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1.  DNA repair genes are selectively mutated in diffuse large B cell lymphomas 
The Journal of Experimental Medicine  2013;210(9):1729-1742.
Mutations in DNA damage response and repair genes correlate with genomic instability in diffuse large B cell lymphomas.
DNA repair mechanisms are fundamental for B cell development, which relies on the somatic diversification of the immunoglobulin genes by V(D)J recombination, somatic hypermutation, and class switch recombination. Their failure is postulated to promote genomic instability and malignant transformation in B cells. By performing targeted sequencing of 73 key DNA repair genes in 29 B cell lymphoma samples, somatic and germline mutations were identified in various DNA repair pathways, mainly in diffuse large B cell lymphomas (DLBCLs). Mutations in mismatch repair genes (EXO1, MSH2, and MSH6) were associated with microsatellite instability, increased number of somatic insertions/deletions, and altered mutation signatures in tumors. Somatic mutations in nonhomologous end-joining (NHEJ) genes (DCLRE1C/ARTEMIS, PRKDC/DNA-PKcs, XRCC5/KU80, and XRCC6/KU70) were identified in four DLBCL tumors and cytogenetic analyses revealed that translocations involving the immunoglobulin-heavy chain locus occurred exclusively in NHEJ-mutated samples. The novel mutation targets, CHEK2 and PARP1, were further screened in expanded DLBCL cohorts, and somatic as well as novel and rare germline mutations were identified in 8 and 5% of analyzed tumors, respectively. By correlating defects in a subset of DNA damage response and repair genes with genomic instability events in tumors, we propose that these genes play a role in DLBCL lymphomagenesis.
PMCID: PMC3754869  PMID: 23960188
2.  Uncovering the DNA methylome in chronic lymphocytic leukemia 
Epigenetics  2013;8(2):138-148.
Over the past two decades, aberrant DNA methylation has emerged as a key player in the pathogenesis of chronic lymphocytic leukemia (CLL), and knowledge regarding its biological and clinical consequences in this disease has evolved rapidly. Since the initial studies relating DNA hypomethylation to genomic instability in CLL, a plethora of reports have followed showing the impact of DNA hypermethylation in silencing vital single gene promoters and the reversible nature of DNA methylation through inhibitor drugs. With the recognition that DNA hypermethylation events could potentially act as novel prognostic and treatment targets in CLL, the search for aberrantly methylated genes, gene families and pathways has ensued. Subsequently, the advent of microarray and next-generation sequencing technologies has supported the hunt for such targets, allowing exploration of the methylation landscape in CLL at an unprecedented scale. In light of these analyses, we now understand that different CLL prognostic subgroups are characterized by differential methylation profiles; we recognize DNA methylation of a number of signaling pathways genes to be altered in CLL, and acknowledge the role of DNA methylation outside of traditional CpG island promoters as fundamental players in the regulation of gene expression. Today, the significance and timing of altered DNA methylation within the complex epigenetic network of concomitant epigenetic messengers such as histones and miRNAs is an intensive area of research. In CLL, it appears that DNA methylation is a rather stable epigenetic mark occurring rather early in the disease pathogenesis. However, other consequences, such as how and why aberrant methylation marks occur, are less explored. In this review, we will not only provide a comprehensive summary of the current literature within the epigenetics field of CLL, but also highlight some of the novel findings relating to when, where, why and how altered DNA methylation materializes in CLL.
PMCID: PMC3592899  PMID: 23321535
chronic lymphocytic leukemia; hypomethylation; hypermethylation; CpG islands; gene silencing; microarrays; next-generation sequencing
3.  Distinct transcriptional control in major immunogenetic subsets of chronic lymphocytic leukemia exhibiting subset-biased global DNA methylation profiles 
Epigenetics  2012;7(12):1435-1442.
