Sex differences in cancer incidence among solid organ transplant recipients.

BACKGROUND: Males have 2-3-fold greater risk of cancer than females at most shared anatomic sites, possibly reflecting enhanced immune surveillance against cancer in females. We examined whether these sex differences remained among immunocompromised adults. METHODS: Using the Transplant Cancer Match (TCM) study, we estimated the male-to-female incidence rate ratio in TCM (M:F IRRTransplant) for 15 cancer sites diagnosed between 1995 and 2017 using Poisson regression. Male to female IRRs in the general population (M:F IRRGP) were calculated using expected cancer counts from the Surveillance, Epidemiology, and End Results Program, standardized to the transplant population on age, race and ethnicity, and diagnosis year. Male to female IRRs were compared using a chi-square test. RESULTS: Among 343 802 solid organ transplants, 211 206 (61.4%) were among men and 132 596 (38.6%) among women. An excess cancer incidence in males was seen in transplant recipients, but the sex difference was attenuated for cancers of the lip (M:F IRRTransplant: 1.81 vs M:F IRRGP: 3.96; P < .0001), stomach (1.51 vs 2.09; P = .002), colorectum (0.98 vs 1.43; P < .0001), liver (2.39 vs 3.44; P = .002), kidney (1.67 vs 2.24; P < .0001), bladder (2.02 vs 4.19; P < .0001), Kaposi sarcoma (1.79 vs 3.26; P = .0009), and non-Hodgkin lymphoma (1.34 vs 1.64; P < .0001). The M:F IRRTransplant was not statistically different from the M:F IRRGP for other cancer sites. CONCLUSIONS: Although male solid organ transplant recipients have higher cancer incidence than female recipients, the attenuation in the male to female ratio for many cancers studied relative to the general population might suggest the importance of immunosurveillance, with some loss of advantage in female recipients due to immunosuppression after transplantation.

Spectrum of Nonkeratinocyte Skin Cancer Risk Among Solid Organ Transplant Recipients in the US.

Importance: Nonkeratinocyte skin cancers are an important cause of morbidity and mortality for immunosuppressed solid organ transplant recipients (SOTRs), but the spectrum of disease and risk factor characteristics are unknown. Objective: To characterize the spectrum of disease and risk factors for common and rare nonkeratinocyte skin cancers in SOTRs. Design, Setting, and Participants: This population-based cohort study included 444 497 SOTRs who underwent a transplant in the US between January 1, 1987, and December 31, 2017, using linked data from the national transplant registry and 32 cancer registries. Data analysis was conducted from April 1, 2021, to September 30, 2021. Main Outcomes and Measures: Standardized incidence ratios (SIRs) were used to assess risk relative to the general population, and Poisson regression was used to evaluate risk factors. Results: A total of 2380 nonkeratinocyte skin cancers were identified among 444 497 SOTRs (median age at transplant, 50 years; range, 0-96 years; 274 276 [61.7%] male; 272 241 [61.2%] non-Hispanic White). Melanoma was the most common cancer (1471 [61.8%]), followed by Merkel cell carcinoma (334 [14.0%]), Kaposi sarcoma (186 [7.8%]), sebaceous carcinoma (170 [7.1%]), and cutaneous lymphomas (108 [4.5%]). Risks were most strongly elevated for cancers associated with viruses, including Kaposi sarcoma (SIR, 20.5; 95% CI, 17.7-23.7), Merkel cell carcinoma (SIR, 16.2; 95% CI, 14.5-18.1), and extranodal natural killer/T-cell lymphoma (SIR, 44.3; 95% CI, 5.37-160). Risks were also significantly elevated for sebaceous carcinoma (SIR, 15.2; 95% CI, 13.0-17.7), anaplastic large cell lymphoma (SIR, 6.82; 95% CI, 4.53-9.85), and diffuse large B-cell lymphoma (SIR, 5.17; 95% CI, 3.28-7.76). Several characteristics were independently associated with greater risk for multiple skin cancer types, including male sex, older age at transplant, factors associated with UV radiation exposure (non-Hispanic White race and ethnicity, living in an area with higher UV radiation exposure, and posttransplant diagnosis of keratinocyte carcinoma), and increasing time since transplantation. Treatment with mammalian target of rapamycin inhibitors was associated with reduced melanoma incidence (incidence rate ratio, 0.75; 95% CI, 0.57-0.98). A total of 847 skin cancers (39.4%) occurred on the head and neck. Conclusions and Relevance: The findings of this cohort study suggest that viruses, UV radiation exposure, and immunosuppression are associated with the development of skin cancer in SOTRs. Certain high-risk subgroups may benefit from increased skin surveillance, and treatment with mammalian target of rapamycin inhibitors could be effective for melanoma chemoprevention in the transplant population.

