Deficient H2A.Z deposition is associated with genesis of uterine leiomyoma.

One in four women suffers from uterine leiomyomas (ULs)-benign tumours of the uterine wall, also known as uterine fibroids-at some point in premenopausal life. ULs can cause excessive bleeding, pain and infertility1, and are a common cause of hysterectomy2. They emerge through at least three distinct genetic drivers: mutations in MED12 or FH, or genomic rearrangement of HMGA23. Here we created genome-wide datasets, using DNA, RNA, assay for transposase-accessible chromatin (ATAC), chromatin immunoprecipitation (ChIP) and HiC chromatin immunoprecipitation (HiChIP) sequencing of primary tissues to profoundly understand the genesis of UL. We identified somatic mutations in genes encoding six members of the SRCAP histone-loading complex4, and found that germline mutations in the SRCAP members YEATS4 and ZNHIT1 predispose women to UL. Tumours bearing these mutations showed defective deposition of the histone variant H2A.Z. In ULs, H2A.Z occupancy correlated positively with chromatin accessibility and gene expression, and negatively with DNA methylation, but these correlations were weak in tumours bearing SRCAP complex mutations. In these tumours, open chromatin emerged at transcription start sites where H2A.Z was lost, which was associated with upregulation of genes. Furthermore, YEATS4 defects were associated with abnormal upregulation of bivalent embryonic stem cell genes, as previously shown in mice5. Our work describes a potential mechanism of tumorigenesis-epigenetic instability caused by deficient H2A.Z deposition-and suggests that ULs arise through an aberrant differentiation program driven by deranged chromatin, emanating from a small number of mutually exclusive driver mutations.

Lynch syndrome-associated and sporadic microsatellite unstable colorectal cancers: different patterns of clonal evolution yield highly similar tumours.

Microsatellite unstable colorectal cancer (MSI-CRC) can arise through germline mutations in mismatch repair (MMR) genes in individuals with Lynch syndrome (LS), or sporadically through promoter methylation of the MMR gene MLH1. Despite the different origins of hereditary and sporadic MSI tumours, their genomic features have not been extensively compared. A prominent feature of MMR-deficient genomes is the occurrence of many indels in short repeat sequences, an understudied mutation type due to the technical challenges of variant calling in these regions. In this study, we performed whole genome sequencing and RNA-sequencing on 29 sporadic and 14 hereditary MSI-CRCs. We compared the tumour groups by analysing genome-wide mutation densities, microsatellite repeat indels, recurrent protein-coding variants, signatures of single base, doublet base, and indel mutations, and changes in gene expression. We show that the mutational landscapes of hereditary and sporadic MSI-CRCs, including mutational signatures and mutation densities genome-wide and in microsatellites, are highly similar. Only a low number of differentially expressed genes were found, enriched to interferon-γ regulated immune response pathways. Analysis of the variance in allelic fractions of somatic variants in each tumour group revealed higher clonal heterogeneity in sporadic MSI-CRCs. Our results suggest that the differing molecular origins of MMR deficiency in hereditary and sporadic MSI-CRCs do not result in substantial differences in the mutational landscapes of these tumours. The divergent patterns of clonal evolution between the tumour groups may have clinical implications, as high clonal heterogeneity has been associated with decreased tumour immunosurveillance and reduced responsiveness to immunotherapy.

Inherited mutations affecting the SRCAP complex are central in moderate-penetrance predisposition to uterine leiomyomas.