Chronic lymphocytic leukemia (CLL) can be divided into prognostic subgroups based on the IGHV gene mutational status, and is further characterized by multiple subsets of cases with quasi-identical or stereotyped B cell receptors that also share clinical and biological features. We recently reported differential DNA methylation profiles in IGHV-mutated and IGHV-unmutated CLL subgroups. For the first time, we here explore the global methylation profiles of stereotyped subsets with different prognosis, by applying high-resolution methylation arrays on CLL samples from three major stereotyped subsets: the poor-prognostic subsets #1 (n = 15) and #2 (n = 9) and the favorable-prognostic subset #4 (n = 15). Overall, the three subsets exhibited significantly different methylation profiles, which only partially overlapped with those observed in our previous study according to IGHV gene mutational status. Specifically, gene ontology analysis of the differentially methylated genes revealed a clear enrichment of genes involved in immune response, such as B cell activation (e.g., CD80, CD86 and IL10), with higher methylation levels in subset #1 than subsets #2 and #4. Accordingly, higher expression of the co-stimulatory molecules CD80 and CD86 was demonstrated in subset #4 vs. subset #1, pointing to a key role for these molecules in the crosstalk of CLL subset #4 cells with the microenvironment. In summary, investigation of three prototypic, stereotyped CLL subsets revealed distinct DNA methylation profiles for each subset, which suggests subset-biased patterns of transcriptional control and highlights a key role for epigenetics during leukemogenesis.
PMCID: PMC3528698  PMID: 23154584
Chronic lymphocytic leukemia; DNA methylation; microarrays; stereotyped B cell receptors; immune response
4.  Temporal Dynamics of Clonal Evolution in Chronic Lymphocytic Leukemia with Stereotyped IGHV4-34/IGKV2-30 Antigen Receptors: Longitudinal Immunogenetic Evidence 
Molecular Medicine  2013;19(1):230-236.
Chronic lymphocytic leukemia (CLL) patients assigned to stereotyped subset 4 possess distinctive patterns of intraclonal diversification (ID) within their immunoglobulin (IG) genes. Although highly indicative of an ongoing response to antigen(s), the critical question concerning the precise timing of antigen involvement is unresolved. Hence, we conducted a large-scale longitudinal study of eight subset 4 cases totaling 511 and 398 subcloned IG heavy and kappa sequences. Importantly, we could establish a hierarchical pattern of subclonal evolution, thus revealing which somatic hypermutations were negatively or positively selected. In addition, distinct clusters of subcloned sequences with cluster-specific mutational profiles were observed initially; however, at later time points, the minor cluster had often disappeared and hence not been selected. Despite the high intensity of ID, it was remarkable that certain residues remained essentially unaltered. These novel findings strongly support a role for persistent antigen stimulation in the clonal evolution of CLL subset 4.
PMCID: PMC3769528  PMID: 23922244
5.  Cernunnos influences human immunoglobulin class switch recombination and may be associated with B cell lymphomagenesis 
B cells from Cernunnos-deficient patients contain aberrant class switch recombination junctions, and a dominant-negative Cernunnos mutation was detected in a diffuse large B cell lymphoma sample.
Cernunnos is involved in the nonhomologous end-joining (NHEJ) process during DNA double-strand break (DSB) repair. Here, we studied immunoglobulin (Ig) class switch recombination (CSR), a physiological process which relies on proper repair of the DSBs, in B cells from Cernunnos-deficient patients. The pattern of in vivo generated CSR junctions is altered in these cells, with unusually long microhomologies and a lack of direct end-joining. The CSR junctions from Cernunnos-deficient patients largely resemble those from patients lacking DNA ligase IV, Artemis, or ATM, suggesting that these factors are involved in the same end-joining pathway during CSR. By screening 269 mature B cell lymphoma biopsies, we also identified a somatic missense Cernunnos mutation in a diffuse large B cell lymphoma sample. This mutation has a dominant-negative effect on joining of a subset of DNA ends in an in vitro NHEJ assay. Translocations involving both Ig heavy chain loci and clonal-like, dynamic IgA switching activities were observed in this tumor. Collectively, our results suggest a link between defects in the Cernunnos-dependent NHEJ pathway and aberrant CSR or switch translocations during the development of B cell malignancies.
