Sebaceous Skin Lesions as Clues to Hereditary Non-Polyposis Colorectal Cancer

Cutaneous lesions consonant with Muir–Torre syndrome strongly suggest hereditary non-polyposis colorectal cancer (HNPCC). Ponti et al. discuss the importance of combining molecular genetic features of the sebaceous neoplasms, including microsatellite instability and immunohistochemistry, with family history, to determine the likelihood of HNPCC. Proof of diagnosis is identification of one of the mismatch repair germline mutations

HNPCC (Lynch Syndrome): Differential Diagnosis, Molecular Genetics and Management - a Review

HNPCC (Lynch syndrome) is the most common form of hereditary colorectal cancer (CRC), wherein it accounts for between 2-7 percent of the total CRC burden. When considering the large number of extracolonic cancers integral to the syndrome, namely carcinoma of the endometrium, ovary, stomach, hepatobiliary system, pancreas, small bowel, brain tumors, and upper uroepithelial tract, these estimates of its frequency are likely to be conservative. The diagnosis is based upon its natural history in concert with a comprehensive cancer family history inclusive of all anatomic sites. In order for surveillance and management to be effective and, indeed, lifesaving, among these high-risk patients, the linchpin to cancer control would be the physician, who must be knowledgeable about hereditary cancer syndromes, their molecular and medical genetics, genetic counseling, and, most importantly, the natural history of the disorders, so that the entirety of this knowledge can be melded to highly-targeted management

Current Hypotheses on How Microsatellite Instability Leads to Enhanced Survival of Lynch Syndrome Patients

High levels of microsatellite instability (MSI-high) are a cardinal feature of colorectal tumors from patients with Lynch Syndrome. Other key characteristics of Lynch Syndrome are that these patients experience fewer metastases and have enhanced survival when compared to patients diagnosed with microsatellite stable (MSS) colorectal cancer. Many of the characteristics associated with Lynch Syndrome including enhanced survival are also observed in patients with sporadic MSI-high colorectal cancer. In this review we will present the current state of knowledge regarding the mechanisms that are utilized by the host to control colorectal cancer in Lynch Syndrome and why these same mechanisms fail in MSS colorectal cancers

Nonparametric versus Parametric Statistical Approaches for Genetic Anticipation: The Pancreatic Cancer Case

2000 Mathematics Subject Classi cation: 62N01, 62N05, 62P10, 92D10, 92D30.Genetic anticipation for a particular disease can involve an earlier age of onset, greater severity, and/or a higher number of affected individuals in successive generations within a family. Comparison between nonparametric and semiparametric tests is studied for matched data, and is one of the main focuses of this study. This comparison is investigated for the variable age of diagnosis among different birth cohorts, before and after adjustment for time under observation. The comparison is illustrated on an example of familial pancreatic cancer, which example is the second main focus of this study. The nonparametric test performed on our example better than the two semi-parametric tests, and was less sensitive to right censoring. After adjusting for follow up time, all methods detected genetic anticipation.This work was supported in part by a grant from the National Cancer Institute (1 R33 CA10595-01A2) to S. A. Sherman. G. R. Haynatzki thanks Mr. Oleg Shats and Mrs. Marsha Ketcham for their help with the PCCR

Risk of colon cancer in hereditary non-polyposis colorectal cancer patients as predicted by fuzzy modeling: Influence of smoking

AIM: To investigate whether a fuzzy logic model could predict colorectal cancer (CRC) risk engendered by smoking in hereditary non-polyposis colorectal cancer (HNPCC) patients. METHODS: Three hundred and forty HNPCC mismatch repair (MMR) mutation carriers from the Creighton University Hereditary Cancer Institute Registry were selected for modeling. Age-dependent curves were generated to elucidate the joint effects between gene mutation (hMLH1 or hMSH2), gender, and smoking status on the probability of developing CRC. RESULTS: Smoking significantly increased CRC risk in male hMSH2 mutation carriers (P \u3c 0.05). hMLH1 mutations augmented CRC risk relative to hMSH2 mutation carriers for males (P \u3c 0.05). Males had a significantly higher risk of CRC than females for hMLH1 non smokers (P \u3c 0.05), hMLH1 smokers (P \u3c 0.1) and hMSH2 smokers (P \u3c 0.1). Smoking promoted CRC in a dose-dependent manner in hMSH2 in males (P \u3c 0.05). Females with hMSH2 mutations and both sexes with the hMLH1 groups only demonstrated a smoking effect after an extensive smoking history (P \u3c 0.05). CONCLUSION: CRC promotion by smoking in HNPCC patients is dependent on gene mutation, gender and age. These data demonstrate that fuzzy modeling may enable formulation of clinical risk scores, thereby allowing individualization of CRC prevention strategies