Uterine leiomyomas (ULs) are benign smooth muscle tumors that are common in premenopausal women. Somatic alterations in MED12, HMGA2, FH, genes encoding subunits of the SRCAP complex, and genes involved in Cullin 3-RING E3 ligase neddylation are mutually exclusive UL drivers. Established predisposition genes explain only partially the estimated heritability of leiomyomas. Here, we examined loss-of-function variants across 18,899 genes in a cohort of 233,614 White European women, revealing variants in four genes encoding SRCAP complex subunits (YEATS4, ZNHIT1, DMAP1, and ACTL6A) with a significant association to ULs, and YEATS4 and ZNHIT1 strikingly rank first and second, respectively. Positive mutation status was also associated with younger age at diagnosis and hysterectomy. Moderate-penetrance UL risk was largely attributed to rare non-synonymous mutations affecting the SRCAP complex. To examine this disease phenotype more closely, we set out to identify inherited mutations affecting the SRCAP complex in our in-house sample collection of Finnish individuals with ULs (n = 860). We detected one individual with an ACTL6A splice-site mutation, two individuals with a YEATS4 missense mutation, and four individuals with DMAP1 mutations: one splice-site, one nonsense, and two missense variants. These individuals had large and/or multiple ULs, were often diagnosed at an early age, and many had family history of ULs. When a somatic second hit was found, ACTL6A and DMAP1 were silenced in tumors by somatic mutation and YEATS4 by promoter hypermethylation. Decreased H2A.Z staining was observed in the tumors, providing further evidence for the pathogenic nature of the germline mutations. Our results establish inactivation of genes encoding SRCAP complex subunits as a central contributor to moderate-penetrance UL predisposition.

Molecular subclass of uterine fibroids predicts tumor shrinkage in response to ulipristal acetate.

Precision medicine carries great potential for management of all tumor types. The aim of this retrospective study was to investigate if the two most common genetically distinct uterine fibroid subclasses, driven by aberrations in MED12 and HMGA2 genes, respectively, influence response to treatment with the progesterone receptor modulator ulipristal acetate. Changes in diameter and mutation status were derived for 101 uterine fibroids surgically removed after ulipristal acetate treatment. A significant difference in treatment response between the two major subclasses was detected. MED12 mutant fibroids had 4.4 times higher odds of shrinking in response to ulipristal acetate treatment as compared to HMGA2 driven fibroids (95% confidence interval 1.37-13.9; P = 0.013), and in a multivariate analysis molecular subclassification was an independent predictive factor. Compatible with this finding, gene expression and DNA methylation analyses revealed subclass specific differences in progesterone receptor signaling. The work provides a proof-of-principle that uterine fibroid treatment response is influenced by molecular subclass and that the genetic subclasses should be taken into account when evaluating current and future uterine fibroid therapies.

Newer Pharmacologic Treatments in Adults With Type 2 Diabetes: A Clinical Guideline From the American College of Physicians.

DESCRIPTION: The American College of Physicians (ACP) developed this clinical guideline to update recommendations on newer pharmacologic treatments of type 2 diabetes. This clinical guideline is based on the best available evidence for effectiveness, comparative benefits and harms, consideration of patients' values and preferences, and costs. METHODS: This clinical guideline is based on a systematic review of the effectiveness and harms of newer pharmacologic treatments of type 2 diabetes, including glucagon-like peptide-1 (GLP-1) agonists, a GLP-1 agonist and glucose-dependent insulinotropic polypeptide agonist, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and long-acting insulins, used either as monotherapy or in combination with other medications. The Clinical Guidelines Committee prioritized the following outcomes, which were evaluated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach: all-cause mortality, major adverse cardiovascular events, myocardial infarction, stroke, hospitalization for congestive heart failure, progression of chronic kidney disease, serious adverse events, and severe hypoglycemia. Weight loss, as measured by percentage of participants who achieved at least 10% total body weight loss, was a prioritized outcome, but data were insufficient for network meta-analysis and were not rated with GRADE. AUDIENCE AND PATIENT POPULATION: The audience for this clinical guideline is physicians and other clinicians. The population is nonpregnant adults with type 2 diabetes. RECOMMENDATION 1: ACP recommends adding a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or glucagon-like peptide-1 (GLP-1) agonist to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control (strong recommendation; high-certainty evidence). • Use an SGLT-2 inhibitor to reduce the risk for all-cause mortality, major adverse cardiovascular events, progression of chronic kidney disease, and hospitalization due to congestive heart failure. • Use a GLP-1 agonist to reduce the risk for all-cause mortality, major adverse cardiovascular events, and stroke. RECOMMENDATION 2: ACP recommends against adding a dipeptidyl peptidase-4 (DPP-4) inhibitor to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control to reduce morbidity and all-cause mortality (strong recommendation; high-certainty evidence).

