AGA Clinical Practice Update on Young Adult-Onset Colorectal Cancer Diagnosis and Management: Expert Review.

DESCRIPTION: The objectives of this expert review are: (1) to prepare clinicians to recognize the presentation and evidence-based risk factors for young adult-onset colorectal cancer (CRC), defined as CRC diagnosed in individuals 18 - <50 years of age; (2) to improve management for patients with young onset CRC. This review will focus on the following topics relevant to young adult-onset CRC: epidemiology and risk factors; clinical presentation; diagnostic and therapeutic management including options for colorectal and extra-colonic surgical intervention, chemotherapy and immune-oncology therapies; genetic testing and its potential impact on preimplantation genetics; fertility preservation; and cancer surveillance recommendations for these individuals and their family members. METHODS: The evidence reviewed in this manuscript is a summation of relevant scientific publications, expert opinion statements, and current practice guidelines. BEST PRACTICE ADVICE 1: With the rising incidence of people developing CRC before 50 years of age, diagnostic evaluation of the colon and rectum is encouraged for all patients, irrespective of age, who present with symptoms that may be consistent with CRC, including but not limited to: rectal bleeding, weight loss, change in bowel habit, abdominal pain, iron deficiency anemia. BEST PRACTICE ADVICE 2: Clinicians should obtain family history of colorectal and other cancers in first and second degree relatives of patients with young adult-onset CRC and discuss genetic evaluation with germline genetic testing either in targeted genes based on phenotypic presentation or in multiplex gene panels regardless of family history. BEST PRACTICE ADVICE 3: Clinicians should present the role of fertility preservation prior to cancer-directed therapy including surgery, pelvic radiation, or chemotherapy BEST PRACTICE ADVICE 4: Clinicians should counsel patients on the benefit of germline genetic testing and familial cancer panel testing in the pre-surgical period to inform which surgical options may be available to the patient with young adult-onset CRC BEST PRACTICE ADVICE 5: Clinicians should consider utilizing germline and somatic genetic testing results to inform chemotherapeutic strategies BEST PRACTICE ADVICE 6: Clinicians should offer hereditary CRC syndrome specific screening for CRC and extra-colonic cancers only to young adult-onset CRC patients who have a genetically or clinically diagnosed hereditary CRC syndrome. For patients with sporadic young adult-onset CRC, extra-colonic screening and CRC surveillance intervals are the same as for patients with older adult-onset CRC.

MetaMarker: a pipeline for de novo discovery of novel metagenomic biomarkers.

SUMMARY: We present MetaMarker, a pipeline for discovering metagenomic biomarkers from whole-metagenome sequencing samples. Different from existing methods, MetaMarker is based on a de novo approach that does not require mapping raw reads to a reference database. We applied MetaMarker on whole-metagenome sequencing of colorectal cancer (CRC) stool samples from France to discover CRC specific metagenomic biomarkers. We showed robustness of the discovered biomarkers by validating in independent samples from Hong Kong, Austria, Germany and Denmark. We further demonstrated these biomarkers could be used to build a machine learning classifier for CRC prediction. AVAILABILITY AND IMPLEMENTATION: MetaMarker is freely available at https://bitbucket.org/mkoohim/metamarker under GPLv3 license. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A mutational comparison of adult and adolescent and young adult (AYA) colon cancer.

BACKGROUND: It is possible that the relative lack of progress in treatment outcomes among adolescent and young adult (AYA) patients with cancer is caused by a difference in disease biology compared with the corresponding diseases in younger and older individuals. There is evidence that colon cancer is more aggressive and has a poorer prognosis in AYA patients than in older adult patients. METHODS: To further understand the molecular basis for this difference, whole-exome sequencing was conducted on a cohort of 30 adult, 30 AYA, and 2 pediatric colon cancers. RESULTS: A statistically significant difference in mutational frequency was observed between AYA and adult samples in 43 genes, including ROBO1, MYC binding protein 2 (MYCBP2), breast cancer 2 (early onset) (BRCA2), MAP3K3, MCPH1, RASGRP3, PTCH1, RAD9B, CTNND1, ATM, NF1; KIT, PTEN, and FBXW7. Many of these mutations were nonsynonymous, missense, stop-gain, or frameshift mutations that were damaging. Next, RNA sequencing was performed on a subset of the samples to confirm the mutations identified by exome sequencing. This confirmation study verified the presence of a significantly greater frequency of damaging mutations in AYA compared with adult colon cancers for 5 of the 43 genes (MYCBP2, BRCA2, PHLPP1, TOPORS, and ATR). CONCLUSIONS: The current results provide the rationale for a more comprehensive study with a larger sample set and experimental validation of the functional impact of the identified variants along with their contribution to the biologic and clinical characteristics of AYA colon cancer. Cancer 2018;124:1070-82. © 2017 American Cancer Society.

