Clinical challenges in interpreting multiple pathogenic mutations in single patients.

Background: In the past two decades, genetic testing for cancer risk assessment has entered mainstream clinical practice due to the availability of low-cost panels of multiple cancer-associated genes. However, the clinical value of multiple-gene panels for cancer susceptibility is not well established, especially in cases where panel testing identifies more than one pathogenic variant. The risk for specific malignancies as a result of a mutated gene is complex and likely influenced by superimposed modifier variants and/or environmental effects.

A role for the vitamin D pathway in non-intestinal lesions in genetic and carcinogen models of colorectal cancer and in familial adenomatous polyposis.

Vitamin D is implicated in the etiology of cancers of the gastrointestinal tract, usually characterized by alteration in the APC/β-catenin/TCF tumor suppressor pathway. The vitamin D receptor (VDR) is also implicated in cardiovascular and skin diseases as well as in immunity. Activated VDR can indirectly alter β-catenin nuclear localization and directly suppress β-catenin/TCF mediated transcriptional activity.

Increased risk of colorectal neoplasia among family members of patients with colorectal cancer: a population-based study in Utah.

Background & Aims: Colorectal cancer (CRC) frequently develops in multiple members of the same families, but more data are needed to prepare effective screening guidelines. We quantified the risk of CRC and adenomas in first-degree relatives (FDRs) and second-degree relatives and first cousins of individuals with CRC, and stratified risk based on age at cancer diagnosis.

Methods: We performed a case-control study of Utah residents, 50-80 years old, who underwent colonoscopy from 1995 through 2009.

Epidemiology and familial risk of synchronous and metachronous colorectal cancer: a population-based study in Utah.

Background & Aims: Patients diagnosed with colorectal cancer (CRC) are at risk for synchronous and metachronous lesions at the time of diagnosis or during follow-up evaluation. We performed a population-based study to evaluate the rate, predictors, and familial risk for synchronous and metachronous CRC in Utah.

Methods: All newly diagnosed cases of CRC between 1980 and 2010 were obtained from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database.

Characteristics of missed or interval colorectal cancer and patient survival: a population-based study.

Background & Aims: Colorectal cancers (CRCs) diagnosed within a few years after an index colonoscopy can arise from missed lesions or the development of a new tumor. We investigated the proportion, characteristics, and factors that predict interval CRCs that develop within 6-60 months of colonoscopy.

Methods: We performed a population-based cohort study of Utah residents who underwent colonoscopy examinations from 1995 through 2009 at Intermountain Healthcare or the University of Utah Health System, which provide care to more than 85% of state residents.

Risk of colorectal cancer and adenomas in the families of patients with adenomas: a population-based study in Utah.

Background: Guidelines recommend that individuals with a first-degree relative (FDR) diagnosed with colorectal cancer (CRC) or advanced adenoma before age 60 years should undergo colonoscopy starting at age 40 years. The authors quantified the risk of adenomas and CRC in FDRs, second-degree relatives (SDRs), and third-degree relatives (TDRs) of patients diagnosed with adenomas and advanced adenomas.

Methods: A population-based, retrospective, case-control study was performed of residents of the state of Utah aged 50 years to 80 years who underwent colonoscopy between 1995 and 2009 at Intermountain Healthcare or the University of Utah.

Shared genomic segment analysis: the power to find rare disease variants.

Shared genomic segment (SGS) analysis uses dense single nucleotide polymorphism genotyping in high-risk (HR) pedigrees to identify regions of sharing between cases. Here, we illustrate the power of SGS to identify dominant rare risk variants. Using simulated pedigrees, we consider 12 disease models based on disease prevalence, minor allele frequency and penetrance to represent disease loci that explain 0.

Maximum-likelihood estimation of recent shared ancestry (ERSA).

Accurate estimation of recent shared ancestry is important for genetics, evolution, medicine, conservation biology, and forensics. Established methods estimate kinship accurately for first-degree through third-degree relatives. We demonstrate that chromosomal segments shared by two individuals due to identity by descent (IBD) provide much additional information about shared ancestry.

Colorectal adenomas and cancer link to chromosome 13q22.1-13q31.3 in a large family with excess colorectal cancer.

Background: Colorectal cancer is the fourth most common type of cancer and the second most common cause of cancer death. Fewer than 5% of colon cancers arise in the presence of a clear hereditary cancer condition; however, current estimates suggest that an additional 15-25% of colorectal cancers arise on the basis of unknown inherited factors.

Aim: To identify additional genetic factors responsible for colon cancer.

Hereditary and familial colon cancer.

