Citations

Abstract TGFβ–SMAD signaling exerts a contextual effect that suppresses malignant growth early in epithelial tumorigenesis but promotes metastasis at later stages. Longstanding challenges in resolving this functional dichotomy may uncover new strategies to treat advanced carcinomas. The Krüppel-like transcription factor, KLF10, is a pivotal effector of TGFβ/SMAD signaling that mediates antiproliferative effects of TGFβ. In this study, we show how KLF10 opposes the prometastatic effects of TGFβ by limiting its ability to induce epithelial-to-mesenchymal transition (EMT). KLF10 depletion accentuated induction of EMT as assessed by multiple metrics. KLF10 occupied GC-rich sequences in the promoter region of the EMT-promoting transcription factor SLUG/SNAI2, repressing its transcription by recruiting HDAC1 and licensing the removal of activating histone acetylation marks. In clinical specimens of lung adenocarcinoma, low KLF10 expression associated with decreased patient survival, consistent with a pivotal role for KLF10 in distinguishing the antiproliferative versus prometastatic functions of TGFβ. Our results establish that KLF10 functions to suppress TGFβ-induced EMT, establishing a molecular basis for the dichotomy of TGFβ function during tumor progression. Cancer Res; 77(9); 2387–400. ©2017 AACR.

184 Background: Patients with CLL are at higher risk of developing melanoma and other skin malignancies. The survival of patients with melanoma is worse, stage for stage, in patients with CLL than patients without. It is thought that early diagnosis of skin cancer is critical to improving survival in CLL patients. To promote early diagnosis and education on skin cancer prevention, the Mayo Clinic CLL group has recommended that CLL patients be referred for full body skin evaluation within 6 months of diagnosis. We sought to determine adherence to these guidelines by our group and identify prevalence of skin malignancies within 6 months of diagnosis. Methods: We identified patients who lived within 30 miles of Mayo Clinic who were diagnosed with CLL between 01/01/2004 and 01/01/2012 using the Mayo Clinic CLL database. Charts were reviewed for skin examinations, referrals to dermatology/primary care within 6 months of diagnosis of CLL, and diagnosis of a skin malignancy. Results: There were 107 patients newly diagnosed with CLL included in this study. Of the 79 patients who received their primary care at Mayo Clinic, 40 (51%) had a documented whole body skin exam by either a dermatologist or primary care provider within six months of diagnosis. Nine of these 40 patients (23% of examined patients; 8% overall cohort) had a skin malignancy: 2 patients had basal cell carcinomas, 6 patients had squamous cell carcinomas, and 1 patient had malignant melanoma. Prophylactic skin care recommendations could be documented for only 28 (26%) of patients. Conclusions: At least 8% of patients in this locally dwelling cohort with newly diagnosed CLL had a skin malignancy identified within six months of diagnosis (number needed to screen for 1 skin cancer: 13). Of patients referred to dermatology 23% had a skin malignancy (number needed to screen: 4.3). Referrals for screening skin examinations at diagnosis in patients with CLL could have an immediate impact for this at-risk population.

397 Background: Carcinomas of the appendix are exceedingly rare tumors and have an annual age-adjusted incidence of around 0.4 cases per 100,000. Appendiceal adenocarcinoma accounts for <0.5% of all gastrointestinal neoplasms and, of these, mucinous adenocarcinomas account for the majority. Published accounts of familial instances of primary appendiceal tumors are strikingly rare. Methods: We report two siblings who both developed primary mucinous adenocarcinomas. A genetics evaluation was conducted to determine if there was a recognizable underlying single gene disorder: no DNA mismatch repair defect was evident and no other diagnosis was apparent. A review of appendiceal cancers seen at Mayo Clinic from l997 to the present was conducted to search for additional familial cases. Results: Among 316 cases of primary appendiceal cancer of any histologic type, this sib pair was the only family reporting a second affected family member. Conclusions: The occurrence of appendiceal cancer in siblings may represent a random occurrence. Adenocarcinomas of the most common type of appendiceal cancer and occur at older ages than other histologic subtypes. A strikingly rare predisposition syndrome cannot be ruled out. [Table: see text] No significant financial relationships to disclose.

Abstract Background: Studies of colorectal cancer screening by multitarget stool DNA (MT-sDNA) show false-positive (FP) rates of 7% to 13%. It is unclear whether FP patients are at increased long-term risk of adverse outcomes. Methods: We compared subsequent clinical events among patients with apparent FP MT-sDNA with those in patients reported as true negative (TN). This was a retrospective cohort study of participants in pre-FDA approval MT-sDNA studies having nonadvanced or negative baseline colonoscopy findings from a single referral center. Per-protocol and calibrated cutoffs defined FP and TN groups. From the time of stool collection, we measured differences between FP and TN groups in time to death, subsequent cancer diagnosis, and onset of alarm symptoms. Results: Of 1,050 eligible patients, only 6 were lost to follow-up. Median age was 65.6 years [interquartile range (IQR), 56.8–72.3]; 54% were female. Median follow-up time was 4 years (IQR, 3.5–5.3). Eight aerodigestive (lung and gastrointestinal tract) cancers occurred. FP status by calibrated, but not per-protocol, cutoffs was associated with subsequent aerodigestive cancer; however, cumulative incidence did not exceed SEER expectations from the general population. By any cutoff method, FP status was not associated with mortality or alarm symptoms. Conclusions: Although FP status was associated with long-term aerodigestive cancers, new cases were not temporally related and did not exceed incidence estimates from general population. Impact: These observations do not justify aggressive follow-up evaluation for patients with FP MT-sDNA at this time. Larger studies are needed to confirm these early findings. Cancer Epidemiol Biomarkers Prev; 26(4); 614–21. ©2016 AACR.

Objective Genome‐wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger‐onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age‐at‐onset informed GWAS meta‐analysis, including a large younger‐onset SVS population, to identify novel associations with stroke. Methods We used a three‐stage age‐at‐onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. Results We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10–1.22]; p = 3.2 × 10 −9 ). The lead single‐nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05–1.16]; p = 5.3 × 10 −5 ; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84–1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues ( p = 9.4 × 10 −7 ) and DNA methylation at probe cg16596957 in whole blood ( p = 5.3 × 10 −6 ). Interpretation 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383–394

Introduction and hypothesis There has been an increasing need for the terminology on the conservative management of female pelvic floor dysfunction to be collated in a clinically based consensus report. Methods This Report combines the input of members and elected nominees of the Standardization and Terminology Committees of two International Organizations, the International Urogynecological Association (IUGA) and the International Continence Society (ICS), assisted at intervals by many external referees. An extensive process of nine rounds of internal and external review was developed to exhaustively examine each definition, with decision‐making by collective opinion (consensus). Before opening up for comments on the webpages of ICS and IUGA, five experts from physiotherapy, neurology, urology, urogynecology, and nursing were invited to comment on the paper. Results A Terminology Report on the conservative management of female pelvic floor dysfunction, encompassing over 200 separate definitions, has been developed. It is clinically based, with the most common symptoms, signs, assessments, diagnoses, and treatments defined. Clarity and ease of use have been key aims to make it interpretable by practitioners and trainees in all the different specialty groups involved in female pelvic floor dysfunction. Ongoing review is not only anticipated, but will be required to keep the document updated and as widely acceptable as possible. Conclusion A consensus‐based terminology report for the conservative management of female pelvic floor dysfunction has been produced, aimed at being a significant aid to clinical practice and a stimulus for research.