Loss of ZG16 is associated with molecular and clinicopathological phenotypes of colorectal cancer.

BACKGROUND: Zymogen granule protein 16 (ZG16) is one of the most significantly down-regulated genes in colorectal cancer (CRC) tissues. This study aimed to further evaluate its expression changes and investigate its association with molecular and clinicopathological characteristics of CRC. METHODS: We applied quantitative RT-PCR to determine expression difference between tumor and matched normal tissues from 23 CRC patients. To further validate the down-regulation in tumor tissues, we performed immunohistochemistry (IHC) analysis in 40 paraffin-embedded normal-tumor pairs and 22 colon tissues with a variety of diseases. To evaluate if the ZG16 gene changes were associated with clinicopathological characteristics, we further analyzed the gene expression and copy number changes from The Cancer Genome Atlas (TCGA) and Oncomine datasets. RESULTS: Quantitative RT-PCR confirmed significant down-regulation (~ 130-fold) of ZG16 in all tumor tissues. ZG16 expression was in an organ-specific manner with an extremely high expression in normal epithelial cells of small intestine, colon and rectum. IHC analysis showed that ZG16 protein was completely lost in all of 40 CRC tissues, and partially lost in premalignant adenomatous polyps (adenomas) and chronic ulcerative colitis tissues. Gene expression and copy number changes were significantly associated with multiple molecular and clinicopathological features of CRC including microsatellite instability (MSI), MLH1 silencing, CpG island methylator phenotype, hyper-mutation status, gender, presence of synchronous adenomas, and histological type (P < 0.05). Patients with lower ZG16 gene expression showed shorter progression-free survival and overall survival than those with relatively higher expression (P < 0.05). Multivariate analysis suggested that the ZG16 expression was an independent prognosis factor (P = 0.012, HR = 6.286, 95% CI = 0.816-0.975). CONCLUSION: For the first time, our study demonstrated that ZG16 expression was sequentially reduced from normal, adenoma, to carcinoma. Association with multiple clinicopathological features indicates that ZG16 may play an important role in cancer initiation and progression. ZG16 may serve as a potential biomarker for diagnosis and prognosis of CRC.

Moderate-to-severe obstructive sleep apnea is associated with telomere lengthening.

Obstructive sleep apnea (OSA) is associated with cardiometabolic diseases. Telomere shortening is linked to hypertension, diabetes mellitus, and cardiovascular diseases. Because these conditions are highly prevalent in OSA, we hypothesized that telomere length (TL) would be reduced in OSA patients. We identified 106 OSA and 104 non-OSA subjects who underwent polysomnography evaluation. Quantitative PCR was used to measure telomere length in genomic DNA isolated from peripheral blood samples. The association between OSA and TL was determined using unadjusted and adjusted linear models. There was no difference in TL between the OSA and non-OSA (control) group. However, we observed a J-shaped relationship between TL and OSA severity: the longest TL in moderate-to-severe OSA [4,918 ± 230 (SD) bp] and the shortest TL in mild OSA (4,735 ± 145 bp). Mean TL in moderate-to-severe OSA was significantly longer than in the control group after adjustment for age, sex, body mass index, hypertension, dyslipidemia, and depression (ß = 96.0, 95% confidence interval: 15.4-176.6, P = 0.020). In conclusion, moderate-to-severe OSA is associated with telomere lengthening. Our findings support the idea that changes in TL are not unidirectional processes, such that telomere shortening occurs with age and disease but may be prolonged in moderate-to-severe OSA.NEW & NOTEWORTHY Here, we show that moderate-to-severe obstructive sleep apnea is associated with longer telomeres, independent of age and cardiovascular risk factors, challenging the hypothesis that telomere shortening is a unidirectional process related to age/disease. A better understanding of the mechanisms underlying telomere dynamics may identify targets for therapeutic intervention in cardiovascular aging/other chronic diseases.