Disparities in post-operative surveillance testing for metastatic recurrence among colorectal cancer survivors.

PURPOSE: Among colorectal cancer (CRC) survivors, treatment for metastatic recurrence is most effective when malignancies are detected early through surveillance with carcinoembryonic antigen (CEA) level test and computer tomography (CT) imaging. However, utilization of these tests is low, and many survivors fail to meet the recommended guidelines. This population-based study assesses individual- and neighborhood-level factors associated with receipt of CEA and CT surveillance testing. METHODS: We used the Surveillance, Epidemiology and End Results (SEER)-Medicare data to identify Medicare beneficiaries diagnosed with CRC stages II-III between 2010 and 2013. We conducted multivariate logistic regression to estimate the effect of individual and neighborhood factors on receipt of CEA and CT tests within 18 months post-surgery. RESULTS: Overall, 78% and 58% of CRC survivors received CEA and CT testing, respectively. We found significant within racial/ethnic differences in receipt of these surveillance tests. Medicare-Medicaid dual coverage was associated with 39% lower odds of receipt of CEA tests among non-Hispanic Whites, and Blacks with dual coverage had almost two times the odds of receiving CEA tests compared to Blacks without dual coverage. CONCLUSIONS: Although this study did not find significant differences in receipt of initial CEA and CT surveillance testing across racial/ethnic groups, the assessment of the factors that measure access to care suggests differences in access to these procedures within racial/ethnic groups. IMPLICATIONS FOR CANCER SURVIVORS: Our findings have implications for developing targeted interventions focused on promoting surveillance for the early detection of metastatic recurrence among colorectal cancer survivors and improve their health outcomes.

Outcomes of Patients with COVID-19 from a Specialized Cancer Care Emergency Room.

PURPOSE: Our goal was to identify discrete clinical characteristics associated with safe discharge from an emergency department/urgent care for patients with a history of cancer and concurrent COVID-19 infection during the SARS-CoV-2 pandemic and prior to widespread vaccination. PATIENTS AND METHODS: We retrospectively analyzed 255 adult patients with a history of cancer who presented to Memorial Sloan Kettering Cancer Center (MSKCC) urgent care center (UCC) from March 1, 2020 to May 31, 2020 with concurrent COVID-19 infection. We evaluated associations between patient characteristics and 30-day mortality from initial emergency department (ED) or urgent care center (UCC) visit and the absence of a severe event within 30 days. External validation was performed on a retrospective data from 29 patients followed at Fred Hutchinson Cancer Research Center that presented to the local emergency department. A late cohort of 108 additional patients at MSKCC from June 1, 2020 to January 31, 2021 was utilized for further validation. RESULTS: In the MSKCC cohort, 30-day mortality and severe event rate was 15% and 32% respectively. Using stepwise regression analysis, elevated BUN and glucose, anemia, and tachypnea were selected as the main predictors of 30-day mortality. Conversely, normal albumin, BUN, calcium, and glucose, neutrophil-lymphocyte ratio <3, lack of (severe) hypoxia, lack of bradycardia or tachypnea, and negative imaging were selected as the main predictors of an uneventful course as defined as a Lack Of a Severe Event within Thirty Days (LOSETD). Utilizing this information, we devised a tool to predict 30-day mortality and LOSETD which achieved an area under the operating curve (AUC) of 79% and 74% respectively. Similar estimates of AUC were obtained in an external validation cohort. A late cohort at MSKCC was consistent with the prior, albeit with a lower AUC. CONCLUSION: We identified easily obtainable variables that predict 30-day mortality and the absence of a severe event for patients with a history of cancer and concurrent COVID-19. This has been translated into a bedside tool that the clinician may utilize to assist disposition of this group of patients from the emergency department or urgent care setting.

