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Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

ABSTRACT: To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

SUBMITTER: Phelan CM

PROVIDER: S-EPMC5612337 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

Phelan Catherine M CM Kuchenbaecker Karoline B KB Tyrer Jonathan P JP Kar Siddhartha P SP Lawrenson Kate K Winham Stacey J SJ Dennis Joe J Pirie Ailith A Riggan Marjorie J MJ Chornokur Ganna G Earp Madalene A MA Lyra Paulo C PC Lee Janet M JM Coetzee Simon S Beesley Jonathan J McGuffog Lesley L Soucy Penny P Dicks Ed E Lee Andrew A Barrowdale Daniel D Lecarpentier Julie J Leslie Goska G Aalfs Cora M CM Aben Katja K H KKH Adams Marcia M Adlard Julian J Andrulis Irene L IL Anton-Culver Hoda H Antonenkova Natalia N Aravantinos Gerasimos G Arnold Norbert N Arun Banu K BK Arver Brita B Azzollini Jacopo J Balmaña Judith J Banerjee Susana N SN Barjhoux Laure L Barkardottir Rosa B RB Bean Yukie Y Beckmann Matthias W MW Beeghly-Fadiel Alicia A Benitez Javier J Bermisheva Marina M Bernardini Marcus Q MQ Birrer Michael J MJ Bjorge Line L Black Amanda A Blankstein Kenneth K Blok Marinus J MJ Bodelon Clara C Bogdanova Natalia N Bojesen Anders A Bonanni Bernardo B Borg Åke Å Bradbury Angela R AR Brenton James D JD Brewer Carole C Brinton Louise L Broberg Per P Brooks-Wilson Angela A Bruinsma Fiona F Brunet Joan J Buecher Bruno B Butzow Ralf R Buys Saundra S SS Caldes Trinidad T Caligo Maria A MA Campbell Ian I Cannioto Rikki R Carney Michael E ME Cescon Terence T Chan Salina B SB Chang-Claude Jenny J Chanock Stephen S Chen Xiao Qing XQ Chiew Yoke-Eng YE Chiquette Jocelyne J Chung Wendy K WK Claes Kathleen B M KBM Conner Thomas T Cook Linda S LS Cook Jackie J Cramer Daniel W DW Cunningham Julie M JM D'Aloisio Aimee A AA Daly Mary B MB Damiola Francesca F Damirovna Sakaeva Dina SD Dansonka-Mieszkowska Agnieszka A Dao Fanny F Davidson Rosemarie R DeFazio Anna A Delnatte Capucine C Doheny Kimberly F KF Diez Orland O Ding Yuan Chun YC Doherty Jennifer Anne JA Domchek Susan M SM Dorfling Cecilia M CM Dörk Thilo T Dossus Laure L Duran Mercedes M Dürst Matthias M Dworniczak Bernd B Eccles Diana D Edwards Todd T Eeles Ros R Eilber Ursula U Ejlertsen Bent B Ekici Arif B AB Ellis Steve S Elvira Mingajeva M Eng Kevin H KH Engel Christoph C Evans D Gareth DG Fasching Peter A PA Ferguson Sarah S Ferrer Sandra Fert SF Flanagan James M JM Fogarty Zachary C ZC Fortner Renée T RT Fostira Florentia F Foulkes William D WD Fountzilas George G Fridley Brooke L BL Friebel Tara M TM Friedman Eitan E Frost Debra D Ganz Patricia A PA Garber Judy J García María J MJ Garcia-Barberan