Novel Approach to Fecal Occult Blood Testing by Assay of Erythrocyte-Specific microRNA Markers.

BACKGROUND: Fecal occult blood testing (FOBT) has historically relied on methods to detect hemoglobin with no fundamental innovations in decades. AIM: To examine microRNA (miRNA) as a new marker class for FOBT. METHODS: Candidate miRNA markers were identified by small RNA sequencing of human whole blood compared to colorectal epithelia. Markers were tested in human blood cell subsets and blood from non-human species. We assessed assay linearity in blood spiking and marker stability in stool over incubation experiments. Levels of candidate erythrocyte markers were explored in stools from colorectal cancer (CRC) cases and controls. RESULTS: Based on small RNA sequencing and validation RT-qPCR, expression level of each of the top blood-enriched markers (hsa-miR-144-3p, 144-5p, 451a, 486-5p, 363-3p, 20b-5p) could perfectly discriminate blood from colorectal epithelia. All six markers arose from and showed specificity to human erythrocytes. Marker levels increased linearly with erythrocyte concentration in saline or stool and demonstrated a broader dynamic range than did immunochemical test for hemoglobin. Degradation of markers occurred in stool but was reduced with preservative buffers. Erythrocyte marker candidates for stool testing were selected in an exploratory set of stools (20 CRC, 40 normal). Candidates were then further tested in a feasibility set (29 CRC, 31 advanced adenoma, and 115 normal); a miRNA panel (hsa-miR-451a, 144-5p, and 200b-3p as normalizer) yielded an AUC of 0.89 (95% CI 0.82-0.95, P < .0001) for CRC. CONCLUSIONS: A novel miRNA-based approach accurately quantifies fecal blood levels over a broad, clinically relevant range.

Biologic and clinical characteristics of adolescent and young adult cancers: Acute lymphoblastic leukemia, colorectal cancer, breast cancer, melanoma, and sarcoma.

Adolescent and young adult (AYA) patients with cancer have not attained the same improvements in overall survival as either younger children or older adults. One possible reason for this disparity may be that the AYA cancers exhibit unique biologic characteristics, resulting in differences in clinical and treatment resistance behaviors. This report from the biologic component of the jointly sponsored National Cancer Institute and LiveStrong Foundation workshop entitled "Next Steps in Adolescent and Young Adult Oncology" summarizes the current status of biologic and translational research progress for 5 AYA cancers; colorectal cancer breast cancer, acute lymphoblastic leukemia, melanoma, and sarcoma. Conclusions from this meeting included the need for basic biologic, genomic, and model development for AYA cancers as well as translational research studies to elucidate any fundamental differences between pediatric, AYA, and adult cancers. The biologic questions for future research are whether there are mutational or signaling pathway differences (for example, between adult and AYA colorectal cancer) that can be clinically exploited to develop novel therapies for treating AYA cancers and to develop companion diagnostics.

Pouchitis Is a Common Complication in Patients With Familial Adenomatous Polyposis Following Ileal Pouch-Anal Anastomosis.

BACKGROUND & AIMS: Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the surgical procedure most commonly selected for patients with familial adenomatous polyposis (FAP) or ulcerative colitis that is refractive to medical treatment. Pouchitis is the most common complication in patients with ulcerative colitis after IPAA, but is thought to rarely occur in patients with FAP. We investigated the frequency of pouchitis and other pouch-related complications in patients with FAP after IPAA. METHODS: We performed a retrospective cohort study of all patients with FAP who underwent IPAA at a single tertiary institution from 1992 through 2015 (n = 113). Patients were identified using International Classification of Diseases-9 diagnostic and current procedural terminology codes. We obtained relevant demographic and clinical data from patients' electronic medical records. The frequencies of pouchitis and pouch-related complications were determined. RESULTS: Twenty-five patients (22.1%) developed pouchitis (mean time to pouchitis, 4.1 years) and 88 did not (77.9%). Patients with pouchitis showed a trend toward developing late (>90 days after IPAA) pouch-related complications (56.0% of patients with pouchitis developed late complications, compared with 36.4% without). In patients who developed pouchitis, the disease course was acute in 72.0% and chronic in 28.0%. Of those treated, 69.6% responded to antibiotics, 13.0% became dependent on antibiotics, and 13.0% developed antibiotic resistance. CONCLUSIONS: Pouchitis is more prevalent in patients with FAP than previously believed. Although pouchitis seems to occur later in patients with FAP than in patients with ulcerative colitis, and have a milder course, it should be considered a common complication among patients with FAP following IPAA.