Outpatient Visits and Antibiotic Use Due to Higher-Valency Pneumococcal Vaccine Serotypes.

BACKGROUND: In 2022-2023, 15- and 20-valent pneumococcal conjugate vaccines (PCV15/PCV20) were recommended for infants. We aimed to estimate the incidence of outpatient visits and antibiotic prescriptions in US children (≤17 years) from 2016-2019 for acute otitis media, pneumonia, and sinusitis associated with PCV15- and PCV20-additional (non-PCV13) serotypes to quantify PCV15/20 potential impacts. METHODS: We estimated the incidence of PCV15/20-additional serotype-attributable visits and antibiotic prescriptions as the product of all-cause incidence rates, derived from national health care surveys and MarketScan databases, and PCV15/20-additional serotype-attributable fractions. We estimated serotype-specific attributable fractions using modified vaccine-probe approaches incorporating incidence changes post-PCV13 and ratios of PCV13 versus PCV15/20 serotype frequencies, estimated through meta-analyses. RESULTS: Per 1000 children annually, PCV15-additional serotypes accounted for an estimated 2.7 (95% confidence interval, 1.8-3.9) visits and 2.4 (95% CI, 1.6-3.4) antibiotic prescriptions. PCV20-additional serotypes resulted in 15.0 (95% CI, 11.2-20.4) visits and 13.2 (95% CI, 9.9-18.0) antibiotic prescriptions annually per 1000 children. PCV15/20-additional serotypes account for 0.4% (95% CI, 0.2%-0.6%) and 2.1% (95% CI, 1.5%-3.0%) of pediatric outpatient antibiotic use. CONCLUSIONS: Compared with PCV15-additional serotypes, PCV20-additional serotypes account for > 5 times the burden of visits and antibiotic prescriptions. Higher-valency PCVs, especially PCV20, may contribute to preventing pediatric pneumococcal respiratory infections and antibiotic use.

Impact of the COVID-19 Pandemic on Inpatient Antibiotic Use in the United States, January 2019 Through July 2022.

Antimicrobial use data reported to the National Healthcare Safety Network's Antimicrobial Use and Resistance Module between January 2019 and July 2022 were analyzed to assess the impact of the COVID-19 pandemic on inpatient antimicrobial use.

GNAS mutation inhibits growth and induces phosphodiesterase 4D expression in colorectal cancer cell lines.

Approximately 5% of colorectal cancers (CRCs) have a gain-of-function mutation in the GNAS gene, which leads to the activation of cAMP-dependent signaling pathways and associates with poor prognosis. We investigated the effect of an activating GNAS mutation in CRC cell lines on gene expression and cell proliferation in vitro, and tumor growth in vivo. GNAS-mutated (GNASmt) HCT116 cells showed stimulated synthesis of cAMP as compared to parental (Par) cells. The most upregulated gene in the GNASmt cells was cAMP-hydrolyzing phosphodiesterase 4D (PDE4D) as detected by RNA sequencing. To further validate our finding, we analyzed PDE4D expression in a set of human CRC tumors (n = 35) and demonstrated overexpression in GNAS mutant CRC tumors as compared to GNAS wild-type tumors. The GNASmt HCT116 cells proliferated more slowly than the Par cells. PDE4 inhibitor Ro 20-1724 and PDE4D subtype selective inhibitor GEBR-7b further suppressed the proliferation of GNASmt cells without an effect on Par cells. The growth inhibitory effect of these inhibitors was also seen in the intrinsically GNAS-mutated SK-CO-1 CRC cell line having high levels of cAMP synthesis and PDE4D expression. In vivo, GNASmt HCT116 cells formed smaller tumors than the Par cells in nude mice. In conclusion, our findings demonstrate that GNAS mutation results in the growth suppression of CRC cells. Moreover, the GNAS mutation-induced overexpression of PDE4D provides a potential avenue to impede the proliferation of CRC cells through the use of PDE4 inhibitors.

