Dataset Information

BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers.

ABSTRACT: BACKGROUND:The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. METHODS:Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. RESULTS:The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. CONCLUSIONS:Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.

SUBMITTER: Meeks HD

PROVIDER: S-EPMC4907358 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers.

Meeks Huong D HD Song Honglin H Michailidou Kyriaki K Bolla Manjeet K MK Dennis Joe J Wang Qin Q Barrowdale Daniel D Frost Debra D McGuffog Lesley L Ellis Steve S Feng Bingjian B Buys Saundra S SS Hopper John L JL Southey Melissa C MC Tesoriero Andrea A James Paul A PA Bruinsma Fiona F Campbell Ian G IG Broeks Annegien A Schmidt Marjanka K MK Hogervorst Frans B L FB Beckman Matthias W MW Fasching Peter A PA Fletcher Olivia O Johnson Nichola N Sawyer Elinor J EJ Riboli Elio E Banerjee Susana S Menon Usha U Tomlinson Ian I Burwinkel Barbara B Hamann Ute U Marme Frederik F Rudolph Anja A Janavicius Ramunas R Tihomirova Laima L Tung Nadine N Garber Judy J Cramer Daniel D Terry Kathryn L KL Poole Elizabeth M EM Tworoger Shelley S SS Dorfling Cecilia M CM van Rensburg Elizabeth J EJ Godwin Andrew K AK Guénel Pascal P Truong Thérèse T Stoppa-Lyonnet Dominique D Damiola Francesca F Mazoyer Sylvie S Sinilnikova Olga M OM Isaacs Claudine C Maugard Christine C Bojesen Stig E SE Flyger Henrik H Gerdes Anne-Marie AM Hansen Thomas V O TV Jensen Allen A Kjaer Susanne K SK Hogdall Claus C Hogdall Estrid E Pedersen Inge Sokilde IS Thomassen Mads M Benitez Javier J González-Neira Anna A Osorio Ana A Hoya Miguel de la Mde L Segura Pedro Perez PP Diez Orland O Lazaro Conxi C Brunet Joan J Anton-Culver Hoda H Eunjung Lee L John Esther M EM Neuhausen Susan L SL Ding Yuan Chun YC Castillo Danielle D Weitzel Jeffrey N JN Ganz Patricia A PA Nussbaum Robert L RL Chan Salina B SB Karlan Beth Y BY Lester Jenny J Wu Anna A Gayther Simon S Ramus Susan J SJ Sieh Weiva W Whittermore Alice S AS Monteiro Alvaro N A AN Phelan Catherine M CM Terry Mary Beth MB Piedmonte Marion M Offit Kenneth K Robson Mark M Levine Douglas D Moysich Kirsten B KB Cannioto Rikki R Olson Sara H SH Daly Mary B MB Nathanson Katherine L KL Domchek Susan M SM Lu Karen H KH Liang Dong D Hildebrant Michelle A T MA Ness Roberta R Modugno Francesmary F Pearce Leigh L Goodman Marc T MT Thompson Pamela J PJ Brenner Hermann H Butterbach Katja K Meindl Alfons A Hahnen Eric E Wappenschmidt Barbara B Brauch Hiltrud H Brüning Thomas T Blomqvist Carl C Khan Sofia S Nevanlinna Heli H Pelttari Liisa M LM Aittomäki Kristiina K Butzow Ralf R Bogdanova Natalia V NV Dörk Thilo T Lindblom Annika A Margolin Sara S Rantala Johanna J Kosma Veli-Matti VM Mannermaa Arto A Lambrechts Diether D Neven Patrick P Claes Kathleen B M KB Maerken Tom Van TV Chang-Claude Jenny J Flesch-Janys Dieter D Heitz Florian F Varon-Mateeva Raymonda R Peterlongo Paolo P Radice Paolo P Viel Alessandra A Barile Monica M Peissel Bernard B Manoukian Siranoush S Montagna Marco M Oliani Cristina C Peixoto Ana A Teixeira Manuel R MR Collavoli Anita A Hallberg Emily E Olson Janet E JE Goode Ellen L EL Hart Steven N SN Shimelis Hermela H Cunningham Julie M JM Giles Graham G GG Milne Roger L RL Healey Sue S Tucker Kathy K Haiman Christopher A CA Henderson Brian E BE Goldberg Mark S MS Tischkowitz Marc M Simard Jacques J Soucy Penny P Eccles Diana M DM Le Nhu N Borresen-Dale Anne-Lise AL Kristensen Vessela V Salvesen Helga B HB Bjorge Line L Bandera Elisa V EV Risch Harvey H Zheng Wei W Beeghly-Fadiel Alicia A Cai Hui H Pylkäs Katri K Tollenaar Robert A E M RA Ouweland Ans M W van der AM Andrulis Irene L IL Knight Julia A JA Narod Steven S Devilee Peter P Winqvist Robert R Figueroa Jonine J Greene Mark H MH Mai Phuong L PL Loud Jennifer T JT García-Closas Montserrat M Schoemaker Minouk J MJ Czene Kamila K Darabi Hatef H McNeish Iain I Siddiquil Nadeem N Glasspool Rosalind R Kwong Ava A Park Sue K SK Teo Soo Hwang SH Yoon Sook-Yee SY Matsuo Keitaro K Hosono Satoyo S Woo Yin Ling YL Gao Yu-Tang YT Foretova Lenka L Singer Christian F CF Rappaport-Feurhauser Christine C Friedman Eitan E Laitman Yael Y Rennert Gad G Imyanitov Evgeny N EN Hulick Peter J PJ Olopade Olufunmilayo I OI Senter Leigha L Olah Edith E Doherty Jennifer A JA Schildkraut Joellen J Koppert Linetta B LB Kiemeney Lambertus A LA Massuger Leon F A G LF Cook Linda S LS Pejovic Tanja T Li Jingmei J Borg Ake A Öfverholm Anna A Rossing Mary Anne MA Wentzensen Nicolas N Henriksson Karin K Cox Angela A Cross Simon S SS Pasini Barbara J BJ Shah Mitul M Kabisch Maria M Torres Diana D Jakubowska Anna A Lubinski Jan J Gronwald Jacek J Agnarsson Bjarni A BA Kupryjanczyk Jolanta J Moes-Sosnowska Joanna J Fostira Florentia F Konstantopoulou Irene I Slager Susan S Jones Michael M Antoniou Antonis C AC Berchuck Andrew A Swerdlow Anthony A Chenevix-Trench Georgia G Dunning Alison M AM Pharoah Paul D P PD Hall Per P Easton Douglas F DF Couch Fergus J FJ Spurdle Amanda B AB Goldgar David E DE