Time and geographic variations in human papillomavirus vaccine uptake in Washington state.

This study examines geographic variations of human papillomavirus (HPV) vaccine uptake, the most significant disparity in HPV vaccination, in Washington State. We evaluated Washington State Immunization Information System (WA-IIS) data on target age (11-12 year old adolescents) between 2008 and 2018. A Bayesian spatio-temporal analysis was conducted to examine uptake at the census tract level. Urban-rural disparities in vaccine rates were assessed using t-tests. Persistently high and low vaccine areas and their contributing sociodemographic factors were then identified using a multinomial logistic regression. HPV vaccine uptake gradually increased after 2010, but remained persistently low. Average vaccine uptake rates from 2010 through 2018 in urban areas were 11%-34% for initiation and 4-19% for completion. These rates were 9-22% initiation and 3-11% completion in rural areas. We observed statistically significant (p < 0.05) differences between the estimated vaccine rates for urban and rural census tracts. Race/ethnicity and socioeconomic status were associated with this urban-rural disparity. The odds of being in low vaccine rural areas increased with increase in Area Deprivation Index (ADI) (OR = 1.14, CI = (1.10, 1.19)), and decreased with percentage increase in Black (OR = 0.43, CI = (0.02, 0.85)) and Hispanic (OR = 0.97, CI = (0.94, 1.00)) population. Bayesian spatial analysis was effective in capturing spatio-temporal patterns in HPV vaccine rates and identifying areas with persistently low vaccination over time. This analytic approach can be used to guide public health policies and geographically target interventions to reduce HPV vaccine disparities and to prevent future HPV-related cancers.

Barriers to Human Papillomavirus Vaccine Series Completion among Insured Individuals in an Integrated Healthcare Setting.

INTRODUCTION: Infection with certain types of human papillomavirus (HPV) can lead to cervical cancer as well as other cancers in both men and women. However, the requirement for multiple doses may limit the vaccine's effectiveness for cancer prevention. We conducted a pilot study to investigate barriers to HPV vaccine series completion among members of an integrated healthcare system with clinical documentation of only 1 dose. METHODS: We surveyed parents or legal guardians of 11-17-year-old girls (n = 10) and boys (n = 18), as well as 18-31-year-old women (n = 20) and men (n = 9), about their reasons for not completing the HPV vaccine series. RESULTS: Most participants (70.2%) were non-Hispanic white. Among parents of children, commonly reported barriers to HPV vaccine series completion included not being aware or informed of the need for additional doses (28.6%), as well as the inconvenience of returning for additional doses (17.9%). Concerns about the HPV vaccine or vaccines in general were more common among parents of girls (30.0%) compared with parents of boys (16.7%). Among adults, barriers to HPV vaccine series completion included the inconvenience of returning for additional doses (31.0%), not being aware or informed of the need for additional doses (10.3%), and forgetting (10.3%). CONCLUSION: Our findings suggest that clinicians and healthcare systems can play a greater role in promoting awareness of the multiple-dose requirement, addressing vaccine concerns, and increasing opportunistic vaccination in a variety of settings. Increasing these efforts may facilitate HPV vaccine completion and increase its effectiveness in cancer prevention.

Outcomes of Patients with Sarcoma and COVID-19 Infection: A Single Institution Cohort Analysis.

Outcomes for patients (pts) with sarcoma and COVID-19 are unknown. This is a single institution retrospective study of adults with sarcoma and COVID-19. Ten pts [median age 60 (range 24-69)] were identified. Five were hospitalized; two died from COVID-19 complications; another died from sarcoma. Time between last systemic treatment dose and COVID-19 diagnosis was 6-41 days in pts who died. 5 underwent prior radiation (RT); time between RT and COVID-19 diagnosis was 20-62 days for pts who died. All three pts with WBC differential data (two died) were lymphopenic. Efforts to capture outcomes for a larger cohort are urgently needed.