Prospective evaluation of adverse events following lower gastrointestinal tract EUS FNA.

OBJECTIVES: There are virtually no data concerning the risk of adverse events (AEs) following lower gastrointestinal (LGI) endoscopic ultrasound (EUS). Our aim was to determine the incidence and factors associated with AEs following LGI EUS fine needle aspiration (FNA). METHODS: We conducted a prospective cohort study at a tertiary referral center. Five hundred and sixty-three patients underwent LGI EUS FNA between 1 January 2004 and 1 January 2012. We analyzed the 502 patients who had complete follow-up. AE severity was graded (1-5) utilizing Common Terminology Criteria or Visual Analog Scale. AEs were assessed during the procedures, in clinical follow-up, during phone interviews conducted at 7-14 days, and final clinical and/or phone interviews at 2-4 months. RESULTS: AEs developed in 103 (20.5%) patients and were classified as grade 1, 2, 3, or 4 in 34 (6.8%), 41 (8.2%), 23 (4.6%), and 5 (1.0%) patients, respectively. Bleeding and pain were the commonest AEs. No deaths occurred. On multivariate analysis, AEs were associated with prior pain (odds ratio (OR): 3.83, 95% confidence interval (CI): 2.35-6.25), FNA from a site other than a lymph node (LN) or gut wall (OR: 2.26, 95% CI: 1.10-4.70), and malignant FNA cytology (OR: 1.80, 95% CI: 1.10-2.97); serious (grade 3-4) AEs were associated with prior pain (OR: 15.21, 95% CI: 5.04-45.85) and FNA from a site other than a LN or gut wall (OR: 3.25, 95% CI: 1.15-9.20). CONCLUSIONS: LGI EUS FNA is associated with a high rate of serious grades 3-4 AEs. This may reflect the total number of associated interventions and the frequency of underlying pathology and symptoms.

Endoscopically identified well-differentiated rectal carcinoid tumors: impact of tumor size on the natural history and outcomes.

BACKGROUND: There is a paucity of data pertaining to the natural history and outcomes of patients with well-differentiated rectal carcinoids. OBJECTIVE: To correlate endoscopic size with the natural history and outcome. DESIGN: Retrospective study. SETTING: Single tertiary referral center. PATIENTS: Eighty-seven patients with endoscopically identified well-differentiated rectal carcinoid tumors. INTERVENTION: Colonoscopy. MAIN OUTCOME MEASUREMENTS: Prevalence of metastasis at diagnosis, disease progression, and survival. RESULTS: Metastasis was present at diagnosis in 3%, 66%, and 73% of tumors measuring ≤10 mm, 11 to 19 mm, and ≥20 mm, respectively. Metastasis was predicted with 100% sensitivity and 87% specificity using an endoscopic lesion size ≥9 mm. In patients without identified metastasis, 64% were identified during screening colonoscopy. Within this select cohort, subsequent metastasis was discovered only at distant extra pelvic sites, in 1.6%, 50%, and 100% of patients with tumors initially measuring ≤10 mm, 11 to 19 mm, and ≥20 mm, respectively. The carcinoid related 5- and 10-year survival rates for locally confined disease were 96%. The corresponding survival rates for local and advanced metastatic disease were 60% and 35%, respectively. LIMITATIONS: Subjective estimation of tumor size, mitotic index or Ki-67 labeling index not reported, and lack of formal and standardized baseline staging algorithm and surveillance program. CONCLUSIONS: The clinical behavior of 11- to 19-mm tumors appears to mimic that of larger (>20 mm) lesions with respect to the presence of metastasis at diagnosis and disease progression. Therefore, if local therapy is contemplated, we propose to make a distinction between ≤10-mm and 11- to 19-mm tumors, favoring an aggressive staging and management protocol for 11- to 19-mm carcinoid tumors.

