Pediatric duodenal cancer and biallelic mismatch repair gene mutations

Gastrointestinal malignancies are extremely rare in the pediatric population, and duodenal cancers represent an even more unusual entity. Intestinal cancers in young adults and children have been observed to be associated with functional deficiencies of the mismatch repair (MMR) system causing a cancer-predisposition syndrome. We report the case of a 16-year-old female with duodenal adenocarcinoma and past history of medulloblastoma found to have a novel germline bialleleic truncating mutation (c.[949C>T]+[949C>T]) of the PMS2 gene. Pediatr Blood Cancer 2009;53:116–120. © 2009 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62997/1/21957_ftp.pd

Human papillomavirus is not associated with colorectal cancer in a large international study

Recent publications have reported an association between colon cancer and human papillomaviruses (HPV), suggesting that HPV infection of the colonic mucosa may contribute to the development of colorectal cancer. The GP5+/GP6+ PCR reverse line blot method was used for detection of 37 types of human papillomavirus (HPV) in DNA from paraffin-embedded or frozen tissues from patients with colorectal cancer (n = 279) and normal adjacent tissue (n = 30) in three different study populations, including samples from the United States (n = 73), Israel (n = 106) and Spain (n = 100). Additionally, SPF10 PCR was run on all samples (n = 279) and the Innogenetics INNO-LiPA assay was performed on a subset of samples (n = 15). All samples were negative for all types of HPV using both the GP5+/GP6+ PCR reverse line blot method and the SPF10 INNO-LiPA method. We conclude that HPV types associated with malignant transformation do not meaningfully contribute to adenocarcinoma of the colon

A human MUTYH variant linking colonic polyposis to redox degradation of the [4Fe4S]²⁺ cluster

The human DNA repair enzyme MUTYH excises mispaired adenine residues in oxidized DNA. Homozygous MUTYH mutations underlie the autosomal, recessive cancer syndrome MUTYH-associated polyposis. We report a MUTYH variant, p.C306W (c.918C>G), with a tryptophan residue in place of native cysteine, that ligates the [4Fe4S] cluster in a patient with colonic polyposis and family history of early age colon cancer. In bacterial MutY, the [4Fe4S] cluster is redox active, allowing rapid localization to target lesions by long-range, DNA-mediated signalling. In the current study, using DNA electrochemistry, we determine that wild-type MUTYH is similarly redox-active, but MUTYH C306W undergoes rapid oxidative degradation of its cluster to [3Fe4S]^+, with loss of redox signalling. In MUTYH C306W, oxidative cluster degradation leads to decreased DNA binding and enzyme function. This study confirms redox activity in eukaryotic DNA repair proteins and establishes MUTYH C306W as a pathogenic variant, highlighting the essential role of redox signalling by the [4Fe4S] cluster

A human MUTYH variant linking colonic polyposis to redox degradation of the [4Fe4S]²⁺ cluster

The human DNA repair enzyme MUTYH excises mispaired adenine residues in oxidized DNA. Homozygous MUTYH mutations underlie the autosomal, recessive cancer syndrome MUTYH-associated polyposis. We report a MUTYH variant, p.C306W (c.918C>G), with a tryptophan residue in place of native cysteine, that ligates the [4Fe4S] cluster in a patient with colonic polyposis and family history of early age colon cancer. In bacterial MutY, the [4Fe4S] cluster is redox active, allowing rapid localization to target lesions by long-range, DNA-mediated signalling. In the current study, using DNA electrochemistry, we determine that wild-type MUTYH is similarly redox-active, but MUTYH C306W undergoes rapid oxidative degradation of its cluster to [3Fe4S]^+, with loss of redox signalling. In MUTYH C306W, oxidative cluster degradation leads to decreased DNA binding and enzyme function. This study confirms redox activity in eukaryotic DNA repair proteins and establishes MUTYH C306W as a pathogenic variant, highlighting the essential role of redox signalling by the [4Fe4S] cluster

Risk of Non-Melanoma Cancers in First-Degree Relatives of CDKN2A Mutation Carriers

The purpose of this study was to quantify the risk of cancers other than melanoma among family members of CDKN2A mutation carriers using data from the Genes, Environment and Melanoma study. Relative risks (RRs) of all non-melanoma cancers among first-degree relatives (FDRs) of melanoma patients with CDKN2A mutations (n = 65) and FDRs of melanoma patients without mutations (n = 3537) were calculated as the ratio of estimated event rates (number of cancers/total person-years) in FDRs of carriers vs noncarriers with exact Clopper–Pearson-type tests and 95% confidence intervals (CIs). All statistical tests were two-sided. There were 56 (13.1%) non-melanoma cancers reported among 429 FDRs of mutation carriers and 2199 (9.4%) non-melanoma cancers in 23 452 FDRs of noncarriers. The FDRs of carriers had an increased risk of any cancer other than melanoma (56 cancers among 429 FDRs of carrier probands vs 2199 cancers among 23 452 FDRs of noncarrier probands; RR = 1.5, 95% CI = 1.2 to 2.0, P = .005), gastrointestinal cancer (20 cancers among 429 FDRs of carrier probands vs 506 cancers among 23 452 FDRs of noncarrier probands; RR = 2.4, 95% CI = 1.4 to 3.7, P = .001), and pancreatic cancer (five cancers among 429 FDRs of carrier probands vs 41 cancers among 23 452 FDRs of noncarrier probands; RR = 7.4, 95% CI = 2.3 to 18.7, P = .002). Wilms tumor was reported in two FDRs of carrier probands and three FDRs of noncarrier probands (RR = 40.4, 95% CI = 3.4 to 352.7, P = .005). The lifetime risk of any cancer other than melanoma among CDKN2A mutation carriers was estimated as 59.0% by age 85 years (95% CI = 39.0% to 75.4%) by the kin-cohort method, under the standard assumptions of Mendelian genetics on the genotype distribution of FDRs conditional on proband genotype

Mismatch repair genes founder mutations and cancer susceptibility in Lynch syndrome

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Oxidative stress homeostasis in grapevine (Vitis vinifera L.)

Plants can maintain growth and reproductive success by sensing changes in the environment and reacting through mechanisms at molecular, cellular, physiological, and developmental levels. Each stress condition prompts a unique response although some overlap between the reactions to abiotic stress (drought, heat, cold, salt or high light) and to biotic stress (pathogens) does occur. A common feature in the response to all stresses is the onset of oxidative stress, through the production of reactive oxygen species (ROS). As hydrogen peroxide and superoxide are involved in stress signaling, a tight control in ROS homeostasis requires a delicate balance of systems involved in their generation and degradation. If the plant lacks the capacity to generate scavenging potential, this can ultimately lead to death. In grapevine, antioxidant homeostasis can be considered at whole plant levels and during the development cycle. The most striking example lies in berries and their derivatives, such as wine, with nutraceutical properties associated with their antioxidant capacity. Antioxidant homeostasis is tightly regulated in leaves, assuring a positive balance between photosynthesis and respiration, explaining the tolerance of many grapevine varieties to extreme environments. In this review we will focus on antioxidant metabolites, antioxidant enzymes, transcriptional regulation and cross-talk with hormones prompted by abiotic stress conditions. We will also discuss three situations that require specific homeostasis balance: biotic stress, the oxidative burst in berries at veraison and in vitro systems. The genetic plasticity of the antioxidant homeostasis response put in evidence by the different levels of tolerance to stress presented by grapevine varieties will be addressed. The gathered information is relevant to foster varietal adaptation to impending climate changes, to assist breeders in choosing the more adapted varieties and suitable viticulture practice