Inequitable access to surveillance colonoscopy among Medicare beneficiaries with surgically resected colorectal cancer.

BACKGROUND: After colorectal cancer (CRC) surgery, surveillance with colonoscopy is an important step for the early detection of local recurrence. Unfortunately, surveillance colonoscopy is underused, especially among racial/ethnic minorities. This study assesses the association between patient and neighborhood factors and receipt of surveillance colonoscopy. METHODS: This retrospective, population-based cohort study used Surveillance, Epidemiology, and End Results-Medicare linked data (2009-2014). Beneficiaries with surgically resected stage II or III CRC between the ages of 66 and 85 years were identified, and multivariable logistic regression was used to assess the effect of factors on receipt of colonoscopy. RESULTS: Overall, 57.5% of the patients received initial surveillance colonoscopy. After adjustments for all factors, Blacks and Hispanics had lower odds of receiving colonoscopy than non-Hispanic Whites (NHWs; 29.6% for Blacks; P = .002; 12.9% for Hispanics; P > .05). NHWs with Medicaid coverage had 35% lower odds of surveillance colonoscopy than NHWs without Medicaid coverage. Minority patients with Medicaid were more likely to receive colonoscopy than their racial/ethnic counterparts without Medicaid coverage (P > .05). Hispanics residing in neighborhoods with incomes of ≥$90,000 had significantly lower odds of surveillance colonoscopy than Hispanics residing in neighborhoods with incomes of $0 to $30,000. CONCLUSIONS: Receipt of initial surveillance colonoscopy remains low, and there are acute disparities between Black and NHW patients. The association between factors that assess a patient's ability to access colonoscopy and actual receipt of colonoscopy suggests inequitable access to surveillance colonoscopy within and across racial/ethnic groups.

Humoral Response to HPV16 Proteins in Persons with Anal High-Grade Squamous Intraepithelial Lesion or Anal Cancer.

BACKGROUND: This study was launched to evaluate the association of early and late antibodies to human papillomavirus 16 (HPV16) detection and risk of anal high-grade squamous intraepithelial lesions (HSIL) or cancer. METHODS: We analyzed data from persons with anal HSIL or cancer and controls from a case-control study in Seattle, Washington. Sera were evaluated for HPV16 early (E1, E2, E4, E6, and E7) and late (L1) antibodies by multiplex serology. Logistic regression models were used to assess serologic associations with risk of anal HSIL or cancer. RESULTS: The study included 67 participants with anal HSIL, 116 with anal cancer, and 830 population-based controls. HPV16 seropositivity to L1 [adjusted OR (aOR), 13.8; 95% confidence interval (CI), 7.4-25.8], E4 (aOR, 2.3; 95% CI, 1.1-4.5), and E6 (aOR, 4.9; 95% CI, 1.1-21.2) was associated with HSIL; and detection of all antibodies to HPV16 late and early proteins was associated with increased risk of anal cancer ranging from aOR 1.7 to 32.5 [L1 aOR, 12.5 (95% CI, 7.3-21.7); E1 aOR, 24.9 (95% CI, 10.3-59.9); E2 aOR, 6.3 (95% CI, 3.4-11.7); E4 aOR, 2.8 (95% CI, 1.6-4.8); E6 aOR, 32.5 (95% CI, 14.2-74.4); and E7 aOR, 1.7 (95% CI, 1.0-3.0)]. CONCLUSIONS: HPV serologic markers proved to be specific for identifying anal cancer. HPV16 E6 seropositivity is relatively uncommon in persons without anal cancer. IMPACT: This large study comprehensively describes the distinct antibody responses to the HPV16 proteins in persons with anal HSIL or anal cancer. Antibodies to HPV16 E6 should be further evaluated as a potential biomarker for anal cancer prevention.

Associations of plasma trimethylamine N-oxide, choline, carnitine, and betaine with inflammatory and cardiometabolic risk biomarkers and the fecal microbiome in the Multiethnic Cohort Adiposity Phenotype Study.