Gastric adenomas in familial adenomatous polyposis are common, but subtle, and have a benign course.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) are known to have an increased risk for gastric adenomas. The clinical features of gastric adenomas in FAP have not been well characterized, and there is a lack of standardized approaches to the management of these lesions. AIMS: To study the endoscopic appearance, risk factors, clinical course, and response to therapy of gastric adenomas in patients with FAP. METHODS: We retrospectively reviewed the records of 97 patients with FAP who underwent esophagogastroduodenoscopy (EGD) at Mayo Clinic (Florida, Rochester and Arizona) between 2004 and 2013. RESULTS: Nine patients (9%) had biopsy-proven gastric adenomas. Adenomas were located in the antrum (five patients), in the body and fundus in the setting of background fundic gland polyps (FGP) (three patients), and in the body not associated with FGP (one patient). Adenoma size was 3-40 mm and the number of adenomas per patient ranged from one to 20. Adenomas in the antrum were flat and subtle, whereas those in the gastric body or fundus were polypoid and difficult to differentiate from the cystic FGPs seen in patients with FAP. The performing endoscopists reported difficulty with identifying adenomas, and six patients had at least one EGD within the previous three years where gastric adenomas were not reported. Adenomas were classified as tubular in eight patients and tubulovillous in one patient. High grade dysplasia was noted in one patient. After a median follow-up of 63 months (interquartile range: 20-149 months), no patient in our entire cohort (with or without gastric adenomas) developed gastric cancer. The patients in whom gastric adenoma developed, compared to those without gastric adenoma, were more likely to be younger [36 ± 12 vs. 48 ± 15 years, p = 0.02], have concomitant chronic gastritis [22% vs. 0%, p = 0.008], and have desmoid tumors [5 (56%) vs. 19 (22%), p = 0.04]. CONCLUSIONS: Gastric adenomas are not uncommon in patients with FAP and are often difficult to identify endoscopically. Endoscopists should have a high degree of suspicion for gastric adenomas in these patients and a low threshold to biopsy. Given the benign clinical course, recommended initial management is conservative with endoscopic therapy and periodic surveillance.

Genomic landscape of diploid and aneuploid microsatellite stable early onset colorectal cancer.

Although colorectal cancer (CRC) remains the second leading cause of cancer-related death in the United States, the overall incidence and mortality from the disease have declined in recent decades. In contrast, there has been a steady increase in the incidence of CRC in individuals under 50 years of age. Hereditary syndromes contribute disproportionately to early onset CRC (EOCRC). These include microsatellite instability high (MSI+) tumors arising in patients with Lynch Syndrome. However, most EOCRCs are not associated with familial syndromes or MSI+ genotypes. Comprehensive genomic profiling has provided the basis of improved more personalized treatments for older CRC patients. However, less is known about the basis of sporadic EOCRC. To define the genomic landscape of EOCRC we used DNA content flow sorting to isolate diploid and aneuploid tumor fractions from 21 non-hereditary cases. We then generated whole exome mutational profiles for each case and whole genome copy number, telomere length, and EGFR immunohistochemistry (IHC) analyses on subsets of samples. These results discriminate the molecular features of diploid and aneuploid EOCRC and provide a basis for larger population-based studies and the development of effective strategies to monitor and treat this emerging disease.

Epidemiologic Factors in Relation to Colorectal Cancer Risk and Survival by Genotoxic Colibactin Mutational Signature.

BACKGROUND: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors' association with colorectal cancer risk and survival differs by SBS88. METHODS: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer-specific survival using Cox proportional hazards regression (N = 3,465 cases). RESULTS: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66-0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer-specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47-7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78-1.21, Pheterogeneity = 0.066). CONCLUSIONS: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer-specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available. IMPACT: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival.