The COVID-19 pandemic and environmental health: Lessons learned

Environmental health is historically an overlooked and underrated discipline. The COVID-19 pandemic highlighted the value of environmental health and environmental health professionals (EHPs). EHPs have a unique set of skills and knowledge that were, or could have been, signifi cant in controlling the pandemic. This skill set includes a thorough understanding of legislation and regulations; the ability to conduct human health risk assessment and implement effective risk-control measures; enforcement, communication, and education skills; and a signifi cant understanding of their own local communities. The opportunities for applying the skills of EHPs vary across the world depending on several factors, including legislative and regulatory frameworks in each jurisdiction. Here we present our early evaluation of the unique skills and knowledge base of EHPs and lessons that can be learned from EHP engagement in public health protection. We also argue that local knowledge and engagement need to be recognized as valuable tools in emergency preparedness. In our increasingly globalized world, mechanisms to maintain and value local knowledge are needed, which could be achieved by embedding the “value of local” into policy to ensure that the importance and value of local knowledge are captured. We also advocate for raising awareness of the value of public health, and specifi cally, environmental health.info:eu-repo/semantics/publishedVersio

Family-specific, novel, deleterious germline variants provide a rich resource to identify genetic predispositions for BRCAx familial breast cancer

BACKGROUND: Genetic predisposition is the primary risk factor for familial breast cancer. For the majority of familial breast cancer, however, the genetic predispositions remain unknown. All newly identified predispositions occur rarely in disease population, and the unknown genetic predispositions are estimated to reach up to total thousands. Family unit is the basic structure of genetics. Because it is an autosomal dominant disease, individuals with a history of familial breast cancer must carry the same genetic predisposition across generations. Therefore, focusing on the cases in lineages of familial breast cancer, rather than pooled cases in disease population, is expected to provide high probability to identify the genetic predisposition for each family. METHODS: In this study, we tested genetic predispositions by analyzing the family-specific variants in familial breast cancer. Using exome sequencing, we analyzed three families and 22 probands with BRCAx (BRCA-negative) familial breast cancer. RESULTS: We observed the presence of family-specific, novel, deleterious germline variants in each family. Of the germline variants identified, many were shared between the disease-affected family members of the same family but not found in different families, which have their own specific variants. Certain variants are putative deleterious genetic predispositions damaging functionally important genes involved in DNA replication and damaging repair, tumor suppression, signal transduction, and phosphorylation. CONCLUSIONS: Our study demonstrates that the predispositions for many BRCAx familial breast cancer families can lie in each disease family. The application of a family-focused approach has the potential to detect many new predispositions

Effect of Prior Bilateral Oophorectomy on the Presentation of Breast Cancer in BRCA1 and BRCA2 Mutation Carriers

Purpose: To compare the presentation of invasive breast cancer in BRCA1 and BRCA2 mutation carriers with and without prior bilateral oophorectomy. Patients and methods: Women with a BRCA1 or BRCA2 mutation with the diagnosis of invasive breast cancer were identified from ten cancer genetics clinics. The medical history, medical treatment records and pathology reports for the breast cancers were reviewed. Information was abstracted from medical charts, including history (and date) of oophorectomy, date of breast cancer diagnosis, stage of disease, and pathologic characteristics of the breast cancer. Women with prior bilateral oophorectomy were matched by age, year of diagnosis, and mutation with one or more women who had two intact ovaries at the time of breast cancer diagnosis. Characteristics of the breast tumours were compared between the two groups

PCCR: Pancreatic Cancer Collaborative Registry

The Pancreatic Cancer Collaborative Registry (PCCR) is a multi-institutional web-based system aimed to collect a variety of data on pancreatic cancer patients and high-risk subjects in a standard and efficient way. The PCCR was initiated by a group of experts in medical oncology, gastroenterology, genetics, pathology, epidemiology, nutrition, and computer science with the goal of facilitating rapid and uniform collection of critical information and biological samples to be used in developing diagnostic, prevention and treatment strategies against pancreatic cancer. The PCCR is a multi-tier web application that utilizes Java/JSP technology and has Oracle 10 g database as a back-end. The PCCR uses a “confederation model” that encourages participation of any interested center, irrespective of its size or location. The PCCR utilizes a standardized approach to data collection and reporting, and uses extensive validation procedures to prevent entering erroneous data. The PCCR controlled vocabulary is harmonized with the NCI Thesaurus (NCIt) or Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT). The PCCR questionnaire has accommodated standards accepted in cancer research and healthcare. Currently, seven cancer centers in the USA, as well as one center in Italy are participating in the PCCR. At present, the PCCR database contains data on more than 2,700 subjects (PC patients and individuals at high risk of getting this disease). The PCCR has been certified by the NCI Center for Biomedical Informatics and Information Technology as a cancer Biomedical Informatics Grid (caBIG®) Bronze Compatible product. The PCCR provides a foundation for collaborative PC research. It has all the necessary prerequisites for subsequent evolution of the developed infrastructure from simply gathering PC-related data into a biomedical computing platform vital for successful PC studies, care and treatment. Studies utilizing data collected in the PCCR may engender new approaches to disease prognosis, risk factor assessment, and therapeutic interventions

Lynch Syndrome-Associated Extracolonic Tumors Are Rare in Two Extended Families With the Same EPCAM Deletion

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