RECQL4 is essential for the transport of p53 to mitochondria in normal human cells in the absence of exogenous stress

Mutations in RECQL4 helicase are associated with Rothmund–Thomson syndrome (RTS). A subset of RTS patients is predisposed to cancer and is sensitive to DNA damaging agents. The enhanced sensitivity of cells from RTS patients correlates with the accumulation of transcriptionally active nuclear p53. We found that in untreated normal human cells these two nuclear proteins, p53 and RECQL4, instead colocalize in the mitochondrial nucleoids. RECQL4 accumulates in mitochondria in all phases of the cell cycle except S phase and physically interacts with p53 only in the absence of DNA damage. p53–RECQL4 binding leads to the masking of the nuclear localization signal of p53. The N-terminal 84 amino acids of RECQL4 contain a mitochondrial localization signal, which causes the localization of RECQL4–p53 complex to the mitochondria. RECQL4–p53 interaction is disrupted after stress, allowing p53 translocation to the nucleus. In untreated normal cells RECQL4 optimizes de novo replication of mtDNA, which is consequently decreased in fibroblasts from RTS patients. Wild-type RECQL4-complemented RTS cells show relocalization of both RECQL4 and p53 to the mitochondria, loss of p53 activation, restoration of de novo mtDNA replication and resistance to different types of DNA damage. In cells expressing Δ84 RECQL4, which cannot translocate to mitochondria, all the above functions are compromised. The recruitment of p53 to the sites of de novo mtDNA replication is also regulated by RECQL4. Thus these findings elucidate the mechanism by which p53 is regulated by RECQL4 in unstressed normal cells and also delineates the mitochondrial functions of the helicase

Colorectal Tumour Microsatellite Instability Test Results: Perspectives from Patients

<p>Abstract</p> <p>Purpose</p> <p>To determine which individuals with colorectal cancer (CRC) were interested in knowing the results of their tumour microsatellite instability (MSI) and immunohistochemistry (IHC) testing. We were also interested in the patients' reasons for choosing to learn their results and in the impact of those results on overall self-assessed quality of life.</p> <p>Patients and Methods</p> <p>CRCs from 414 individuals were assayed for MSI and IHC for DNA mismatch repair gene products (<it>MLH1</it>, <it>MSH2</it>, <it>MSH6</it>). Individuals were invited to learn their MSI/IHC results. They randomly received either brief or extended educational materials about the testing and a pretest survey to learn reasons for their interest and to assess their pretest quality of life.</p> <p>Results</p> <p>Of the 414 individuals, 307 (74%) chose to learn their results. There was no significant difference in interest in knowing test results according to gender, age, educational level, or family history of colon cancer. The level of detail in the information piece received by the patients did not influence their desire to know their test results. Self-assessed quality of life was not altered by receiving results and was not correlated with the test outcome.</p> <p>Conclusions</p> <p>Individuals with colorectal cancer had a high level of interest in learning their individual MSI/IHC test results and did not seem deterred by the inherent complexity or ambiguity of this information. Regardless of test outcome, results did not significantly affect self-assessed quality of life. Further studies are needed to assess comprehension of results and behavioural changes resulting from the learning of MSI/IHC results.</p

Colorectal cancer and self-reported tooth agenesis

BACKGROUND: Germline mutations in APC and AXIN2 are both associated with colon neoplasia as well as anomalous dental development. We tested the hypothesis that congenitally missing teeth may occur more commonly in individuals diagnosed with colorectal cancer than in individuals without this diagnosis. METHODS: Via a survey conducted on 1636 individuals with colorectal cancer (CRC) and 2788 individuals with no colorectal cancer from the Colon Cancer Family Registry, self-reported information on congenitally missing teeth was collected. The frequency of missing teeth between cases and controls was compared using Pearson’s chi-squared test or Fisher’s exact test. RESULTS: 4.8% of cases and 5.7% of controls reported having at least one missing tooth (p = 0.20). When we stratified by recruitment site, gender, and mutation status where available, frequency of missing teeth was not statistically significantly different between cases and controls. CONCLUSIONS: This study did not provide support for there being a general predisposition to missing teeth among a large cohort of CRC patients. The study neither addresses nor excludes the possibility, however, that individuals presenting with notable hypodontia/oligodontia might still have an increased risk for colorectal neoplasia

