Microsatellite Instability and DNA Mismatch Repair Protein Deficiency in Lynch Syndrome Colorectal Polyps

Colorectal cancers associated with Lynch syndrome (LS) are characterized by deficient DNA mismatch repair (MMR) function. Our aim was to evaluate the prevalence of microsatellite instability (MSI) and loss of MMR protein expression in LS-associated polyps. Sixty two colorectal polyps – 37 adenomas (APs), 23 hyperplastic polyps (HPs), and 2 sessile serrated polyps (SSPs) – from 34 subjects with germline MMR gene mutations were tested for MSI using a single pentaplex PCR for five mononucleotide repeat microsatellite markers, and also for expression of MLH1, MSH2, MSH6, and PMS2 proteins by immunohistochemistry (IHC). High-level MSI (MSI-H) was seen in 15/37 (41%) APs, 1/23 (4%) HPs, and 1/2 (50%) SSPs. Loss of MMR protein expression was seen in 18/36 (50%) APs, 0/21 HPs, and 0/2 SSPs. APs ≥8 mm were significantly more likely to demonstrate MSI-H (OR = 9.98, 95% CI: 1.52-65.65, p = 0.02) and deficient MMR protein expression (OR = 3.17, 95% CI: 1.20-8.37, p = 0.02) compared with those <8 mm. All (6/6) APs ≥10 mm demonstrated both MSI-H and loss of MMR protein expression by IHC. Our finding that the prevalence of MMR deficiency increases with the size of APs suggests that loss of MMR function is a late event in LS-associated colorectal neoplasia. Although testing large APs may be of value in the diagnostic evaluation of patients with suspected LS, the absence of an MMR deficient phenotype in an adenoma cannot be considered strong evidence against LS, as it is with colorectal carcinomas

Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines

Background & aims: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. Methods: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. Results: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. Conclusions: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC

Correspondence Between Perceived Pubertal Development and Hormone Levels in 9-10 Year-Olds From the Adolescent Brain Cognitive Development Study.

Aim: To examine individual variability between perceived physical features and hormones of pubertal maturation in 9-10-year-old children as a function of sociodemographic characteristics. Methods: Cross-sectional metrics of puberty were utilized from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study—a multi-site sample of 9–10 year-olds (n = 11,875)—and included perceived physical features via the pubertal development scale (PDS) and child salivary hormone levels (dehydroepiandrosterone and testosterone in all, and estradiol in females). Multi-level models examined the relationships among sociodemographic measures, physical features, and hormone levels. A group factor analysis (GFA) was implemented to extract latent variables of pubertal maturation that integrated both measures of perceived physical features and hormone levels. Results: PDS summary scores indicated more males (70%) than females (31%) were prepubertal. Perceived physical features and hormone levels were significantly associated with child\u27s weight status and income, such that more mature scores were observed among children that were overweight/obese or from households with low-income. Results from the GFA identified two latent factors that described individual differences in pubertal maturation among both females and males, with factor 1 driven by higher hormone levels, and factor 2 driven by perceived physical maturation. The correspondence between latent factor 1 scores (hormones) and latent factor 2 scores (perceived physical maturation) revealed synchronous and asynchronous relationships between hormones and concomitant physical features in this large young adolescent sample. Conclusions: Sociodemographic measures were associated with both objective hormone and self-report physical measures of pubertal maturation in a large, diverse sample of 9-10 year-olds. The latent variables of pubertal maturation described a complex interplay between perceived physical changes and hormone levels that hallmark sexual maturation, which future studies can examine in relation to trajectories of brain maturation, risk/resilience to substance use, and other mental health outcomes

Historical Perspective on Familial Gastric CancerSummary

Gastric cancer is a common disease worldwide, typically associated with acquired chronic inflammation in the stomach, related in most instances to infection by Helicobacter pylori. A small percentage of cases occurs in familial clusters, and some of these can be linked to specific germline mutations. This article reviews the historical background to the current understanding of familial gastric cancer, focuses on the entity of hereditary diffuse gastric cancer, and also reviews the risks for gastric cancer related to a number of other familial genetic diseases. Keywords: Gastric cancer, E-cadherin, H pylori, Diffuse Gastric Cancer, GAPPS, Lynch Syndrome, Li-Fraumeni Syndrome, Peutz-Jeghers Syndrome, Juvenile Polyposis Syndrom