Displaying publications 1 - 20 of 33 in total

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  1. Zeng C, Guo X, Long J, Kuchenbaecker KB, Droit A, Michailidou K, et al.
    Breast Cancer Res, 2016 06 21;18(1):64.
    PMID: 27459855 DOI: 10.1186/s13058-016-0718-0
    BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.

    METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.

    RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P 

  2. Yang Y, Shu X, Shu XO, Bolla MK, Kweon SS, Cai Q, et al.
    EBioMedicine, 2019 Oct;48:203-211.
    PMID: 31629678 DOI: 10.1016/j.ebiom.2019.09.006
    BACKGROUND: We previously conducted a systematic field synopsis of 1059 breast cancer candidate gene studies and investigated 279 genetic variants, 51 of which showed associations. The major limitation of this work was the small sample size, even pooling data from all 1059 studies. Thereafter, genome-wide association studies (GWAS) have accumulated data for hundreds of thousands of subjects. It's necessary to re-evaluate these variants in large GWAS datasets.

    METHODS: Of these 279 variants, data were obtained for 228 from GWAS conducted within the Asian Breast Cancer Consortium (24,206 cases and 24,775 controls) and the Breast Cancer Association Consortium (122,977 cases and 105,974 controls of European ancestry). Meta-analyses were conducted to combine the results from these two datasets.

    FINDINGS: Of those 228 variants, an association was observed for 12 variants in 10 genes at a Bonferroni-corrected threshold of P 

  3. Yang Y, Wu L, Shu X, Lu Y, Shu XO, Cai Q, et al.
    Cancer Res, 2019 Feb 01;79(3):505-517.
    PMID: 30559148 DOI: 10.1158/0008-5472.CAN-18-2726
    DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.
  4. Wen W, Shu XO, Guo X, Cai Q, Long J, Bolla MK, et al.
    Breast Cancer Res, 2016 12 08;18(1):124.
    PMID: 27931260
    BACKGROUND: Approximately 100 common breast cancer susceptibility alleles have been identified in genome-wide association studies (GWAS). The utility of these variants in breast cancer risk prediction models has not been evaluated adequately in women of Asian ancestry.

    METHODS: We evaluated 88 breast cancer risk variants that were identified previously by GWAS in 11,760 cases and 11,612 controls of Asian ancestry. SNPs confirmed to be associated with breast cancer risk in Asian women were used to construct a polygenic risk score (PRS). The relative and absolute risks of breast cancer by the PRS percentiles were estimated based on the PRS distribution, and were used to stratify women into different levels of breast cancer risk.

    RESULTS: We confirmed significant associations with breast cancer risk for SNPs in 44 of the 78 previously reported loci at P 

  5. Tang LP, Lee SS, Zeng NK, Cai Q, Zhang P, Yang ZL
    Mycologia, 2017 12 04;109(4):557-567.
    PMID: 29200380 DOI: 10.1080/00275514.2017.1394789
    Some Amanita specimens collected from Malaysia are critically investigated by morphological examination and molecular analysis of two gene fragments, the nuc rDNA partial 28S (28S) gene and the internal transcriber spacer (ITS1-5.8S-ITS2 = ITS) regions. Six phylogenetic species of Amanita section Caesareae are recognized among the studied collections. One of them is described as new, A. malayensis. Four of the phylogenetic species correspond with existing morphology-based taxa: A. aporema, A. javanica, A. princeps, and A. similis. The remaining species is not described because of the paucity of material. Detailed descriptions and the distribution of these southeastern Asian species are provided, along with a key to the species of section Caesareae from Malaysia.
  6. Shu X, Long J, Cai Q, Kweon SS, Choi JY, Kubo M, et al.
    Nat Commun, 2020 Mar 05;11(1):1217.
    PMID: 32139696 DOI: 10.1038/s41467-020-15046-w
    Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P 
  7. Shi J, Zhang Y, Zheng W, Michailidou K, Ghoussaini M, Bolla MK, et al.
    Int J Cancer, 2016 Sep 15;139(6):1303-1317.
    PMID: 27087578 DOI: 10.1002/ijc.30150
    Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2)  = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.
  8. Orr N, Dudbridge F, Dryden N, Maguire S, Novo D, Perrakis E, et al.
    Hum Mol Genet, 2015 May 15;24(10):2966-84.
    PMID: 25652398 DOI: 10.1093/hmg/ddv035
    We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.
  9. Milne RL, Kuchenbaecker KB, Michailidou K, Beesley J, Kar S, Lindström S, et al.
    Nat Genet, 2017 Dec;49(12):1767-1778.
    PMID: 29058716 DOI: 10.1038/ng.3785
    Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.
  10. Milne RL, Burwinkel B, Michailidou K, Arias-Perez JI, Zamora MP, Menéndez-Rodríguez P, et al.
    Hum Mol Genet, 2014 Nov 15;23(22):6096-111.
    PMID: 24943594 DOI: 10.1093/hmg/ddu311
    Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
  11. Michailidou K, Beesley J, Lindstrom S, Canisius S, Dennis J, Lush MJ, et al.
    Nat Genet, 2015 Apr;47(4):373-80.
    PMID: 25751625 DOI: 10.1038/ng.3242
    Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.
  12. Michailidou K, Lindström S, Dennis J, Beesley J, Hui S, Kar S, et al.
    Nature, 2017 Nov 02;551(7678):92-94.
    PMID: 29059683 DOI: 10.1038/nature24284
    Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P 
  13. Mekaroonkamol P, Tiankanon K, Pittayanon R, Ridtitid W, Shams F, Tayyab GUN, et al.
    Clin Endosc, 2021 Sep 29.
    PMID: 34583452 DOI: 10.5946/ce.2021.051
    Background/Aims: The Thai Association for Gastrointestinal Endoscopy published recommendations on safe endoscopy during the coronavirus disease 2019 (COVID-19) pandemic. This study aimed to assess the practicality and applicability of the recommendations and the perceptions of endoscopy personnel on them.