Journal of the National Cancer Institute 20151119 2

<h4>Background</h4>The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers.<h4>Methods</h4>Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 can ...[more]

PMID: 26586665

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Project description:BACKGROUND:BRCA1/2 germline mutation related cancers are candidates for new immune therapeutic interventions. This study was a hypothesis generating exploration of genomic data collected at diagnosis for 19 patients. The prominent tumor mutation burden (TMB) in hereditary breast and ovarian cancers in this cohort was not correlated with high global immune activity in their microenvironments. More information is needed about the relationship between genomic instability, phenotypes and immune microenvironments of these hereditary tumors in order to find appropriate markers of immune activity and the most effective anticancer immune strategies. METHODS:Mining and statistical analyses of the original DNA and RNA sequencing data and The Cancer Genome Atlas data were performed. To interpret the data, we have used published literature and web available resources such as Gene Ontology, The Cancer immunome Atlas and the Cancer Research Institute iAtlas. RESULTS:We found that BRCA1/2 germline related breast and ovarian cancers do not represent a unique phenotypic identity, but they express a range of phenotypes similar to sporadic cancers. All breast and ovarian BRCA1/2 related tumors are characterized by high homologous recombination deficiency (HRD) and low aneuploidy. Interestingly, all sporadic high grade serous ovarian cancers (HGSOC) and most of the subtypes of triple negative breast cancers (TNBC) also express a high degree of HRD. CONCLUSIONS:TMB is not associated with the magnitude of the immune response in hereditary BRCA1/2 related breast and ovarian cancers or in sporadic TNBC and sporadic HGSOC. Hereditary tumors express phenotypes as heterogenous as sporadic tumors with various degree of "BRCAness" and various characteristics of the immune microenvironments. The subtyping criteria developed for sporadic tumors can be applied for the classification of hereditary tumors and possibly also characterization of their immune microenvironment. A high HRD score may be a good candidate biomarker for response to platinum, and potentially PARP-inhibition. TRIAL REGISTRATION:Phase I Study of the Oral PI3kinase Inhibitor BKM120 or BYL719 and the Oral PARP Inhibitor Olaparib in Patients With Recurrent TNBC or HGSOC (NCT01623349), first posted on June 20, 2012. The design and the outcome of the clinical trial is not in the scope of this study.

Project description:Tumor-associated macrophages (TAMs) are major innate immune cells that constitute up to 50% of the cell mass of human tumors. TAMs are highly heterogeneous cells that originate from resident tissue-specific macrophages and from newly recruited monocytes. TAMs' variability strongly depends on cancer type, stage, and intratumor heterogeneity. Majority of TAMs are programmed by tumor microenvironment to support primary tumor growth and metastatic spread. However, TAMs can also restrict tumor growth and metastasis. In this review, we summarized the knowledge about the role of TAMs in tumor growth, metastasis and in the response to cancer therapy in patients with five aggressive types of cancer: breast, colorectal, lung, ovarian, and prostate cancers that are frequently metastasize into distant organs resulting in high mortality of the patients. Two major TAM parameters are applied for the evaluation of TAM correlation with the cancer progression: total amount of TAMs and specific phenotype of TAMs identified by functional biomarkers. We summarized the data generated in the wide range of international patient cohorts on the correlation of TAMs with clinical and pathological parameters of tumor progression including lymphatic and hematogenous metastasis, recurrence, survival, therapy efficiency. We described currently available biomarkers for TAMs that can be measured in patients' samples (tumor tissue and blood). CD68 is the major biomarker for the quantification of total TAM amounts, while transmembrane receptors (stabilin-1, CD163, CD206, CD204, MARCO) and secreted chitinase-like proteins (YKL-39, YKL-40) are used as biomarkers for the functional TAM polarization. We also considered that specific role of TAMs in tumor progression can depend on the localization in the intratumoral compartments. We have made the conclusion for the role of TAMs in primary tumor growth, metastasis, and therapy sensitivity for breast, colorectal, lung, ovarian, and prostate cancers. In contrast to other cancer types, majority of clinical studies indicate that TAMs in colorectal cancer have protective role for the patient and interfere with primary tumor growth and metastasis. The accumulated data are essential for using TAMs as biomarkers and therapeutic targets to develop cancer-specific immunotherapy and to design efficient combinations of traditional therapy and new immunomodulatory approaches.

Dataset Information

BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers.

Publications

BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers.

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