Randomized, Double-Blind, Placebo-Controlled Trial of MUC1 Peptide Vaccine for Prevention of Recurrent Colorectal Adenoma.

PURPOSE: To assess whether MUC1 peptide vaccine produces an immune response and prevents subsequent colon adenoma formation. PATIENTS AND METHODS: Multicenter, double-blind, placebo-controlled randomized trial in individuals age 40 to 70 with diagnosis of an advanced adenoma ≤1 year from randomization. Vaccine was administered at 0, 2, and 10 weeks with a booster injection at week 53. Adenoma recurrence was assessed ≥1 year from randomization. The primary endpoint was vaccine immunogenicity at 12 weeks defined by anti-MUC1 ratio ≥2.0. RESULTS: Fifty-three participants received the MUC1 vaccine and 50 placebo. Thirteen of 52 (25%) MUC1 vaccine recipients had a ≥2-fold increase in MUC1 IgG (range, 2.9-17.3) at week 12 versus 0/50 placebo recipients (one-sided Fisher exact P < 0.0001). Of 13 responders at week 12, 11 (84.6%) responded to a booster injection at week 52 with a ≥2-fold increase in MUC1 IgG measured at week 55. Recurrent adenoma was observed in 31 of 47 (66.0%) in the placebo group versus 27 of 48 (56.3%) in the MUC1 group [adjusted relative risk (aRR), 0.83; 95% confidence interval (CI), 0.60-1.14; P = 0.25]. Adenoma recurrence occurred in 3/11 (27.3%) immune responders at week 12 and week 55 (aRR, 0.41; 95% CI, 0.15-1.11; P = 0.08 compared with placebo). There was no difference in serious adverse events. CONCLUSIONS: An immune response was observed only in vaccine recipients. Adenoma recurrence was not different than placebo, but a 38% absolute reduction in adenoma recurrence compared with placebo was observed in participants who had an immune response at week 12 and with the booster injection.

Generation and external validation of a tumor-derived 5-gene prognostic signature for recurrence of lymph node-negative, invasive colorectal carcinoma.

BACKGROUND: One in 4 patients with lymph node-negative, invasive colorectal carcinoma (CRC) develops recurrent disease after undergoing curative surgery, and most die of advanced disease. Predicting which patients will develop a recurrence is a significantly growing, unmet medical need. METHODS: Archival formalin-fixed, paraffin-embedded (FFPE) primary adenocarcinoma tissues obtained at surgery were retrieved from 74 patients with CRC (15 with stage I disease and 59 with stage II disease) for Training/Test Sets. In addition, FFPE tissues were retrieved from 49 patients with stage I CRC and 215 patients with stage II colon cancer for an External Validation (EV) Set (n = 264) from 18 hospitals in 4 countries. No patients had received neoadjuvant/adjuvant therapy. Proprietary genetic programming analysis of expression profiles for 225 prespecified tumor genes was used to create a 36-month recurrence risk signature. RESULTS: Using reverse transcriptase-polymerase chain reaction, a 5-gene rule correctly classified 62 of 92 recurrent patients and 87 of 172 nonrecurrent patients in the EV Set (sensitivity, 0.67; specificity, 0.51). "High-risk" patients had a greater probability of 36-month recurrence (42%) than "low-risk" patients (26%; hazard ratio, 1.80; 95% confidence interval, 1.19-2.71; P = .007; Cox regression) independent of T-classification, the number of lymph nodes examined, histologic grade/subtype, anatomic location, age, sex, or race. The rule outperformed (P = .021) current National Comprehensive Cancer Network Guidelines (hazard ratio, 0.897). The same rule also differentiated the risk of recurrence (hazard ratio, 1.63; P = .031) in a subset of patients from the EV Set who had stage I/II colon cancer only (n = 251). CONCLUSIONS: To the authors' knowledge, the 5-gene rule (OncoDefender-CRC) is the first molecular prognostic that has been validated in both stage I CRC and stage II colon cancer. It outperforms standard clinicopathologic prognostic criteria and obviates the need to retrieve ≥12 lymph nodes for accurate prognostication. It identifies those patients most likely to develop recurrent disease within 3 years after curative surgery and, thus, those most likely to benefit from adjuvant treatment.