Genome-Wide Association Study Identifies 4 Novel Risk Loci for Small Intestinal Neuroendocrine Tumors Including a Missense Mutation in LGR5.

BACKGROUND & AIMS: Small intestinal neuroendocrine tumor (SI-NET) is a rare disease, but its incidence has increased over the past 4 decades. Understanding the genetic risk factors underlying SI-NETs can help in disease prevention and may provide clinically beneficial markers for diagnosis. Here the results of the largest genome-wide association study of SI-NETs performed to date with 405 cases and 614,666 controls are reported. METHODS: Samples from 307 patients with SI-NETs and 287,137 controls in the FinnGen study were used for the identification of SI-NET risk-associated genetic variants. The results were also meta-analyzed with summary statistics from the UK Biobank (n = 98 patients with SI-NET and n = 327,529 controls). RESULTS: We identified 6 genome-wide significant (P < 5 × 10-8) loci associated with SI-NET risk, of which 4 (near SEMA6A, LGR5, CDKAL1, and FERMT2) are novel and 2 (near LTA4H-ELK and in KIF16B) have been reported previously. Interestingly, the top hit (rs200138614; P = 1.80 × 10-19) was a missense variant (p.Cys712Phe) in the LGR5 gene, a bona-fide marker of adult intestinal stem cells and a potentiator of canonical WNT signaling. The association was validated in an independent Finnish collection of 70 patients with SI-NETs, as well as in the UK Biobank exome sequence data (n = 92 cases and n = 392,814 controls). Overexpression of LGR5 p.Cys712Phe in intestinal organoids abolished the ability of R-Spondin1 to support organoid growth, indicating that the mutation perturbed R-Spondin-LGR5 signaling. CONCLUSIONS: Our study is the largest genome-wide association study to date on SI-NETs and reported 4 new associated genome-wide association study loci, including a novel missense mutation (rs200138614, p.Cys712Phe) in LGR5, a canonical marker of adult intestinal stem cells.

Cancer incidence following non-neoplastic medical conditions: a prospective population-based cohort study.

BACKGROUND AND PURPOSE: Many non-neoplastic diseases have been established to be tumorigenic, and cancers are sometimes misdiagnosed as non-neoplastic diseases. We conducted a comprehensive registry-based study of site-specific cancer diagnosis risk following the diagnosis of any preceding medical condition (PMC) encoded by the International Classification of Diseases (ICD)-10 classification. MATERIAL AND METHODS: We analyzed healthcare data and cancer data for a random population-based sample of 2.5 million individuals living in Finland on January 1, 2000. Hazard ratios for each PMC and cancer pair were estimated using piecewise constant hazard regression models. P-values were corrected for multiple testing with the Bonferroni method. RESULTS: Several lifestyle-related PMCs were associated with the risk of cancer diagnosis, exemplified by chronic obstructive pulmonary disease and subsequent lung cancer diagnosis risk (female hazard ratio [HR] = 9.91, 95% confidence interval [CI]: 9.18-19.7, p-adj. < 0.0001; male HR = 5.69, 95% CI: 5.43-5.96, p-adj. < 0.0001). Diagnosis risk of ill-defined cancers appeared to increase following diagnosis of Alzheimer's disease (AD). We identified rare PMCs of potential interest. INTERPRETATION: A considerable proportion of the statistically significant associations were explainable by tobacco smoking and alcohol use. The enrichment of ill-defined cancer diagnoses in persons with AD, together with the overall inverse association between AD and cancer, may reflect underdiagnosis of cancer in this patient population. Our results provide a useful resource for research on the prevention and early detection of cancer.

Pharmacologic Treatment of Primary Osteoporosis or Low Bone Mass to Prevent Fractures in Adults: A Living Clinical Guideline From the American College of Physicians.