PMCID: PMC3280866  PMID: 22312109
6.  Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers 
Antoniou, Antonis C | Kuchenbaecker, Karoline B | Soucy, Penny | Beesley, Jonathan | Chen, Xiaoqing | McGuffog, Lesley | Lee, Andrew | Barrowdale, Daniel | Healey, Sue | Sinilnikova, Olga M | Caligo, Maria A | Loman, Niklas | Harbst, Katja | Lindblom, Annika | Arver, Brita | Rosenquist, Richard | Karlsson, Per | Nathanson, Kate | Domchek, Susan | Rebbeck, Tim | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Złowowcka-Perłowska, Elżbieta | Osorio, Ana | Durán, Mercedes | Andrés, Raquel | Benítez, Javier | Hamann, Ute | Hogervorst, Frans B | van Os , Theo A | Verhoef, Senno | Meijers-Heijboer, Hanne EJ | Wijnen, Juul | Gómez Garcia, Encarna B | Ligtenberg, Marjolijn J | Kriege, Mieke | Collée, J Margriet | Ausems, Margreet GEM | Oosterwijk, Jan C | Peock, Susan | Frost, Debra | Ellis, Steve D | Platte, Radka | Fineberg, Elena | Evans, D Gareth | Lalloo, Fiona | Jacobs, Chris | Eeles, Ros | Adlard, Julian | Davidson, Rosemarie | Cole, Trevor | Cook, Jackie | Paterson, Joan | Douglas, Fiona | Brewer, Carole | Hodgson, Shirley | Morrison, Patrick J | Walker, Lisa | Rogers, Mark T | Donaldson, Alan | Dorkins, Huw | Godwin, Andrew K | Bove, Betsy | Stoppa-Lyonnet, Dominique | Houdayer, Claude | Buecher, Bruno | de Pauw, Antoine | Mazoyer, Sylvie | Calender, Alain | Léoné, Mélanie | Bressac- de Paillerets, Brigitte | Caron, Olivier | Sobol, Hagay | Frenay, Marc | Prieur, Fabienne | Ferrer, Sandra Fert | Mortemousque, Isabelle | Buys, Saundra | Daly, Mary | Miron, Alexander | Terry, Mary Beth | Hopper, John L | John, Esther M | Southey, Melissa | Goldgar, David | Singer, Christian F | Fink-Retter, Anneliese | Tea, Muy-Kheng | Kaulich, Daphne Geschwantler | Hansen, Thomas VO | Nielsen, Finn C | Barkardottir, Rosa B | Gaudet, Mia | Kirchhoff, Tomas | Joseph, Vijai | Dutra-Clarke, Ana | Offit, Kenneth | Piedmonte, Marion | Kirk, Judy | Cohn, David | Hurteau, Jean | Byron, John | Fiorica, James | Toland, Amanda E | Montagna, Marco | Oliani, Cristina | Imyanitov, Evgeny | Isaacs, Claudine | Tihomirova, Laima | Blanco, Ignacio | Lazaro, Conxi | Teulé, Alex | Valle, J Del | Gayther, Simon A | Odunsi, Kunle | Gross, Jenny | Karlan, Beth Y | Olah, Edith | Teo, Soo-Hwang | Ganz, Patricia A | Beattie, Mary S | Dorfling, Cecelia M | van Rensburg, Elizabeth Jansen | Diez, Orland | Kwong, Ava | Schmutzler, Rita K | Wappenschmidt, Barbara | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Heidemann, Simone | Niederacher, Dieter | Preisler-Adams, Sabine | Gadzicki, Dorothea | Varon-Mateeva, Raymonda | Deissler, Helmut | Gehrig, Andrea | Sutter, Christian | Kast, Karin | Fiebig, Britta | Schäfer, Dieter | Caldes, Trinidad | de la Hoya, Miguel | Nevanlinna, Heli | Muranen, Taru A | Lespérance, Bernard | Spurdle, Amanda B | Neuhausen, Susan L | Ding, Yuan C | Wang, Xianshu | Fredericksen, Zachary | Pankratz, Vernon S | Lindor, Noralane M | Peterlongo, Paolo | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Bonanni, Bernardo | Bernard, Loris | Dolcetti, Riccardo | Papi, Laura | Ottini, Laura | Radice, Paolo | Greene, Mark H | Loud, Jennifer T | Andrulis, Irene L | Ozcelik, Hilmi | Mulligan, Anna Marie | Glendon, Gord | Thomassen, Mads | Gerdes, Anne-Marie | Jensen, Uffe B | Skytte, Anne-Bine | Kruse, Torben A | Chenevix-Trench, Georgia | Couch, Fergus J | Simard, Jacques | Easton, Douglas F
Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).