The stool DNA test is more accurate than the plasma septin 9 test in detecting colorectal neoplasia.

BACKGROUND & AIMS: Several noninvasive tests have been developed for colorectal cancer (CRC) screening. We compared the sensitivities of a multimarker test for stool DNA (sDNA) and a plasma test for methylated septin 9 (SEPT9) in identifying patients with large adenomas or CRC. METHODS: We analyzed paired stool and plasma samples from 30 patients with CRC and 22 with large adenomas from Mayo Clinic archives. Stool (n = 46) and plasma (n = 49) samples from age- and sex-matched patients with normal colonoscopy results were used as controls. The sDNA test is an assay for methylated BMP3, NDRG4, vimentin, and TFPI2; mutant KRAS; the ß-actin gene, and quantity of hemoglobin (by the porphyrin method). It was performed blindly at Exact Sciences (Madison, Wisconsin); the test for SEPT9 was performed at ARUP Laboratories (Salt Lake City, Utah). Results were considered positive based on the manufacturer's specificity cutoff values of 90% and 89%, respectively. RESULTS: The sDNA test detected adenomas (median, 2 cm; range, 1-5 cm) with 82% sensitivity (95% confidence interval [CI], 60%-95%); SEPT9 had 14% sensitivity (95% CI, 3%-35%; P = .0001). The sDNA test identified patients with CRC with 87% sensitivity (95% CI, 69%-96%); SEPT9 had 60% sensitivity (95% CI, 41%-77%; P = .046). The sDNA test identified patients with stage I-III CRC with 91% sensitivity (95% CI, 71%-99%); SEPT9 had 50% sensitivity (95% CI, 28%-72%; P = .013); for stage IV CRC, sensitivity values were 75% (95% CI, 35%-97%) and 88% (95% CI, 47%-100%), respectively (P = .56). False positive rates were 7% for the sDNA test and 27% for SEPT9. CONCLUSIONS: Based on analyses of paired samples, the sDNA test detects nonmetastatic CRC and large adenomas with significantly greater levels of sensitivity than the SEPT9 test. These findings might be used to modify approaches for CRC prevention and early detection.

Clinicopathologic features and treatment outcomes in Cronkhite-Canada syndrome: support for autoimmunity.

BACKGROUND AND AIMS: Cronkhite-Canada syndrome (CCS) is a noninherited condition, associated with high morbidity, and characterized by gastrointestinal hamartomatous polyposis, alopecia, onychodystrophy, hyperpigmentation, and diarrhea. All features may respond to immunosuppressive therapy, but little is known about the etiology. An autoimmune origin has been suggested but not proved. From a retrospectively selected cohort, we evaluated clinicopathologic features, including immunostaining for IgG4 (an antibody associated with autoimmunity), and therapeutic outcomes in a cohort of CCS patients to provide further insights into this disease. METHODS: Cases included 14 consecutive CCS patients seen at the Mayo Clinic on whom tissue and follow-up were available. All histology was reviewed by an expert gastrointestinal pathologist. Immunostaining for IgG4 was performed on 42 polyps from CCS cases and on control tissues, including 46 histologically similar hamartomas [from juvenile polyposis syndrome (JPS)] and 20 normal mucosae (six stomach, three small bowel, and 11 colon). Clinical features and treatment outcomes were descriptive. RESULTS: All CCS cases had both upper and lower gastrointestinal polyps; most had typical dermatologic features of alopecia, hyperpigmentation, and onychodystrophy; and most had evidence of protein-losing enteropathy. Ten patients (71%) had adenomatous polyps and 2 (14%) had colorectal cancer. IgG4 immunostaining was positive (>5 cells/HPF) in 52% of CCS polyps compared to 12% of JPS polyps (P = 0.001); IgG4 staining was negative in all other control tissues. Of 11 CCS patients treated with oral corticosteroids, 91% achieved remission. Relapse was common with steroid tapering. Five patients who initially responded to corticosteroids were maintained in remission on azathioprine (2 mg/kg/day) with no relapse after a median of 4.5 years. CONCLUSIONS: Immunostaining for the autoimmune-related IgG4 antibody is significantly increased in CCS polyps compared to disease and normal control tissues. Furthermore, immunosuppression by corticosteroids or long-term azathioprine may eradicate or lessen manifestations of CCS. These histologic findings and treatment responses are consistent with an autoimmune mechanism underlying CCS.

