EPCAM deletions, Lynch syndrome, and cancer risk Lynch, Henry T; Lynch, Jane F; Snyder, Carrie L ...
The lancet oncology,
2011, 2011-Jan, 2011-01-00, 20110101, Letnik:
12, Številka:
1
Journal Article
Inherited BRCA1 mutations confer elevated cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated ...a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, and TOPBP1, and was associated with time to breast and ovarian cancer diagnosis. Statistically significant false discovery rate (FDR) adjusted P values for overall association of haplotypes (P(FDR)) with breast cancer were identified at ATM (P(FDR) = 0.029), BRCC45 (P(FDR) = 0.019), BRIP1 (P(FDR) = 0.008), CTIP (P(FDR) = 0.017), MERIT40 (P(FDR) = 0.019), NBS1 (P(FDR) = 0.003), RAD50 (P(FDR) = 0.014), and TOPBP1 (P(FDR) = 0.011). Haplotypes at ABRA1 (P(FDR) = 0.007), BRCC45 (P(FDR) = 0.016 and P(FDR) = 0.005 in two haplotype blocks), and RAP80 (P(FDR) < 0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations.
Cancer risk assessment, genetic counseling and genetic testing have experienced advances and changes over the past two decades due to improved technology, legal movements to protect those at an ...increased risk for cancer due to genetics, as well as advances in detection, prevention and treatment. This brief article will provide a summary of these advances over three eras of cancer genetics: pre-discovery of the more common high impact genes, namely
BRCA1
/
BRCA2
and the mismatch repair genes associated with Lynch syndrome; the time during which the genes were being discovered; and current day.
We have recently reported that, among BRCA1 mutation carriers, the consumption of caffeinated coffee was associated with a significant reduction in breast cancer risk. Because the metabolism of ...caffeine is primarily by CYP1A2, we examined whether or not the CYP1A2 genotype modifies the association between a history of coffee consumption and the risk of breast cancer. A common A to C polymorphism in the CYP1A2 gene is associated with decreased enzyme inducibility and impaired caffeine metabolism. Information regarding coffee consumption habits and the CYP1A2 genotype was available for 411 BRCA1 mutation carriers (170 cases and 241 controls). We estimated the odds ratios (ORs) and 95% confidence intervals (95% CIs) for breast cancer associated with the CYP1A2 genotype and a history of coffee consumption before age 35, adjusting for potential confounders. The CYP1A2 genotype did not affect breast cancer risk. Among women with at least one variant C allele (AC or CC), those who consumed coffee had a 64% reduction in breast cancer risk, compared with women who never consumed coffee (OR, 0.36; 95% CI, 0.18-0.73). A significant protective effect of coffee consumption was not observed among women with the CYP1A2 AA genotype (OR, 0.93; 95% CI, 0.49-1.77). Similar results were obtained when the analysis was restricted to caffeinated coffee. This study suggests that caffeine protects against breast cancer in women with a BRCA1 mutation and illustrates the importance of integrating individual genetic variability when assessing diet-disease associations.
To review the most common hereditary colorectal cancer syndromes with known associated mutated genes, associated cancer risks, and current screening and prevention current.
Online search of PubMed, ...EBSCOhost, and Medline, review of the literature for each syndrome described.
Hereditary colon cancer accounts for approximately 10% of all colorectal cancers in the United States. There are multiple hereditary colorectal cancer syndromes known with respective associated genetic mutations, cancer risks, and screening and prevention recommendations.
Nurses at all levels of practice need to be knowledgeable about the various hereditary colorectal cancer syndromes to guide appropriate referral to a genetics professional and to provide appropriate care to these high-risk individuals.
Purpose.
This study evaluated the policy and built and recreation environmental supports for physical activity on 13 university campuses.
Design.
Environmental audit survey.
Setting.
Thirteen U.S. ...universities, 2009.
Subjects.
University policies, recreation programs and facilities, and at least five additional buildings per campus.
Measures.
The Physical Activity Campus Environmental Supports Audit was developed for this study.
Analysis.
Analysis of variance with post hoc Tukey's B and χ2 assessed differences by institution and building type.