To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.
Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).
The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.
PMCID: PMC3496151  PMID: 22348646
7.  Lymphoblastoid cell line with B1 cell characteristics established from a chronic lymphocytic leukemia clone by in vitro EBV infection 
Oncoimmunology  2012;1(1):18-27.
Chronic lymphocytic leukemia (CLL) cells express the receptor for Epstein-Barr virus (EBV) and can be infected in vitro. Infected cells do not express the growth-promoting set of EBV-encoded genes and therefore they do not yield LCLs, in most experiments. With exceptional clones, lines were obtained however. We describe a new line, HG3, established by in vitro EBV-infection from an IGHV1–2 unmutated CLL patient clone. All cells expressed EBNA-2 and LMP-1, the EBV-encoded genes pivotal for transformation. The karyotype, FISH cytogenetics and SNP-array profile of the line and the patient's ex vivo clone showed biallelic 13q14 deletions with genomic loss of DLEU7, miR15a/miR16–1, the two micro-RNAs that are deleted in 50% of CLL cases. Further features of CLL cells were: expression of CD5/CD20/CD27/CD43 and release of IgM natural antibodies reacting with oxLDL-like epitopes on apoptotic cells (cf. stereotyped subset-1). Comparison with two LCLs established from normal B cells showed 32 genes expressed at higher levels (> 2-fold). Among these were LHX2 and LILRA. These genes may play a role in the development of the disease. LHX2 expression was shown in self-renewing multipotent hematopoietic stem cells, and LILRA4 codes for a receptor for bone marrow stromal cell antigen-2 that contributes to B cell development. Twenty-four genes were expressed at lower levels, among these PARD3 that is essential for asymmetric cell division. These genes may contribute to establish precursors of CLL clones by regulation of cellular phenotype in the hematopoietic compartment. Expression of CD5/CD20/CD27/CD43 and spontaneous production of natural antibodies may identify the CLL cell as a self-renewing B1 lymphocyte.
PMCID: PMC3376971  PMID: 22720208
cell-of-origin; chronic lymphocytic leukemia; human B1 cells; leukemogenesis; lymphoblastoid cell line; self-renewing hematopoietic stem cells
8.  Epidural Steroid Injections for the Treatment of Cervical Radiculopathy in Elite Wrestlers: Case Series and Literature Review 
The Iowa Orthopaedic Journal  2012;32:207-214.
Elite wrestlers place tremendous stress through their cervical spine. These athletes are at risk for cervical trauma and may develop radiculopathy from recurrent episodes of injury. Team physicians and athletic trainers are faced with the challenge of treating these injuries in such a way as to allow the athlete to safely and expeditiously return to competition. Epidural steroid injections can be a successful complement to a conservative treatment algorithm for these complex injuries.