BACKGROUND: Trimethylamine N-oxide (TMAO), a compound derived from diet and metabolism by the gut microbiome, has been associated with several chronic diseases, although the mechanisms of action are not well understood and few human studies have investigated microbes involved in its production. OBJECTIVES: Our study aims were 1) to investigate associations of TMAO and its precursors (choline, carnitine, and betaine) with inflammatory and cardiometabolic risk biomarkers; and 2) to identify fecal microbiome profiles associated with TMAO. METHODS: We conducted a cross-sectional analysis using data collected from 1653 participants (826 men and 827 women, aged 60-77 y) in the Multiethnic Cohort Study. Plasma concentrations of TMAO and its precursors were measured by LC-tandem MS. We also analyzed fasting blood for markers of inflammation, glucose and insulin, cholesterol, and triglycerides (TGs), and further measured blood pressure. Fecal microbiome composition was evaluated by sequencing the 16S ribosomal RNA gene V1-V3 region. Associations of TMAO and its precursors with disease risk biomarkers were assessed by multivariable linear regression, whereas associations between TMAO and the fecal microbiome were assessed by permutational multivariate ANOVA and hurdle regression models using the negative binomial distribution. RESULTS: Median (IQR) concentration of plasma TMAO was 3.05 µmol/L (2.10-4.60 µmol/L). Higher concentrations of TMAO and carnitine, and lower concentrations of betaine, were associated with greater insulin resistance (all P < 0.02). Choline was associated with higher systolic blood pressure, TGs, lipopolysaccharide-binding protein, and lower HDL cholesterol (P ranging from <0.001 to 0.03), reflecting an adverse cardiometabolic risk profile. TMAO was associated with abundance of 13 genera (false discovery rate < 0.05), including Prevotella, Mitsuokella, Fusobacterium, Desulfovibrio, and bacteria belonging to the families Ruminococcaceae and Lachnospiraceae, as well as the methanogen Methanobrevibacter smithii. CONCLUSIONS: Plasma TMAO concentrations were associated with a number of trimethylamine-producing bacterial taxa, and, along with its precursors, may contribute to inflammatory and cardiometabolic risk pathways.

Age-Specific Incidence of Melanoma in the United States.

Importance: Melanoma is epidemiologically linked to UV exposure, particularly childhood sunburn. Public health campaigns are increasing sun-protective behavior in the United States, but the effect on melanoma incidence is unknown. Objective: To examine the incidence of melanoma in the United States and whether any age-specific differences are present. Design, Setting, and Participants: Observational, population-based registry data were extracted on July 3, 2018, from the combined National Program of Cancer Registries-Surveillance Epidemiology and End Results United States Cancer Statistics database for 2001-2015. Deidentified data for 988 103 cases of invasive melanoma, with International Classification of Diseases for Oncology histologic categorization codes 8720 to 8790, were used for analysis. Data analysis was performed from July 1, 2018, to March 1, 2019. Main Outcomes and Measures: The annual rates of melanoma in pediatric, adolescent, young adult, and adult age groups were determined. Analyses were stratified by sex, and incidence rates were age-adjusted to the 2000 US standard population. Annual percentage change (APC) in incidence rate was calculated over the most recent decade for which data were available (2006-2015) using the weighted least squares method. Results: In 2015, 83 362 cases of invasive melanoma were reported in the United States, including 67 in children younger than 10 years, 251 in adolescents (10-19 years), and 1973 in young adults (20-29 years). Between 2006 and 2015, the overall incidence rate increased from 200.1 to 229.1 cases per million person-years. In adults aged 40 years or older, melanoma rates increased by an APC of 1.8% in both men (95% CI, 1.4%-2.1%) and women (95% CI, 1.4%-2.2%). In contrast, clinically and statistically significant decreases were seen in melanoma incidence for adolescents and young adults. Specifically, incidence rates decreased by an APC of -4.4% for male adolescents (95% CI, -1.7% to -7.0%), -5.4% for female adolescents (95% CI, -3.3% to -7.4%), -3.7% for male young adults (95% CI, -2.5% to -4.8%), and -3.6% for female young adults (95% CI, -2.8% to -4.5%). Data on skin pigmentation and sun protection history were unavailable; similar trends were observed with data limited to non-Hispanic whites. Young adult women appeared to have twice the risk of melanoma as young adult men. Conclusions and Relevance: The incidence of invasive melanoma in the United States appeared to decrease in adolescents and young adults from 2006 to 2015, and this finding contrasted with increases in older populations. These incidence trends suggest that public health efforts may be favorably influencing melanoma incidence in the United States.