DESCRIPTION: This guideline updates the 2017 American College of Physicians (ACP) recommendations on pharmacologic treatment of primary osteoporosis or low bone mass to prevent fractures in adults. METHODS: The ACP Clinical Guidelines Committee based these recommendations on an updated systematic review of evidence and graded them using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. AUDIENCE AND PATIENT POPULATION: The audience for this guideline includes all clinicians. The patient population includes adults with primary osteoporosis or low bone mass. RECOMMENDATION 1A: ACP recommends that clinicians use bisphosphonates for initial pharmacologic treatment to reduce the risk of fractures in postmenopausal females diagnosed with primary osteoporosis (strong recommendation; high-certainty evidence). RECOMMENDATION 1B: ACP suggests that clinicians use bisphosphonates for initial pharmacologic treatment to reduce the risk of fractures in males diagnosed with primary osteoporosis (conditional recommendation; low-certainty evidence). RECOMMENDATION 2A: ACP suggests that clinicians use the RANK ligand inhibitor (denosumab) as a second-line pharmacologic treatment to reduce the risk of fractures in postmenopausal females diagnosed with primary osteoporosis who have contraindications to or experience adverse effects of bisphosphonates (conditional recommendation; moderate-certainty evidence). RECOMMENDATION 2B: ACP suggests that clinicians use the RANK ligand inhibitor (denosumab) as a second-line pharmacologic treatment to reduce the risk of fractures in males diagnosed with primary osteoporosis who have contraindications to or experience adverse effects of bisphosphonates (conditional recommendation; low-certainty evidence). RECOMMENDATION 3: ACP suggests that clinicians use the sclerostin inhibitor (romosozumab, moderate-certainty evidence) or recombinant PTH (teriparatide, low-certainty evidence), followed by a bisphosphonate, to reduce the risk of fractures only in females with primary osteoporosis with very high risk of fracture (conditional recommendation). RECOMMENDATION 4: ACP suggests that clinicians take an individualized approach regarding whether to start pharmacologic treatment with a bisphosphonate in females over the age of 65 with low bone mass (osteopenia) to reduce the risk of fractures (conditional recommendation; low-certainty evidence).

Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major Depressive Disorder: A Living Clinical Guideline From the American College of Physicians.

DESCRIPTION: The purpose of this guideline from the American College of Physicians (ACP) is to present updated clinical recommendations on nonpharmacologic and pharmacologic interventions as initial and second-line treatments during the acute phase of a major depressive disorder (MDD) episode, based on the best available evidence on the comparative benefits and harms, consideration of patient values and preferences, and cost. METHODS: The ACP Clinical Guidelines Committee based these recommendations on an updated systematic review of the evidence. AUDIENCE AND PATIENT POPULATION: The audience for this guideline includes clinicians caring for adult patients in the acute phase of MDD in ambulatory care. The patient population includes adults in the acute phase of MDD. RECOMMENDATION 1A: ACP recommends monotherapy with either cognitive behavioral therapy or a second-generation antidepressant as initial treatment in patients in the acute phase of moderate to severe major depressive disorder (strong recommendation; moderate-certainty evidence). RECOMMENDATION 1B: ACP suggests combination therapy with cognitive behavioral therapy and a second-generation antidepressant as initial treatment in patients in the acute phase of moderate to severe major depressive disorder (conditional recommendation; low-certainty evidence). The informed decision on the options of monotherapy with cognitive behavioral therapy versus second-generation antidepressants or combination therapy should be personalized and based on discussion of potential treatment benefits, harms, adverse effect profiles, cost, feasibility, patients' specific symptoms (such as insomnia, hypersomnia, or fluctuation in appetite), comorbidities, concomitant medication use, and patient preferences. RECOMMENDATION 2: ACP suggests monotherapy with cognitive behavioral therapy as initial treatment in patients in the acute phase of mild major depressive disorder (conditional recommendation; low-certainty evidence). RECOMMENDATION 3: ACP suggests one of the following options for patients in the acute phase of moderate to severe major depressive disorder who did not respond to initial treatment with an adequate dose of a second-generation antidepressant: • Switching to or augmenting with cognitive behavioral therapy (conditional recommendation; low-certainty evidence) • Switching to a different second-generation antidepressant or augmenting with a second pharmacologic treatment (see Clinical Considerations) (conditional recommendation; low-certainty evidence) The informed decision on the options should be personalized and based on discussion of potential treatment benefits, harms, adverse effect profiles, cost, feasibility, patients' specific symptoms (such as insomnia, hypersomnia, or fluctuation in appetite), comorbidities, concomitant medication use, and patient preferences.