Local recurrence detection following transanal excision facilitated by EUS-FNA.

BACKGROUND/AIMS: Local excision is an alternative management approach for early rectal cancers and patients unfit for radical surgery. It is associated with a high local recurrence rate. Our aims were to evaluate the rate, pattern, method of local recurrence detection, the opportunity for salvage resection and finally to explore the utility of endoscopic ultrasound fine needle aspiration during surveillance. METHODOLOGY: A retrospective, non-controlled, cohort study from a single tertiary referral center comprised of patients undergoing surveillance following a transanal excision. RESULTS: Post-operative surveillance was performed in 155 transanal excision patients of which 46 (30%) underwent =1 endoscopic ultrasound examinations. Intra and extra luminal recurrence (n=16/24; (67%)) was detected more frequently in the endoscopic ultrasound surveillance population, p=0.0008. Mucosal scar biopsy (n=10/16;63%) and endoscopic ultrasound fine needle aspiration (6/16; 38%) of either a lymph node or the deep rectal wall were the methods for establishing local recurrence. An unremarkable proctoscopy with endoscopic ultrasound fine needle aspiration positive cytological findings was noted in 4 (9%) of the patients. CONCLUSIONS: Local recurrence following transanal excision is often in an intraluminal location. Endoscopic ultrasound fine needle aspiration confirmed nodal metastases in mesenteric and extra mesenteric locations more frequently than subepithelial locations.

Germline PKHD1 mutations are protective against colorectal cancer.

The autosomal recessive polycystic kidney disease (ARPKD) gene, PKHD1, has been implicated in the genesis or growth of colorectal adenocarcinoma, as a high level of somatic mutations was found in colorectal tumor tissue. To determine whether carriers of a single PKHD1 mutation are at increased risk of colorectal carcinoma, we assessed the prevalence of the commonest European mutation, T36M. First, we assayed a European cohort of ARPKD patients and found T36M was responsible for 13.1% of mutations. We then investigated two European cohorts with colorectal adenocarcinoma versus two control cohorts of similar age and gender. Screening for the most common PKHD1 mutation, T36M, we detected 15:3,603 (0.42%) controls versus 1:3,767 (0.027%) colorectal cancer individuals, indicating that heterozygous PKHD1 mutations are not a risk factor and are protective (p=0.0002). We also show that the carriage rate for PKHD1 mutations in the European population is higher than previous accepted at 3.2% (1:31 genomes).

Lynch syndrome-associated extracolonic tumors are rare in two extended families with the same EPCAM deletion.

OBJECTIVES: The Lynch syndrome (LS) is an inherited cancer syndrome showing a preponderance of colorectal cancer (CRC) in context with endometrial cancer and several other extracolonic cancers, which is due to pathogenic mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2. Some families were found to show a LS phenotype without an identified MMR mutation, although there was microsatellite instability and absence of MSH2 expression by immunohistochemistry. Studies of a subset of these families found a deletion at the 3' end of the epithelial cell adhesion molecule (EPCAM) gene, causing transcription read-through resulting in silencing of MSH2 through hypermethylation of its promoter. The tumor spectrum of such families appears to differ from classical LS. METHODS: Our study of two large families (USA Family R and Dutch Family A) with an EPCAM deletion was carried out using each institution's standard family study protocol. DNA was extracted from peripheral blood and EPCAM deletion analysis was performed. RESULTS: Both families were found to harbor the same deletion at the 3' end of EPCAM. Analysis showed that the deletion originated from a common ancestor. Family R and Family A members showed segregation of CRC with the presence of this EPCAM mutation. Compared with classic LS, there were almost no extracolonic cancers. CONCLUSIONS: Members of Family R and Family A, all with the same EPCAM deletion, predominantly presented with CRC but no LS-associated endometrial cancer, confirming findings seen in other, smaller, LS families with EPCAM mutations. In these EPCAM mutation carriers, cancer surveillance should be focused on CRC.