Effect of Human Papillomavirus Vaccine to Interrupt Recurrence of Vulvar and Anal Neoplasia (VIVA): A Trial Protocol.

Importance: Human papillomavirus (HPV), particularly HPV type 16, causes most anal and vulvar high-grade squamous intraepithelial lesions (HSIL), which are precursors to cancer. After initial treatment of HSIL, more than 30% of patients will have disease recurrence, with even higher recurrence among HIV-positive individuals and men who have sex with men. Recurrences can be debilitating and lead to significant morbidity and medical expense. Observational studies suggest a possible therapeutic benefit of the licensed HPV vaccines in reducing recurrent lesions in previously infected persons. Objective: To test whether the licensed prophylactic HPV vaccine (Gardasil-9) can reduce the risk of HSIL recurrence by 50% in previously unvaccinated individuals recently treated for anal or vulvar HSIL. Design, Setting, and Participants: This is a trial protocol for a randomized, double-blind, placebo-controlled, proof-of-concept clinical trial. Eligible participants are aged 27 to 69 at study start and have not received prior HPV vaccination, have had anal or vulvar HSIL diagnosed on or after January 1, 2014, and have no evidence of HSIL recurrence at screening. Persons infected with HIV are eligible for the study provided they are receiving antiretroviral therapy. Target enrollment is 345 individuals. The primary outcome is time to histopathologically confirmed recurrence of HSIL. Differences in the risk for recurrence of HSIL will be evaluated using Cox proportional hazard models. Additional analyses include (1) frequency of HSIL recurrence; (2) role of HPV antibodies in deterring recurrence; (3) role of HPV persistence in recurrence, as measured by HPV genotype or HPV-16 variant lineage determined using swab samples collected at months 0, 18, and 36; and (4) incidence of adverse events. The study will be conducted at the University of Washington Virology Research Clinic from 2017 through 2022. Participants will be followed up for up to 36 months in the clinic, and up to 42 months by telephone. Discussion: Management of persistent or rapidly recurring anogenital HSIL remains challenging. Results from this study will provide evidence on whether incorporating the nonavalent HPV vaccine into routine care can decrease recurrence of anal and vulvar HSIL. Trial Registration: ClinicalTrials.gov identifier: NCT03051516.

Gynecologic cancers and solid organ transplantation.

Solid organ transplant (SOT) recipients have an approximately 2-fold greater risk of developing and dying from a malignancy compared to the general population. Among the gynecologic cancers, including uterine, cervical, vaginal, vulvar, and ovarian, the HPV-related cancers are known to increase among women posttransplant compared to women in the general population, but less is known about the risk of uterine and ovarian cancers. This review provides an overview of the epidemiology of gynecologic cancers after solid organ transplantation, as well as the pathophysiology, management, and specific risk factors associated with these cancers. Closer surveillance for cervical cancers is warranted and larger studies are needed to assess whether and how uterine and ovarian cancers are associated with excess incidence and mortality. Such studies may lead to improvements in screening, prevention, and treatment before and after transplantation.

Risk of lip cancer after solid organ transplantation in the United States.