Management of Uterine Fibroids and Sarcomas: The Palermo Position Paper.

BACKGROUND: Uterine fibroids are benign monoclonal tumors originating from the smooth muscle cells of the myometrium, constituting the most prevalent pathology within the female genital tract. Uterine sarcomas, although rare, still represent a diagnostic challenge and should be managed in centers with adequate expertise in gynecological oncology. OBJECTIVES: This article is aimed to summarize and discuss cutting-edge elements about the diagnosis and management of uterine fibroids and sarcomas. METHODS: This paper is a report of the lectures presented in an expert meeting about uterine fibroids and sarcomas held in Palermo in February 2023. OUTCOME: Overall, the combination of novel molecular pathways may help combine biomarkers and expert ultrasound for the differential diagnosis of uterine fibroids and sarcomas. On the one hand, molecular and cellular maps of uterine fibroids and matched myometrium may enhance our understanding of tumor development compared to histologic analysis and whole tissue transcriptomics, and support the development of minimally invasive treatment strategies; on the other hand, ultrasound imaging allows in most of the cases a proper mapping the fibroids and to differentiate between benign and malignant lesions, which need appropriate management. CONCLUSIONS AND OUTLOOK: The choice of uterine fibroid management, including pharmacological approaches, surgical treatment, or other strategies, such as high-intensity focused ultrasound (HIFU), should be carefully considered, taking into account the characteristics of the patient and reproductive prognosis.

Antibiotic Stewardship in Outpatient Telemedicine: Adapting Centers for Disease Control and Prevention Core Elements to Optimize Antibiotic Use.

The rapid expansion of telemedicine has highlighted challenges and opportunities to improve antibiotic use and effectively adapt antibiotic stewardship best practices to outpatient telemedicine settings. Antibiotic stewardship integration into telemedicine is essential to optimize antibiotic prescribing for patients and ensure health care quality. We performed a narrative review of published literature on antibiotic prescribing and stewardship in outpatient telemedicine to inform the adaptation of the Core Elements of Outpatient Antibiotic Stewardship framework to outpatient telemedicine settings. Our narrative review suggests that in-person antibiotic stewardship interventions can be adapted to outpatient telemedicine settings. We present considerations for applying the Core Elements of Outpatient Antibiotic Stewardship to outpatient telemedicine which builds upon growing evidence describing care delivery and quality improvement in this setting. Additional applied implementation research is necessary to inform the application of effective, sustainable, and equitable antibiotic stewardship interventions across the spectrum of outpatient telemedicine.

Prescribing of Outpatient Antibiotics Commonly Used for Respiratory Infections Among Adults Before and During the Coronavirus Disease 2019 Pandemic in Brazil.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic may have impacted outpatient antibiotic prescribing in low- and middle-income countries such as Brazil. However, outpatient antibiotic prescribing in Brazil, particularly at the prescription level, is not well-described. METHODS: We used the IQVIA MIDAS database to characterize changes in prescribing rates of antibiotics commonly prescribed for respiratory infections (azithromycin, amoxicillin-clavulanate, levofloxacin/moxifloxacin, cephalexin, and ceftriaxone) among adults in Brazil overall and stratified by age and sex, comparing prepandemic (January 2019-March 2020) and pandemic periods (April 2020-December 2021) using uni- and multivariate Poisson regression models. The most common prescribing provider specialties for these antibiotics were also identified. RESULTS: In the pandemic period compared to the prepandemic period, outpatient azithromycin prescribing rates increased across all age-sex groups (incidence rate ratio [IRR] range, 1.474-3.619), with the greatest increase observed in males aged 65-74 years; meanwhile, prescribing rates for amoxicillin-clavulanate and respiratory fluoroquinolones mostly decreased, and changes in cephalosporin prescribing rates varied across age-sex groups (IRR range, 0.134-1.910). For all antibiotics, the interaction of age and sex with the pandemic in multivariable models was an independent predictor of prescribing changes comparing the pandemic versus prepandemic periods. General practitioners and gynecologists accounted for the majority of increases in azithromycin and ceftriaxone prescribing during the pandemic period. CONCLUSIONS: Substantial increases in outpatient prescribing rates for azithromycin and ceftriaxone were observed in Brazil during the pandemic with prescribing rates being disproportionally different by age and sex. General practitioners and gynecologists were the most common prescribers of azithromycin and ceftriaxone during the pandemic, identifying them as potential specialties for antimicrobial stewardship interventions.