Between 2% to 5% of all colon cancers arise in the setting of well-defined inherited syndromes, including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, and certain hamartomatous polyposis conditions. Each is associated with a high risk of colon cancer. In addition to the syndromes, up to one-third of colon cancers exhibit increased familial risk, likely related to inheritance.

Parental attitudes, beliefs, and perceptions about genetic testing for FAP and colorectal cancer surveillance in minors.

Familial adenomatous polyposis (FAP) is the second most common hereditary colorectal cancer syndrome and confers a nearly 100% lifetime risk of developing colorectal cancer. Understanding factors that facilitate and inhibit genetic testing and cancer surveillance in children who are members of families affected by FAP will better equip clinicians to clarify misunderstandings and facilitate appropriate care. The aims of this study were to examine parental attitudes and beliefs regarding endoscopic surveillance and genetic testing in minors at risk for developing FAP.

Large intron 14 rearrangement in APC results in splice defect and attenuated FAP.

Familial adenomatous polyposis [FAP (OMIM 175100)] is an autosomal dominant colorectal cancer predisposition syndrome characterized by hundreds to thousands of colonic polyps and, if untreated by a combination of screening and/or surgical intervention, an approximately 99% lifetime risk of colorectal cancer. A subset of FAP patients develop an attenuated form of the condition characterized by lower numbers of colonic polyps (highly variable, but generally less than 100) and a lower lifetime risk of colorectal cancer, on the order of 70%. We report the diagnosis of three attenuated FAP families due to a 1.

DMD pseudoexon mutations: splicing efficiency, phenotype, and potential therapy.

Objective: The degenerative muscle diseases Duchenne (DMD) and Becker muscular dystrophy result from mutations in the DMD gene, which encodes the dystrophin protein. Recent improvements in mutational analysis techniques have resulted in the increasing identification of deep intronic point mutations, which alter splicing such that intronic sequences are included in the messenger RNA as "pseudoexons." We sought to test the hypothesis that the clinical phenotype correlates with splicing efficiency of these mutations, and to test the feasibility of antisense oligonucleotide (AON)-mediated pseudoexon skipping.

Gonadal mosaicism and familial adenomatous polyposis.

De novo mutations in the adenomatous polyposis coli (APC) gene are estimated to constitute approximately 25% of familial adenomatous polyposis (FAP) cases. A small percentage of these arise in the mosaic form, affecting only a subset of cells in the affected individual. A family is described here whereby an unaffected mother with no detectible mutation in APC, transmitted the identical APC c.

RNA interference-mediated suppression and replacement of human rhodopsin in vivo.

Mutational heterogeneity represents a significant barrier to development of therapies for many dominantly inherited diseases. For example, >100 mutations in the rhodopsin gene (RHO) have been identified in patients with retinitis pigmentosa (RP). The development of therapies for dominant disorders that correct the primary genetic lesion and overcome mutational heterogeneity is challenging.

Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation.

Demyelination is the hallmark of numerous neurodegenerative conditions, including multiple sclerosis. Oligodendrocyte progenitors (OPCs), which normally mature into myelin-forming oligodendrocytes, are typically present around demyelinated lesions but do not remyelinate affected axons. Here, we find that the glycosaminoglycan hyaluronan accumulates in demyelinated lesions from individuals with multiple sclerosis and in mice with experimental autoimmune encephalomyelitis.

CD44 expression identifies astrocyte-restricted precursor cells.

The precise lineage between neural stem cells and mature astrocytes remains poorly defined. To examine astrocyte development, we have characterized glial precursors from neural tissue derived from early embryonic ages. We show that CD44 identifies an astrocyte-restricted precursor cell (ARP) that is committed to generating astrocytes in vitro and in vivo in both rodent and human tissue.

CD44 overexpression by oligodendrocytes: a novel mouse model of inflammation-independent demyelination and dysmyelination.

The CD44 transmembrane glycoprotein family has been implicated in cell-cell adhesion and cell signaling in response to components of the extracellular matrix but its role in the nervous system is not understood. CD44 proteins are elevated in Schwann cells and oligodendrocytes following nervous system insults, in inflammatory demyelinating lesions, and in tumors. Here, we tested the hypothesis that elevated CD44 expression influences Schwann cell and oligodendrocyte functions by generating transgenic mice that express CD44 under the control of the 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) promoter.

Attenuated APC alleles produce functional protein from internal translation initiation.

Some truncating mutations of the APC tumor suppressor gene are associated with an attenuated phenotype of familial adenomatous polyposis coli (AAPC). This work demonstrates that APC alleles with 5' mutations produce APC protein that down-regulates beta-catenin, inhibits beta-catenin/T cell factor-mediated transactivation, and induces cell-cycle arrest. Transfection studies demonstrate that cap-independent translation is initiated internally at an AUG at codon 184 of APC.