Solid organ transplant recipients have an increased risk of lip cancer, but the reasons are uncertain. Using data from the Transplant Cancer Match Study, we describe the epidemiology of lip cancer among 261 500 transplant recipients in the United States. Two hundred thirty-one lip cancers were identified, corresponding to elevated risks for both invasive and in situ lip cancers (standardized incidence ratios of 15.3 and 26.2, respectively). Invasive lip cancer incidence was associated with male sex (adjusted incidence rate ratio [aIRR] 2.01, 95% CI 1.44-2.82), transplanted organ (0.33, 0.20-0.57, for liver transplants and 3.07, 1.96-4.81, for lung transplants, compared with kidney transplants), and racial/ethnic groups other than non-Hispanic whites (0.09, 0.04-0.2). In addition, incidence increased with age and during the first 3 years following transplant, and was higher in recipients prescribed cyclosporine/azathioprine maintenance therapy (aIRR 1.79, 95% CI 1.09-2.93, compared with use of tacrolimus/mycophenolate mofetil) and following a diagnosis of cutaneous squamous cell carcinoma (4.21, 2.69-0.94). The elevation in lip cancer incidence is consistent with an effect of immunosuppression. Notably, the very strong associations with white race and history of prior skin cancer point to an important role for ultraviolet radiation exposure, and cyclosporine and azathioprine may contribute as photosensitizing or DNA damaging agents.

HLA and KIR Associations of Cervical Neoplasia.

Background: Cervical cancer is the fourth most common cancer in women, and we recently reported human leukocyte antigen (HLA) alleles showing strong associations with cervical neoplasia risk and protection. HLA ligands are recognized by killer immunoglobulin-like receptors (KIRs) expressed on a range of immune cell subsets, governing their proinflammatory activity. We hypothesized that the inheritance of particular HLA-KIR combinations would increase cervical neoplasia risk. Methods: Here, we used HLA and KIR dosages imputed from single-nucleotide polymorphism genotype data from 2143 cervical neoplasia cases and 13858 healthy controls of European decent. Results: The following 4 novel HLA alleles were identified in association with cervical neoplasia, owing to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles: HLA-DRB3*9901 (odds ratio [OR], 1.24; P = 2.49 × 10-9), HLA-DRB5*0101 (OR, 1.29; P = 2.26 × 10-8), HLA-DRB5*9901 (OR, 0.77; P = 1.90 × 10-9), and HLA-DRB3*0301 (OR, 0.63; P = 4.06 × 10-5). We also found that homozygosity of HLA-C1 group alleles is a protective factor for human papillomavirus type 16 (HPV16)-related cervical neoplasia (C1/C1; OR, 0.79; P = .005). This protective association was restricted to carriers of either KIR2DL2 (OR, 0.67; P = .00045) or KIR2DS2 (OR, 0.69; P = .0006). Conclusions: Our findings suggest that HLA-C1 group alleles play a role in protecting against HPV16-related cervical neoplasia, mainly through a KIR-mediated mechanism.

Risk of oral tongue cancer among immunocompromised transplant recipients and human immunodeficiency virus-infected individuals in the United States.

BACKGROUND: Oral tongue cancer incidence has increased among whites in the United States; however, the cause remains unknown. If an infectious agent is implicated, then elevated risk would be expected among immunosuppressed individuals. METHODS: By using population-based registry linkage information from the US Transplant Cancer Match and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) Cancer Match studies, the authors examined the risk of oral tongue squamous cell carcinoma (SCC) among immunocompromised transplantation recipients and HIV-infected individuals. In addition, the risks of oropharyngeal SCC (strongly related to human papillomavirus infection; modestly affected by immunosuppression), other tobacco/alcohol-related oral cavity SCCs (not thought to be infection/immunosuppression-related), and non-Hodgkin lymphoma of oral cavity/pharynx (strongly related to Epstein-Barr virus; profoundly affected by immunosuppression) were evaluated. RESULTS: Compared with the general population, the risk of non-Hodgkin lymphoma was strongly increased (standardized incidence ratio [SIR] > 8.0). The risk of all SCCs was modestly and similarly elevated among transplantation recipients (SIR range, 2.2-2.7; Pheterogeneity = .2); whereas, among HIV-infected individuals, the risk of oral tongue SCC was higher compared with the risk of other SCCs (SIR, 3.0 vs 1.7 [for oropharyngeal SCCs] and 2.3 [for other oral cavity SCCs]; Pheterogeneity < .001). The risk of SCCs was significantly higher among men, older individuals, and whites; and risk increased with the time since transplantation/AIDS onset. The risk of oral tongue SCC was significantly higher among HIV-infected men who have sex with men compared with the average risk in HIV-infected individuals (adjusted incidence rate ratio = 2.0). CONCLUSIONS: Similar modest increases in the risk of oral tongue and other oral cavity SCCs do not suggest that an infectious agent or exposure profoundly affected by immunosuppression underlies the increase in oral tongue cancer. Cancer 2018;124:2515-22. © 2018 American Cancer Society.