Vanesa V Gehrig Andrea A Gentry-Maharaj Aleksandra A Gerdes Anne-Marie AM Giles Graham G GG Glasspool Rosalind R Glendon Gord G Godwin Andrew K AK Goldgar David E DE Goranova Teodora T Gore Martin M Greene Mark H MH Gronwald Jacek J Gruber Stephen S Hahnen Eric E Haiman Christopher A CA Håkansson Niclas N Hamann Ute U Hansen Thomas V O TVO Harrington Patricia A PA Harris Holly R HR Hauke Jan J Hein Alexander A Henderson Alex A Hildebrandt Michelle A T MAT Hillemanns Peter P Hodgson Shirley S Høgdall Claus K CK Høgdall Estrid E Hogervorst Frans B L FBL Holland Helene H Hooning Maartje J MJ Hosking Karen K Huang Ruea-Yea RY Hulick Peter J PJ Hung Jillian J Hunter David J DJ Huntsman David G DG Huzarski Tomasz T Imyanitov Evgeny N EN Isaacs Claudine C Iversen Edwin S ES Izatt Louise L Izquierdo Angel A Jakubowska Anna A James Paul P Janavicius Ramunas R Jernetz Mats M Jensen Allan A Jensen Uffe Birk UB John Esther M EM Johnatty Sharon S Jones Michael E ME Kannisto Päivi P Karlan Beth Y BY Karnezis Anthony A Kast Karin K Kennedy Catherine J CJ Khusnutdinova Elza E Kiemeney Lambertus A LA Kiiski Johanna I JI Kim Sung-Won SW Kjaer Susanne K SK Köbel Martin M Kopperud Reidun K RK Kruse Torben A TA Kupryjanczyk Jolanta J Kwong Ava A Laitman Yael Y Lambrechts Diether D Larrañaga Nerea N Larson Melissa C MC Lazaro Conxi C Le Nhu D ND Le Marchand Loic L Lee Jong Won JW Lele Shashikant B SB Leminen Arto A Leroux Dominique D Lester Jenny J Lesueur Fabienne F Levine Douglas A DA Liang Dong D Liebrich Clemens C Lilyquist Jenna J Lipworth Loren L Lissowska Jolanta J Lu Karen H KH Lubinński Jan J Luccarini Craig C Lundvall Lene L Mai Phuong L PL Mendoza-Fandiño Gustavo G Manoukian Siranoush S Massuger Leon F A G LFAG May Taymaa T Mazoyer Sylvie S McAlpine Jessica N JN McGuire Valerie V McLaughlin John R JR McNeish Iain I Meijers-Heijboer Hanne H Meindl Alfons A Menon Usha U Mensenkamp Arjen R AR Merritt Melissa A MA Milne Roger L RL Mitchell Gillian G Modugno Francesmary F Moes-Sosnowska Joanna J Moffitt Melissa M Montagna Marco M Moysich Kirsten B KB Mulligan Anna Marie AM Musinsky Jacob J Nathanson Katherine L KL Nedergaard Lotte L Ness Roberta B RB Neuhausen Susan L SL Nevanlinna Heli H Niederacher Dieter D Nussbaum Robert L RL Odunsi Kunle K Olah Edith E Olopade Olufunmilayo I OI Olsson Håkan H Olswold Curtis C O'Malley David M DM Ong Kai-Ren KR Onland-Moret N Charlotte NC Orr Nicholas N Orsulic Sandra S Osorio Ana A Palli Domenico D Papi Laura L Park-Simon Tjoung-Won TW Paul James J Pearce Celeste L CL Pedersen Inge Søkilde IS Peeters Petra H M PHM Peissel Bernard B Peixoto Ana A Pejovic Tanja T Pelttari Liisa M LM Permuth