Study Design
Case Series
Five upper-level NCAA collegiate wrestlers who experienced symptomatic cervical radiculopathy were identified from an archival review. The majority of the athletes had MRI evidence of cervical disc disease, with corresponding subjective complaints and physical examination findings including pain and weakness that precluded continued competition. All athletes were treated conservatively with initial activity modification, strengthening, rehabilitation, NSAIDs, and, ultimately, cervical epidural steroid injections.
All five athletes successfully returned to competition without negative clinical sequelae or need for operative intervention. The athletes demonstrated subjective improvement in their symptoms and strength, and all were able to return to a high level of competition. The cervical epidural steroid injections were found to be safe, effective, and well tolerated in all of the athletes.
Elite wrestlers with cervical radiculopathy can be effectively and safely managed with a conservative regimen that includes cervical epidural steroid injections, which may allow them to continue to compete at a high level.
PMCID: PMC3565403  PMID: 23576942
9.  Analysis of a set of missense, frameshift, and in-frame deletion variants of BRCA1 
Mutation research  2008;660(1-2):1-11.
Germline mutations that inactivate BRCA1 are responsible for breast and ovarian cancer susceptibility. One possible outcome of genetic testing for BRCA1 is the finding of a genetic variant of uncertain significance for which there is no information regarding its cancer association. This outcome leads to problems in risk assessment, counseling and preventive care. The purpose of the present study was to functionally evaluate seven unclassified variants of BRCA1 including a genomic deletion that leads to the in-frame loss of exons 16/17 (Δ exons 16/17) in the mRNA, an insertion that leads to a frameshift and an extended carboxy-terminus (5673insC), and five missense variants (K1487R, S1613C, M1652I, Q1826H and V1833M). We analyzed the variants using a functional assay based on the transcription activation property of BRCA1 combined with supervised learning computational models. Functional analysis indicated that variants S1613C, Q1826H, and M1652I are likely to be neutral, whereas variants V1833M, Δ exons 16/17, and 5673insC are likely to represent deleterious variants. In agreement with the functional analysis, the results of the computational analysis also indicated that the latter three variants are likely to be deleterious. Taken together, a combined approach of functional and bioinformatics analysis, plus structural modeling, can be utilized to obtain valuable information pertaining to the effect of a rare variant on the structure and function of BRCA1. Such information can, in turn, aid in the classification of BRCA1 variants for which there is a lack of genetic information needed to provide reliable risk assessment.
PMCID: PMC2682550  PMID: 18992264
BRCA1; breast cancer; unclassified variants; functional analysis; BRCT domain
10.  Quantification of Normal Cell Fraction and Copy Number Neutral LOH in Clinical Lung Cancer Samples Using SNP Array Data 
PLoS ONE  2009;4(6):e6057.
Technologies based on DNA microarrays have the potential to provide detailed information on genomic aberrations in tumor cells. In practice a major obstacle for quantitative detection of aberrations is the heterogeneity of clinical tumor tissue. Since tumor tissue invariably contains genetically normal stromal cells, this may lead to a failure to detect aberrations in the tumor cells.
Principal Finding
Using SNP array data from 44 non-small cell lung cancer samples we have developed a bioinformatic algorithm that accurately models the fractions of normal and tumor cells in clinical tumor samples. The proportion of normal cells in combination with SNP array data can be used to detect and quantify copy number neutral loss-of-heterozygosity (CNNLOH) in the tumor cells both in crude tumor tissue and in samples enriched for tumor cells by laser capture microdissection.
Genome-wide quantitative analysis of CNNLOH using the CNNLOH Quantifier method can help to identify recurrent aberrations contributing to tumor development in clinical tumor samples. In addition, SNP-array based analysis of CNNLOH may become important for detection of aberrations that can be used for diagnostic and prognostic purposes.
PMCID: PMC2699026  PMID: 19557126
11.  Normalization of Illumina Infinium whole-genome SNP data improves copy number estimates and allelic intensity ratios 
BMC Bioinformatics  2008;9:409.
