with justifications of sex, age of diagnosis, stage of disease, and Breslow depth of the tumor confirmed the AR-OS association in all patients. However, the significance of AR was lost when ulceration was included in the model. When stratified by sex, the multivariate Cox models indicated significant role of AR in OS of female patients but not in males. AR-associated genes were identified and enrichment analysis revealed shared and distinct gene network in male and female patients. Furthermore, AR was found significantly associated with OS in RAS mutant subtypes of melanoma but not in BRAF, NF1, or triple-wild type subtypes of melanoma. Our study may provide insight into the well-known female survival advantage in melanoma patients.

The ionophore thiomaltol induces rapid lysosomal accumulation of copper and apoptosis in melanoma.

In this report, we investigate the toxicity of the ionophore thiomaltol (Htma) and Cu salts to melanoma. Divalent metal complexes of thiomaltol display toxicity against A375 melanoma cell culture resulting in a distinct apoptotic response at submicromolar concentrations, with toxicity of Cu(tma)2 > Zn(tma)2 >> Ni(tma)2. In metal-chelated media, Htma treatment shows little toxicity, but the combination with supplemental CuCl2, termed Cu/Htma treatment, results in toxicity that increases with suprastoichiometric concentrations of CuCl2 and correlates with the accumulation of intracellular copper. Electron microscopy and confocal laser scanning microscopy of Cu/Htma treated cells shows a rapid accumulation of copper within lysosomes over the course of hours, concurrent with the onset of apoptosis. A buildup of ubiquitinated proteins due to proteasome inhibition is seen on the same timescale and correlates with increases of copper without additional Htma.

Novel therapeutic strategy for melanoma based on albendazole and the CDK4/6 inhibitor palbociclib.

Although an increasing number of patients benefit from immunotherapy and targeted therapies, melanoma remains incurable with increasing incidence. Drug repositioning and repurposing is an alternative strategy to discover and develop novel anticancer drugs or combined therapeutic regimens. In this study, we demonstrated that albendazole (ABZ), an Food and Drug Administration (FDA)-approved broad-spectrum antiparasitic agent, significantly inhibits the proliferation of melanoma cells in vitro and in vivo. RNA sequencing and flow cytometry analysis revealed that ABZ arrests melanoma cells at the G2/M phase of the cell cycle and induces cell apoptosis. More importantly, the CDK4/6 inhibitor palbociclib, as a member of the first and only class of highly specific CDK inhibitors approved for cancer treatment to date, showed significant synergistic effects with ABZ treatment in melanoma cells and mouse models. Taken together, we revealed a previously unappreciated function of ABZ in antimelanoma proliferation by inducing cell cycle arrest and apoptosis and provided a novel combined therapeutic regimen of ABZ plus CDK4/6 inhibitor treatment in melanoma.

The Sex Differences in Uveal Melanoma: Potential Roles of EIF1AX, Immune Response and Redox Regulation.

BACKGROUND: Uveal melanoma (UVM) is a rare cancer that shows sex difference in incidence and survival, with little previous report for the underlying mechanism. METHODS: This study used the SEER data (1974-2016) for an age-dependent analysis on sex difference in UVM, and further used the TCGA-UVM genomics dataset for analyzing the differential gene expression profiles in tumors from men and women. RESULTS: Our results demonstrate a sex difference in older age (≥40 years) but not in younger patients, with men exhibiting a higher incidence rate than women. However, younger women have shown a continuous increasing trend since 1974. Examining the 11 major oncogenes and tumor suppressors in UVM revealed that EIF1AX showed a significant sex difference in mRNA accumulation and copy number variation, with female tumors expressing higher levels of EIF1AX and exhibiting more variations in copy numbers. EIF1AX mRNA levels were significantly inversely correlated with EIF1AX copy numbers in female tumors only, but not in male tumors. Differential gene expression analysis at the whole genomic level identified a set of 92 protein-coding and 16 RNA-coding genes which exhibited differential expression in men and women (fold of change cutoff at 1.7, adjusted p value < 0.05, FDR < 0.05). Network analysis showed significant difference in immune response and in disulfide bond formation, with EGR1/EGR2 and PDIA2 genes as regulators for immune response and disulfide bond formation, respectively. The melanocortin pathway which is linked to both melanin synthesis and obesity seems to be altered with unclear significance, as the sex difference in POMC, DCT/TYRP2, and MRAP2 was observed but with no clear direction. CONCLUSION: This study reveals possible mechanisms for the sex difference in tumorigenesis of UVM which has potentials for better understanding and prevention of UVM.

Opposite Roles of BAP1 in Overall Survival of Uveal Melanoma and Cutaneous Melanoma.

BACKGROUND: BRCA1-Associated Protein 1 (BAP1) germline mutations predispose individuals to cancers, including uveal melanoma (UM) and cutaneous melanoma (CM). BAP1 loss is common in UM and is associated with a worse prognosis. BAP1 loss is rare in CM and the outcome is unclear. METHODS: UM and CM data was retrieved from The Cancer Genome Atlas (TCGA) database. Cox regression model was performed to examine whether BAP1 mRNA levels or copy number variations were associated with overall survival (OS). RESULTS: BAP1-low mRNA predicted a poor OS in UM (HR = 9.57, 95% CI: 2.82, 32.5) but a contrasting better OS in CM (HR = 0.73, 95% CI: 0.56, 0.95). These results remained unchanged after adjusting for sex, age, and stage in UM and CM, or after adjusting for ulceration or Breslow depth in CM. Additionally, low BAP1 mRNA predicted a better OS in CM patients older than 50 years but not in younger patients. Co-expression and enrichment analysis revealed differential genes and mutations that were correlated with BAP1 expression levels in UM and CM tumors. CONCLUSIONS: Low BAP1 mRNA was significantly associated with a better OS in CM patients, in sharp contrast to UM. High BAP1 expression in CM was significantly associated with over-expressed CDK1, BCL2, and KIT at the protein level which may explain the poor OS in this sub-group of patients. Function of BAP1 was largely different in CM and UM despite of a small subset of shared co-expressed genes.

Increased incidence of early onset colorectal adenocarcinoma is accompanied by an increased incidence of rectal neuroendocrine tumors.

Recent studies have reported an increasing incidence of early onset colorectal cancer (CRC). Few studies compared the changing incidence of CRC by the major histological type, adenocarcinoma and neuroendocrine tumors (NETs). Using data from the Surveillance, Epidemiology, and End Results Program (SEER), we identified CRC from 1992 to 2015 with site and histological codes. Standardized incidence rates of CRC by anatomical locations (proximal, distal and rectal colon) and histological types (adenocarcinoma, NETs and others) were calculated over calendar years. Annual percent changes (APC) and joint-point regression were further computed. A significant increase of cancers in the distal colon and rectum was observed in young populations (20-44 and 45-54 years) but not in the proximal colon. Further analyses found that the highest rise of rectal NETs was in the 45-54 years which contributed 53.47% to the total increase of rectal cancer. The APCs for NETs in the rectum were 2.9 (95% CI: -0.1, 6.0) and 6.1 (95% CI: 3.8-8.4) for 20-44 years or 45-54 years respectively. The increase of NETs in the rectum was still significant in the older than 55 years (APC=3.7, 95% CI: 2.8-4.7), although the total CRC in this group was decreasing. Incidence of NETs in the distal colon is not apparently changing. The increase of CRC incidence among young populations (age < 55) is mainly due to the increased incidence in the rectum and distal colon. Moreover, the increase of early onset cancer in the rectum could be ascribed to increased incidence of adenocarcinoma and NETs.