Results.
The mean obesogenic policy score was significantly lower than the desired score, ≥ 7 (p = .002), with only one campus scoring 10. The mean built environment audit score (5.4 ± 1.7) was low, with significant differences between institutions (p < .001) and only three campuses scoring above the desired score, ≥ 7. Although generally stairwells were clean and well lighted, there was a lack of signage to encourage stair use (p < .001). Overall, recreation programs (7.1 ± .7) and facilities (7.1 ± 1.2) scored well, but amenities scores were lower for satellite (2.8 ± 1.6) versus main (4.1 ± 1.8) recreation facilities (p = .04).
Conclusion.
On these 13 university campuses, recreation programs and facilities were supportive of healthful lifestyles for obesity prevention, but policies and the built environment were not. This physical activity environmental audit survey requires testing in a wider sample of postsecondary institutions to corroborate its utility and provide evidence to support initiatives to improve campus environments for physical activity.
Cancer cells expressing PD-1 ligands (PD-L1/PD-L2) inhibit immune-modulatory T-cell activation facilitating disease progression. Preliminary clinical trials exploring interruption of PD-1/PD-L1 ...signaling showed benefit in several cancer types. We analyzed the distribution of PD-1-positive tumor-infiltrating lymphocytes (TIL) and cancer cells' expression of PD-L1 in a molecularly profiled cohort of 437 malignancies (380 carcinomas, 33 sarcomas, and 24 melanomas). We showed that the presence of PD-1(+) TILs significantly varied among cancer types (from 0% in extraskeletal myxoid chondrosarcomas to 93% in ovarian cancer), and was generally associated with the increased number of mutations in tumor cells (P = 0.029). Cancer cell expression of PD-L1 varied from absent (in Merkel cell carcinomas) to 100% (in chondro- and liposarcomas), but showed the inverse association with the number of detected mutations (P = 0.004). Both PD-1 and PD-L1 expression were significantly higher in triple-negative breast cancers (TNBC) than in non-TNBC (P < 0.001 and 0.017, respectively). Similarly, MSI-H colon cancers had higher PD-1 and PD-L1 expression than the microsatellite stable tumors (P = 0.002 and 0.02, respectively). TP53-mutated breast cancers had significantly higher PD-1 positivity than those harboring other driver mutations (e.g., PIK3CA; P = 0.002). In non-small cell lung cancer, PD-1/PD-L1 coexpression was identified in 8 cases (19%), which lacked any other targetable alterations (e.g., EGFR, ALK, or ROS1). Our study demonstrated the utility of exploring the expression of two potentially targetable immune checkpoint proteins (PD-1/PD-L1) in a substantial proportion of solid tumors, including some aggressive subtypes that lack other targeted treatment modalities.
To provide practical considerations for diagnosing, counseling, and managing patients at high risk for hereditary breast cancer.
We have studied 98 extended hereditary breast cancer (HBC)/hereditary ...breast-ovarian cancer (HBOC) families with BRCA1/2 germline mutations. From these families, 1,315 individuals were counseled and sampled for DNA testing. Herein, 716 of these individuals received their DNA test results in concert with genetic counseling. Several challenging pedigrees were selected from Creighton University's hereditary cancer family registry, as well as one family from Evanston/Northwestern Healthcare, to be discussed in this present report.
Many obstacles were identified in diagnosis, counseling, and managing patients at high risk for HBC/HBOC. These obstacles were early noncancer death of key relatives, perception of insurance or employment discrimination, fear, anxiety, apprehension, reduced gene penetrance, and poor compliance. Other important issues such as physician culpability and malpractice implications for failure to collect or act on the cancer family history were identified.
When clinical gene testing emerged for BRCA1 and BRCA2, little was known about the efficacy of medical interventions. Potential barriers to uptake of testing were largely unexplored. Identification and referral of high-risk patients and families to genetic counseling can greatly enhance the care of the population at the highest risk for cancer. However, because premonitory physical stigmata are absent in most of these syndromes, an HBOC diagnosis may be missed unless a careful family history of cancer of the breast, ovary, or several integrally associated cancers is obtained.
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