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Objective: Lynch Syndrome (LS) carriers have a significantly increased risk of developing colorectal cancer (CRC) during their lifetimes. Further stratification of this patient population may help in identifying additional risk factors that predispose to colorectal carcinogenesis. In most LS patients CRC may arise from adenomas, although an alternative non-polypoid carcinogenesis pathway has been proposed for PMS2 carriers. Using data from our institutional LS cohort, our aim was to describe our current colorectal screening outcomes with a focus on the incidence of adenomas in the context of different MMR genotypes and patient demographics such as gender, race, and ethnicity. Design: We collected demographics, genetic, colonoscopy, and pathology results from a total of 163 LS carriers who obtained regular screening care at MD Anderson Cancer Center. Data were extracted from the electronic health records into a REDCap database for analysis. Logistic regressions were performed to measure the association between MMR variants and the likelihood of adenomas, advanced adenomas, and CRC. Then, we analyzed the cumulative incidences of these outcomes for the first 36 months following enrollment using Kaplan-Meier incidence curves, and Cox proportional hazard regressions. Results: On multivariate analysis, age (=45 years old) was associated with an increased risk of developing adenomas (P=0.034). Patients with a prior or active cancer status were less likely to develop adenomas (P=0.015), despite of the lack of association between surgical history with this outcome (P=0.868). We found no statistically significant difference in likelihood of adenoma development between MLH1 and MSH2/EPCAM, MSH6, and PMS2 carriers. Moreover, we observed no statistically significant difference in the likelihood of advanced adenomas or CRC for any measured covariates. On Cox proportional hazard, compared to MLH1 carriers, the incidence of adenomas was highest among MSH2/EPCAM carriers during for the first 36-months of follow-up (P<0.001). We observed a non-statistically significant trend for Hispanics having a higher and earlier cumulative incidence of adenomas compared to non-Hispanics (P=0.073). No MMR carrier was more likely to develop advanced adenomas. No difference in the incidence of CRC by MMR gene (P=0.198). Conclusion: Screening recommendations for CRC in LS patients should be based on specific MMR variants and should also be tailored to consider patient demographics. [ABSTRACT FROM AUTHOR]

ObjectiveLynch Syndrome (LS) carriers have a significantly increased risk of developing colorectal cancer (CRC) during their lifetimes. Further stratification of this patient population may help in identifying additional risk factors that predispose to colorectal carcinogenesis. In most LS patients CRC may arise from adenomas, although an alternative non-polypoid carcinogenesis pathway has been proposed for PMS2 carriers. Using data from our institutional LS cohort, our aim was to describe our current colorectal screening outcomes with a focus on the incidence of adenomas in the context of different MMR genotypes and patient demographics such as gender, race, and ethnicity.DesignWe collected demographics, genetic, colonoscopy, and pathology results from a total of 163 LS carriers who obtained regular screening care at MD Anderson Cancer Center. Data were extracted from the electronic health records into a REDCap database for analysis. Logistic regressions were performed to measure the association between MMR variants and the likelihood of adenomas, advanced adenomas, and CRC. Then, we analyzed the cumulative incidences of these outcomes for the first 36 months following enrollment using Kaplan-Meier incidence curves, and Cox proportional hazard regressions.ResultsOn multivariate analysis, age (≥45 years old) was associated with an increased risk of developing adenomas (P=0.034). Patients with a prior or active cancer status were less likely to develop adenomas (P=0.015), despite of the lack of association between surgical history with this outcome (P=0.868). We found no statistically significant difference in likelihood of adenoma development between MLH1 and MSH2/EPCAM, MSH6, and PMS2 carriers. Moreover, we observed no statistically significant difference in the likelihood of advanced adenomas or CRC for any measured covariates. On Cox proportional hazard, compared to MLH1 carriers, the incidence of adenomas was highest among MSH2/EPCAM carriers during for the first 36-months of follow-up (P