Jennifer B JB Peterlongo Paolo P Pezzani Lidia L Pfeiler Georg G Phillips Kelly-Anne KA Piedmonte Marion M Pike Malcolm C MC Piskorz Anna M AM Poblete Samantha R SR Pocza Timea T Poole Elizabeth M EM Poppe Bruce B Porteous Mary E ME Prieur Fabienne F Prokofyeva Darya D Pugh Elizabeth E Pujana Miquel Angel MA Pujol Pascal P Radice Paolo P Rantala Johanna J Rappaport-Fuerhauser Christine C Rennert Gad G Rhiem Kerstin K Rice Patricia P Richardson Andrea A Robson Mark M Rodriguez Gustavo C GC Rodríguez-Antona Cristina C Romm Jane J Rookus Matti A MA Rossing Mary Anne MA Rothstein Joseph H JH Rudolph Anja A Runnebaum Ingo B IB Salvesen Helga B HB Sandler Dale P DP Schoemaker Minouk J MJ Senter Leigha L Setiawan V Wendy VW Severi Gianluca G Sharma Priyanka P Shelford Tameka T Siddiqui Nadeem N Side Lucy E LE Sieh Weiva W Singer Christian F CF Sobol Hagay H Song Honglin H Southey Melissa C MC Spurdle Amanda B AB Stadler Zsofia Z Steinemann Doris D Stoppa-Lyonnet Dominique D Sucheston-Campbell Lara E LE Sukiennicki Grzegorz G Sutphen Rebecca R Sutter Christian C Swerdlow Anthony J AJ Szabo Csilla I CI Szafron Lukasz L Tan Yen Y YY Taylor Jack A JA Tea Muy-Kheng MK Teixeira Manuel R MR Teo Soo-Hwang SH Terry Kathryn L KL Thompson Pamela J PJ Thomsen Liv Cecilie Vestrheim LCV Thull Darcy L DL Tihomirova Laima L Tinker Anna V AV Tischkowitz Marc M Tognazzo Silvia S Toland Amanda Ewart AE Tone Alicia A Trabert Britton B Travis Ruth C RC Trichopoulou Antonia A Tung Nadine N Tworoger Shelley S SS van Altena Anne M AM Van Den Berg David D van der Hout Annemarie H AH van der Luijt Rob B RB Van Heetvelde Mattias M Van Nieuwenhuysen Els E van Rensburg Elizabeth J EJ Vanderstichele Adriaan A Varon-Mateeva Raymonda R Vega Ana A Edwards Digna Velez DV Vergote Ignace I Vierkant Robert A RA Vijai Joseph J Vratimos Athanassios A Walker Lisa L Walsh Christine C Wand Dorothea D Wang-Gohrke Shan S Wappenschmidt Barbara B Webb Penelope M PM Weinberg Clarice R CR Weitzel Jeffrey N JN Wentzensen Nicolas N Whittemore Alice S AS Wijnen Juul T JT Wilkens Lynne R LR Wolk Alicja A Woo Michelle M Wu Xifeng X Wu Anna H AH Yang Hannah H Yannoukakos Drakoulis D Ziogas Argyrios A Zorn Kristin K KK Narod Steven A SA Easton Douglas F DF Amos Christopher I CI Schildkraut Joellen M JM Ramus Susan J SJ Ottini Laura L Goodman Marc T MT Park Sue K SK Kelemen Linda E LE Risch Harvey A HA Thomassen Mads M Offit Kenneth K Simard Jacques J Schmutzler Rita Katharina RK Hazelett Dennis D Monteiro Alvaro N AN Couch Fergus J FJ Berchuck Andrew A Chenevix-Trench Georgia G Goode Ellen L EL Sellers Thomas A TA Gayther Simon A SA Antoniou Antonis C AC Pharoah Paul D P PDP