Primary appendiceal mucinous adenocarcinoma in two first-degree relatives: case report and review

Carcinomas of the appendix are exceedingly rare tumors and have an annual age-adjusted incidence of around 0.4 cases per 100,000. Appendiceal adenocarcinoma accounts for < 0.5% of all gastrointestinal neoplasms and, of these, mucinous adenocarcinomas account for the majority. Published accounts of familial instances of primary appendiceal tumors are strikingly rare. We report two siblings who both developed primary mucinous adenocarcinomas. A genetics evaluation was conducted to determine if there was a recognizable underlying single gene disorder; no DNA mismatch repair defect was evident, and no other diagnosis was apparent. A review of appendiceal cancers seen at Mayo Clinic from l997 to the present was conducted to search for additional familial cases. Among 316 cases of primary appendiceal cancer of any histologic type, this sib pair was the only family reporting a second affected family member. The occurrence of appendiceal cancer in siblings may represent a random occurrence. An exceedingly rare predisposition syndrome cannot be ruled out

Colon and Rectal Cancer Survival by Tumor Location and Microsatellite Instability: The Colon Cancer Family Registry

Cancers in the proximal colon, distal colon, and rectum are frequently studied together; however, there are biological differences in cancers across these sites, particularly in the prevalence of microsatellite instability

Associations of Height With the Risks of Colorectal and Endometrial Cancer in Persons With Lynch Syndrome

People with Lynch syndrome (LS), who carry a pathogenic mutation in a DNA mismatch repair gene, have increased risks of colorectal cancer (CRC) and endometrial cancer (EC). A high reported variability in cancer risk suggests the existence of factors that modify cancer risk for persons with LS. We aimed to investigate the associations between height and CRC and EC risk for persons with LS using data from 2 large studies. Information on 1,115 men and 1,553 women with LS from the Colon Cancer Family Registry (1998-2007) and the GEOLynch Cohort Study (2006-2017) was harmonized. We used weighted Cox proportional hazards regression models with age on the time axis to estimate adjusted hazard ratios and 95% confidence intervals for each 5-cm increment in self-reported height. CRC was diagnosed in 947 persons during 65,369 person-years of observation, and 171 women were diagnosed with EC during 39,227 person-years. Height was not associated with CRC for either men (per 5-cm increment, hazard ratio (HR) = 1.00, 95% confidence interval (CI): 0.91, 1.11) or women (per 5-cm increment, HR = 1.01, 95% CI: 0.92, 1.11), nor was height associated with EC (per 5-cm increment, HR = 1.08, 95% CI: 0.94, 1.24). Hence, we observed no evidence for an association of height with either CRC or EC among persons with LS.</p

Clinicopathologic Risk Factor Distributions for MLH1 Promoter Region Methylation in CIMP-Positive Tumors

The CpG Island Methylator Phenotype (CIMP) is a major molecular pathway in colorectal cancer (CRC). Approximately 25% to 60% of CIMP tumors are microsatellite unstable (MSI-H) due to DNA hypermethylation of the MLH1 gene promoter. Our aim was to determine if the distributions of clinicopathologic factors in CIMP-positive tumors with MLH1 DNA methylation differed from those in CIMP-positive tumors without DNA methylation of MLH1

Survival after inflammatory bowel disease-associated colorectal cancer in the Colon Cancer Family Registry

AIM: To investigate the survival of individuals with colorectal cancer (CRC) with inflammatory bowel disease (IBD-associated CRC) compared to that of individuals without IBD diagnosed with CRC