In this registry‐based cohort study, we estimated the risk of human papillomavirus (HPV)‐related anogenital premalignancies and cancer in renal transplant recipients (RTRs) compared to a nontransplanted comparison cohort. We identified all first‐time RTRs in Denmark during 1990–2015 in a nationwide nephrology register. For each RTR, we randomly selected 50 age‐ and sex‐matched non‐RTRs from the background population. The study population was followed for diagnoses of cervical, vaginal, vulvar, penile and anal intraepithelial neoplasia grades 2–3 (IN2/3) and cancer for up to 27 years. We estimated hazard ratios (HRs) of anogenital IN2/3 and cancer in RTRs vs. non‐RTRs by Cox regression separately for men and women using age as underlying timescale, adjusting for income, education, HPV vaccination and immunocompromising conditions. We included 4,261 RTRs and 213,673 non‐RTRs. RTRs had increased hazard of cervical (HR = 2.1, 95% CI: 1.7–2.8), vaginal (HR = 35.0, 95% CI: 13.9–87.7), vulvar (HR = 16.4, 95% CI: 10.4–25.8), penile (HR = 21.9, 95% CI: 11.1–43.5) and anal (women: HR = 51.1, 95% CI: 28.0–93.1; men: HR = 39.0, 95% CI: 16.7–91.1) IN2/3. The HRs of anogenital cancers were also increased at most sites. The HR of anogenital IN2/3 in female RTRs tended to be higher during graft function than during dialysis. In female RTRs aged <40 years at transplantation, 10–15% had cervical IN2/3 and 5–12% had vaginal/vulvar/anal IN2/3 within 20 years after transplantation, compared to 4–8 and 0.2–0.4%, respectively, of female non‐RTRs. In conclusion, RTRs had substantially higher risk of HPV‐related anogenital premalignancies and cancer than non‐RTRs. What's new? Kidney transplant recipients are vulnerable to infections resulting from immunosuppressive treatments. As these patients live longer with their new organs, they also develop more cancer, especially cancers caused by viruses. Here, the authors investigated the rate of HPV‐related premalignancies in renal transplant recipients. Using data from Danish registries, they identified 4,200 renal transplant recipients and 210,000 randomly selected age‐ and sex‐matched controls. Looking at incidence of anogenital intraepithelial neoplasia and cancer over 27 years, they found that transplant recipients had substantially higher risk of developing lesions than healthy controls, and would potentially benefit from more vigilant screening. [ABSTRACT FROM AUTHOR]

Ductal carcinoma in situ (DCIS) is a common precursor of invasive breast cancer. Our understanding of its genomic progression to recurrent disease remains poor, partly due to challenges associated with the genomic profiling of formalin-fixed paraffin-embedded (FFPE) materials. Here, we developed Arc-well, a high-throughput single-cell DNA-sequencing method that is compatible with FFPE materials. We validated our method by profiling 40,330 single cells from cell lines, a frozen tissue, and 27 FFPE samples from breast, lung, and prostate tumors stored for 3–31 years. Analysis of 10 patients with matched DCIS and cancers that recurred 2–16 years later show that many primary DCIS had already undergone whole-genome doubling and clonal diversification and that they shared genomic lineages with persistent subclones in the recurrences. Evolutionary analysis suggests that most DCIS cases in our cohort underwent an evolutionary bottleneck, and further identified chromosome aberrations in the persistent subclones that were associated with recurrence. [Display omitted] • Arc-well is a high-throughput single-cell DNA-seq method for archival FFPE tissues • Arc-well reliably profiled thousands of cells from 27 FFPE tissues archived for years • Persistent subclones from DCIS and matched recurrences were identified • Most DCIS cases in this cohort underwent an evolutionary bottleneck Arc-well enables reliable high-throughput single-cell genomic sequencing from formalin-fixed paraffin-embedded clinical oncology samples archived for years to decades, and the application of this method reveals genomic features and evolutionary models in ductal carcinoma in situ associated with cancer progression and recurrence. [ABSTRACT FROM AUTHOR]