    Methods: A validated questionnaire was sent to 1290 endoscopy personnel globally. Of these, the data of all 330 responders (25.6%) from 15 countries, related to the current recommendations on proper personal protective equipment (PPE), case selection, scope cleaning, and safety perception, were analyzed. Ordinal logistic regression was used to determine the relationships between the variables.

    Results: Despite an overwhelming agreement with the recommendations on PPE (94.5%) and case selection (95.5%), their practicality and applicability on PPE recommendations and case selection were significantly lower (p=0.001, p=0.047, p<0.001, and p=0.032, respectively). Factors that were associated with lower sense of safety in endoscopy units were younger age (p=0.004), less working experience (p=0.008), in-training status (p=0.04), and higher national prevalence of COVID-19 (p=0.003). High prevalent countries also had more difficulty implementing the guidelines (p<0.001) and they considered the PPE recommendations less practical and showed lower agreement with them (p<0.001 and p=0.008, respectively). A higher number of in-hospital COVID-19 patients was associated with less agreement with PPE recommendations (p=0.039).

    Conclusions: Using appropriate PPE and case selection in endoscopic practice during a pandemic remains a challenge. Resource availability and local prevalence are critical factors influencing the adoption of the current guidelines.

  14. Liu J, Prager-van der Smissen WJC, Collée JM, Bolla MK, Wang Q, Michailidou K, et al.
    Sci Rep, 2020 Jun 16;10(1):9688.
    PMID: 32546843 DOI: 10.1038/s41598-020-65665-y
    In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.
  15. Lin WY, Camp NJ, Ghoussaini M, Beesley J, Michailidou K, Hopper JL, et al.
    Hum Mol Genet, 2015 Jan 01;24(1):285-98.
    PMID: 25168388 DOI: 10.1093/hmg/ddu431
    Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.
  16. Lawrenson K, Kar S, McCue K, Kuchenbaeker K, Michailidou K, Tyrer J, et al.
    Nat Commun, 2016 Sep 07;7:12675.
    PMID: 27601076 DOI: 10.1038/ncomms12675
    A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
  17. Koo JH, Leong RW, Ching J, Yeoh KG, Wu DC, Murdani A, et al.
    Gastrointest Endosc, 2012 Jul;76(1):126-35.
    PMID: 22726471 DOI: 10.1016/j.gie.2012.03.168
    BACKGROUND: The rapid increase in the incidence of colorectal cancer (CRC) in the Asia-Pacific region in the past decade has resulted in recommendations to implement mass CRC screening programs. However, the knowledge of screening and population screening behaviors between countries is largely lacking.
    OBJECTIVE: This multicenter, international study investigated the association of screening test participation with knowledge of, attitudes toward, and barriers to CRC and screening tests in different cultural and sociopolitical contexts.
    METHODS: Person-to-person interviews by using a standardized survey instrument were conducted with subjects from 14 Asia-Pacific countries/regions to assess the prevailing screening participation rates, knowledge of and attitudes toward and barriers to CRC and screening tests, intent to participate, and cues to action. Independent predictors of the primary endpoint, screening participation was determined from subanalyses performed for high-, medium-, and low-participation countries.
    RESULTS: A total of 7915 subjects (49% male, 37.8% aged 50 years and older) were recruited. Of the respondents aged 50 years and older, 809 (27%) had undergone previous CRC testing; the Philippines (69%), Australia (48%), and Japan (38%) had the highest participation rates, whereas India (1.5%), Malaysia (3%), Indonesia (3%), Pakistan (7.5%), and Brunei (13.7%) had the lowest rates. Physician recommendation and knowledge of screening tests were significant predictors of CRC test uptake. In countries with low-test participation, lower perceived access barriers and higher perceived severity were independent predictors of participation. Respondents from low-participation countries had the least knowledge of symptoms, risk factors, and tests and reported the lowest physician recommendation rates. "Intent to undergo screening" and "perceived need for screening" was positively correlated in most countries; however, this was offset by financial and access barriers.
    LIMITATIONS: Ethnic heterogeneity may exist in each country that was not addressed. In addition, the participation tests and physician recommendation recalls were self-reported.
    CONCLUSIONS: In the Asia-Pacific region, considerable differences were evident in the participation of CRC tests, physician recommendations, and knowledge of, attitudes toward, and barriers to CRC screening. Physician recommendation was the uniform predictor of screening behavior in all countries. Before implementing mass screening programs, improving awareness of CRC and promoting the physicians' role are necessary to increase the screening participation rates.
  18. Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, Abdellatif M, Abdoli A, Abel S, et al.
    Autophagy, 2021 Jan;17(1):1-382.
    PMID: 33634751 DOI: 10.1080/15548627.2020.1797280
    In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
  19. Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, et al.
    Autophagy, 2016;12(1):1-222.
    PMID: 26799652 DOI: 10.1080/15548627.2015.1100356
  20. Kar SP, Beesley J, Amin Al Olama A, Michailidou K, Tyrer J, Kote-Jarai Z, et al.
    Cancer Discov, 2016 Sep;6(9):1052-67.
    PMID: 27432226 DOI: 10.1158/2159-8290.CD-15-1227
    Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis.

    SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.

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