From APC to the genetics of hereditary and familial colon cancer syndromes.

Hereditary colorectal cancer (CRC) syndromes attributable to high penetrance mutations represent 9-26% of young-onset CRC cases. The clinical significance of many of these mutations is understood well enough to be used in diagnostics and as an aid in patient care. However, despite the advances made in the field, a significant proportion of familial and early-onset cases remains molecularly uncharacterized and extensive work is still needed to fully understand the genetic nature of CRC susceptibility. With the emergence of next-generation sequencing and associated methods, several predisposition loci have been unraveled, but validation is incomplete. Individuals with cancer-predisposing mutations are currently enrolled in life-long surveillance, but with the development of new treatments, such as cancer vaccinations, this might change in the not so distant future for at least some individuals. For individuals without a known cause for their disease susceptibility, prevention and therapy options are less precise. Herein, we review the progress achieved in the last three decades with a focus on how CRC predisposition genes were discovered. Furthermore, we discuss the clinical implications of these discoveries and anticipate what to expect in the next decade.

WNT2 activation through proximal germline deletion predisposes to small intestinal neuroendocrine tumors and intestinal adenocarcinomas.

Many hereditary cancer syndromes are associated with an increased risk of small and large intestinal adenocarcinomas. However, conditions bearing a high risk to both adenocarcinomas and neuroendocrine tumors are yet to be described. We studied a family with 16 individuals in four generations affected by a wide spectrum of intestinal tumors, including hyperplastic polyps, adenomas, small intestinal neuroendocrine tumors, and colorectal and small intestinal adenocarcinomas. To assess the genetic susceptibility and understand the novel phenotype, we utilized multiple molecular methods, including whole genome sequencing, RNA sequencing, single cell sequencing, RNA in situ hybridization and organoid culture. We detected a heterozygous deletion at the cystic fibrosis locus (7q31.2) perfectly segregating with the intestinal tumor predisposition in the family. The deletion removes a topologically associating domain border between CFTR and WNT2, aberrantly activating WNT2 in the intestinal epithelium. These consequences suggest that the deletion predisposes to small intestinal neuroendocrine tumors and small and large intestinal adenocarcinomas, and reveals the broad tumorigenic effects of aberrant WNT activation in the human intestine.

Novel germline variant in the histone demethylase and transcription regulator KDM4C induces a multi-cancer phenotype.

BACKGROUND: Genes involved in epigenetic regulation are central for chromatin structure and gene expression. Specific mutations in these might promote carcinogenesis in several tissue types. METHODS: We used exome, whole-genome and Sanger sequencing to detect rare variants shared by seven affected individuals in a striking early-onset multi-cancer family. The only variant that segregated with malignancy resided in a histone demethylase KDM4C. Consequently, we went on to study the epigenetic landscape of the mutation carriers with ATAC, ChIP (chromatin immunoprecipitation) and RNA-sequencing from lymphoblastoid cell lines to identify possible pathogenic effects. RESULTS: A novel variant in KDM4C, encoding a H3K9me3 histone demethylase and transcription regulator, was found to segregate with malignancy in the family. Based on Roadmap Epigenomics Project data, differentially accessible chromatin regions between the variant carriers and controls enrich to normally H3K9me3-marked chromatin. We could not detect a difference in global H3K9 trimethylation levels. However, carriers of the variant seemed to have more trimethylated H3K9 at transcription start sites. Pathway analyses of ChIP-seq and differential gene expression data suggested that genes regulated through KDM4C interaction partner EZH2 and its interaction partner PLZF are aberrantly expressed in mutation carriers. CONCLUSIONS: The apparent dysregulation of H3K9 trimethylation and KDM4C-associated genes in lymphoblastoid cells supports the hypothesis that the KDM4C variant is causative of the multi-cancer susceptibility in the family. As the variant is ultrarare, located in the conserved catalytic JmjC domain and predicted pathogenic by the majority of available in silico tools, further studies on the role of KDM4C in cancer predisposition are warranted.