Nature genetics 20170327 5

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for hi ...[more]

PMID: 28346442

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Project description:The circulating concentrations of triglycerides, high density lipoprotein (HDL)?cholesterol, and low density lipoprotein (LDL)?cholesterol have a substantial genetic component, and the heritability of early?onset dyslipidemia might be expected to be higher compared with late?onset forms. In the present study, exome?wide association studies (EWASs) were performed for early?onset hypertriglyceridemia, hypo?HDL?cholesterolemia, and hyper?LDL?cholesterolemia, with the aim to identify genetic variants that confer susceptibility to these conditions in the Japanese population. A total of 8,073 individuals aged ?65 years were enrolled in the study. The EWASs for hypertriglyceridemia (2,664 cases and 5,294 controls), hypo?HDL?cholesterolemia (974 cases and 7,085 controls), and hyper?LDL?cholesterolemia (2,911 cases and 5,111 controls) were performed with Illumina Human Exome?12 v1.2 DNA Analysis BeadChip or Infinium Exome?24 v1.0 BeadChip arrays. The association of allele frequencies for 31,198, 31,133, or 31,175 single nucleotide polymorphisms (SNPs) to hypertriglyceridemia, hypo?HDL?cholesterolemia, or hyper?LDL?cholesterolemia, respectively, was examined with Fisher's exact test. To compensate for multiple comparisons of genotypes with each of the three conditions, Bonferroni's correction was applied for statistical significance of association. The results demonstrated that 25, 28 and 65 SNPs were significantly associated with hypertriglyceridemia, hypo?HDL?cholesterolemia and hyper?LDL?cholesterolemia, respectively. Multivariable logistic regression analysis with adjustment for age and sex revealed that all 25, 28 and 65 of these SNPs were significantly associated with hypertriglyceridemia, hypo?HDL?cholesterolemia and hyper?LDL?cholesterolemia, respectively. Following examination of the association of the identified SNPs to serum concentrations of triglycerides, HDL?cholesterol, or LDL?cholesterol, linkage disequilibrium of the SNPs, and results of previous genome?wide association studies, we newly identified chromosomal region 19p12 as a susceptibility locus for hypertriglyceridemia, eight loci (MOB3C?TMOD4, LPGAT1, EHD3, COL6A3, ZNF860?CACNA1D, COL6A5, DCLRE1C, ZNF77) for hypo?HDL?cholesterolemia, and three loci (KIAA0319?FAM65B, UBD, LOC105375015) for hyper?LDL?cholesterolemia. The present study thus identified 12 novel loci that may confer susceptibility to early?onset dyslipidemia. Determination of genotypes for the SNPs at these loci may prove informative for assessment of genetic risk for hypertriglyceridemia, hypo?HDL?cholesterolemia, or hyper?LDL?cholesterolemia in the Japanese population.

Project description:ObjectiveOvarian cancer in Black women is common in many West African countries but is relatively rare in North America. Black women have worse survival outcomes when compared to White women. Ovarian cancer histotype, diagnosis, and age at presentation are known prognostic factors for outcome. We sought to conduct a preliminary comparative assessment of these factors across the African diaspora.MethodsPatients diagnosed with ovarian cancer (all histologies) between June 2016-December 2019 in Departments of Pathology at 25 participating sites in Nigeria were identified. Comparative population-based data, inclusive of Caribbean-born Blacks (CBB) and US-born Blacks (USB), were additionally captured from the International Agency for Research on Cancer and Florida Cancer Data Systems. Histology, country of birth, and age at diagnosis data were collected and evaluated across the three subgroups: USB, CBB and Nigerians. Statistical analyses were done using chi-square and student's t-test with significance set at p<0.05.ResultsNigerians had the highest proportion of germ cell tumor (GCT, 11.5%) and sex-cord stromal (SCST, 16.2%) ovarian cancers relative to CBB and USB (p=0.001). CBB (79.4%) and USB (77.3%) women were diagnosed with a larger proportion of serous ovarian cancer than Nigerians (60.4%) (p<0.0001). Nigerians were diagnosed with epithelial ovarian cancers at the youngest age (51.7± 12.8 years) relative to USB (58.9 ± 15.0) and CBB (59.0± 13.0,p<0.001). Black women [CBB (25.2 ± 15.0), Nigerians (29.5 ± 15.1), and USB (33.9 ± 17.9)] were diagnosed with GCT younger than White women (35.4 ± 20.5, p=0.011). Black women [Nigerians (47.5 ± 15.9), USB (50.9 ± 18.3) and CBB (50.9 ± 18.3)] were also diagnosed with SCST younger than White women (55.6 ± 16.5, p<0.01).ConclusionThere is significant variation in age of diagnosis and distribution of ovarian cancer histotype/diagnosis across the African diaspora. The etiology of these findings requires further investigation.

Dataset Information

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

Publications

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

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