Correction: Defining the genetic susceptibility to cervical neoplasia-A genome-wide association study.

[This corrects the article DOI: 10.1371/journal.pgen.1006866.].

Defining the genetic susceptibility to cervical neoplasia-A genome-wide association study.

A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4%) of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately >7.1% risk, and those in the highest 5% have approximately >21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods.

Risk of Second Malignancies in Solid Organ Transplant Recipients Who Develop Keratinocyte Cancers.

Solid organ transplant recipients have increased risk for developing keratinocyte cancers, including cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), in part as a result of immunosuppressive medications administered to prevent graft rejection. In the general population, keratinocyte cancers are associated with increased risks of subsequent malignancy, however, the risk in organ transplant populations has not been evaluated. We addressed this question by linking the U.S. Scientific Registry of Transplant Recipients, which includes data on keratinocyte cancer occurrence, with 15 state cancer registries. Risk of developing malignancies after keratinocyte cancer was assessed among 118,440 Caucasian solid organ transplant recipients using multivariate Cox regression models. Cutaneous SCC occurrence (n = 6,169) was associated with 1.44-fold increased risk [95% confidence interval (CI), 1.31-1.59] for developing later malignancies. Risks were particularly elevated for non-cutaneous SCC, including those of the oral cavity/pharynx (HR, 5.60; 95% CI, 4.18-7.50) and lung (HR, 1.66; 95% CI, 1.16-2.31). Cutaneous SCC was also associated with increased risk of human papillomavirus-related cancers, including anal cancer (HR, 2.77; 95% CI, 1.29-5.96) and female genital cancers (HR, 3.43; 95% CI, 1.44-8.19). In contrast, BCC (n = 3,669) was not associated with overall risk of later malignancy (HR, 0.98; 95% CI, 0.87-1.12), including any SCC. Our results suggest that transplant recipients with cutaneous SCC, but not BCC, have an increased risk of developing other SCC. These findings somewhat differ from those for the general population and suggest a shared etiology for cutaneous SCC and other SCC in the setting of immunosuppression. Cutaneous SCC occurrence after transplantation could serve as a marker for elevated malignancy risk. Cancer Res; 77(15); 4196-203. ©2017 AACR.

Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma.

OBJECTIVE: Oesophageal adenocarcinoma (OA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation is considered an important contributor to OA pathogenesis. Established risk factors for OA and its precursor, Barrett's oesophagus (BE), include symptomatic reflux, obesity and smoking. The role of inherited genetic susceptibility remains an area of active investigation. Here, we explore whether germline variation related to inflammatory processes influences susceptibility to BE/OA. DESIGN: We used data from a genomewide association study of 2515 OA cases, 3295 BE cases and 3207 controls. Our analysis included 7863 single-nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signalling, oxidative stress, human leucocyte antigen and nuclear factor-κB. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk. RESULTS: We identified a significant signal for the COX pathway in relation to BE risk (p=0.0059, false discovery rate q=0.03), and in gene-level analyses found an association with microsomal glutathione-S-transferase 1 (MGST1); (p=0.0005, q=0.005). Assessment of 36 MGST1 SNPs identified 14 variants associated with elevated BE risk (q<0.05). Four of these were subsequently confirmed (p<5.5×10-5) in a meta-analysis encompassing an independent set of 1851 BE cases and 3496 controls, and are known strong expression quantitative trait loci for MGST1. Three such variants were associated with similar elevations in OA risk. CONCLUSIONS: This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/OA and suggests that variants in MGST1 influence disease susceptibility.