Mutational processes of distinct POLE exonuclease domain mutants drive an enrichment of a specific TP53 mutation in colorectal cancer.

Cancer genomes with mutations in the exonuclease domain of Polymerase Epsilon (POLE) present with an extraordinarily high somatic mutation burden. In vitro studies have shown that distinct POLE mutants exhibit different polymerase activity. Yet, genome-wide mutation patterns and driver mutation formation arising from different POLE mutants remains unclear. Here, we curated somatic mutation calls from 7,345 colorectal cancer samples from published studies and publicly available databases. These include 44 POLE mutant samples including 9 with whole genome sequencing data available. The POLE mutant samples were categorized based on the specific POLE mutation present. Mutation spectrum, associations of somatic mutations with epigenomics features and co-occurrence with specific driver mutations were examined across different POLE mutants. We found that different POLE mutants exhibit distinct mutation spectrum with significantly higher relative frequency of C>T mutations in POLE V411L mutants. Our analysis showed that this increase frequency in C>T mutations is not dependent on DNA methylation and not associated with other genomic features and is thus specifically due to DNA sequence context alone. Notably, we found strong association of the TP53 R213* mutation specifically with POLE P286R mutants. This truncation mutation occurs within the TT[C>T]GA context. For C>T mutations, this sequence context is significantly more likely to be mutated in POLE P286R mutants compared with other POLE exonuclease domain mutants. This study refines our understanding of DNA polymerase fidelity and underscores genome-wide mutation spectrum and specific cancer driver mutation formation observed in POLE mutant cancers.

Colonoscopy for Diagnostic Evaluation and Interventions to Prevent Recurrence After Acute Left-Sided Colonic Diverticulitis: A Clinical Guideline From the American College of Physicians.

DESCRIPTION: The American College of Physicians (ACP) developed this guideline to provide clinical recommendations on the role of colonoscopy for diagnostic evaluation of colorectal cancer (CRC) after a presumed diagnosis of acute left-sided colonic diverticulitis and on the role of pharmacologic, nonpharmacologic, and elective surgical interventions to prevent recurrence after initial treatment of acute complicated and uncomplicated left-sided colonic diverticulitis. This guideline is based on the current best available evidence about benefits and harms, taken in the context of costs and patient values and preferences. METHODS: The ACP Clinical Guidelines Committee (CGC) based these recommendations on a systematic review on the role of colonoscopy after acute left-sided colonic diverticulitis and pharmacologic, nonpharmacologic, and elective surgical interventions after initial treatment. The systematic review evaluated outcomes rated by the CGC as critical or important. This guideline was developed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method. TARGET AUDIENCE AND PATIENT POPULATION: The target audience is all clinicians, and the target patient population is adults with recent episodes of acute left-sided colonic diverticulitis. RECOMMENDATION 1: ACP suggests that clinicians refer patients for a colonoscopy after an initial episode of complicated left-sided colonic diverticulitis in patients who have not had recent colonoscopy (conditional recommendation; low-certainty evidence). RECOMMENDATION 2: ACP recommends against clinicians using mesalamine to prevent recurrent diverticulitis (strong recommendation; high-certainty evidence). RECOMMENDATION 3: ACP suggests that clinicians discuss elective surgery to prevent recurrent diverticulitis after initial treatment in patients who have either uncomplicated diverticulitis that is persistent or recurs frequently or complicated diverticulitis (conditional recommendation; low-certainty evidence). The informed decision whether or not to undergo surgery should be personalized based on a discussion of potential benefits, harms, costs, and patient's preferences.