Illumina Infinium whole genome genotyping (WGG) arrays are increasingly being applied in cancer genomics to study gene copy number alterations and allele-specific aberrations such as loss-of-heterozygosity (LOH). Methods developed for normalization of WGG arrays have mostly focused on diploid, normal samples. However, for cancer samples genomic aberrations may confound normalization and data interpretation. Therefore, we examined the effects of the conventionally used normalization method for Illumina Infinium arrays when applied to cancer samples.
We demonstrate an asymmetry in the detection of the two alleles for each SNP, which deleteriously influences both allelic proportions and copy number estimates. The asymmetry is caused by a remaining bias between the two dyes used in the Infinium II assay after using the normalization method in Illumina's proprietary software (BeadStudio). We propose a quantile normalization strategy for correction of this dye bias. We tested the normalization strategy using 535 individual hybridizations from 10 data sets from the analysis of cancer genomes and normal blood samples generated on Illumina Infinium II 300 k version 1 and 2, 370 k and 550 k BeadChips. We show that the proposed normalization strategy successfully removes asymmetry in estimates of both allelic proportions and copy numbers. Additionally, the normalization strategy reduces the technical variation for copy number estimates while retaining the response to copy number alterations.
The proposed normalization strategy represents a valuable tool that improves the quality of data obtained from Illumina Infinium arrays, in particular when used for LOH and copy number variation studies.
PMCID: PMC2572624  PMID: 18831757
12.  Segmentation-based detection of allelic imbalance and loss-of-heterozygosity in cancer cells using whole genome SNP arrays 
Genome Biology  2008;9(9):R136.
A strategy is presented for detection of loss-of-heterozygosity and allelic imbalance in cancer cells from whole genome SNP genotyping data.
We present a strategy for detection of loss-of-heterozygosity and allelic imbalance in cancer cells from whole genome single nucleotide polymorphism genotyping data. Using a dilution series of a tumor cell line mixed with its paired normal cell line and data generated on Affymetrix and Illumina platforms, including paired tumor-normal samples and tumors characterized by fluorescent in situ hybridization, we demonstrate a high sensitivity and specificity of the strategy for detecting both minute and gross allelic imbalances in heterogeneous tumor samples.
PMCID: PMC2592714  PMID: 18796136
13.  A hypothesis-generating search for new genetic breast cancer syndromes - a national study in 803 Swedish families 
Among Swedish families with an inherited predisposition for breast cancer, less than one third segregate mutations in genes known to be associated with an increased risk of breast cancer in combination with other types of tumours. In a search for new putative familial breast cancer syndromes we studied Swedish families undergoing genetic counselling during 1992-2000.
Four thousand families from counselling clinics in Sweden were eligible for study. Families with breast cancer only were excluded, as were families with mutations in genes already known to be associated with malignant diseases. We identified 803 families with two or more cases of breast cancer and at least one other type of cancer. The observed proportion of different types of non-breast cancer was compared with the percentage distribution of non-breast cancer tumours in Sweden in 1958 and 1999.
We found tumours in the colon, ovary, endometrium, pancreas and liver, as well as leukaemia in a significantly larger proportion of the study population than in the general population in both years. These tumours were also seen among families where several members had one additional tumour, suggesting that malignancies at these sites, in combination with breast tumours, could constitute genetic syndromes. Endometrial carcinoma has not previously been described in the context of breast cancer syndromes and the excess of malignancies at this site could not be explained by secondary tumours. Thus, we suggest that endometrial carcinoma and breast cancer constitute a new breast cancer syndrome. Further investigation is warranted to categorize phenotypes of both breast and endometrial tumours in this subgroup.
PMCID: PMC3401933  PMID: 19769788
breast cancer; endometrial cancer; family history; syndromes; genetics

Results 1-13 (13)