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1.  Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma 
Nature genetics  2014;46(5):482-486.
Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin POT1 gene (g.7:124493086 C>T, Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere length and elevated fragile telomeres suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two other Italian families, yielding a frequency of POT1 variants comparable to that of CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in American and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations.
doi:10.1038/ng.2941
PMCID: PMC4056593  PMID: 24686846
2.  Genetic Susceptibility to Chronic Lymphocytic Leukemia 
Seminars in hematology  2013;50(4):10.1053/j.seminhematol.2013.09.007.
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the West and is an incurable malignancy. No firmly established evidence exists for environmental risk-factors in the etiology of CLL. However, CLL is estimated to have one of the highest familial risks for a hematologic malignancy; this along with other evidence strongly supports an inherited genetic component. In the past five years, genome-wide association studies have provided the foundation for new avenues in the investigation of pathogenesis of this disease with 22 susceptibility loci currently identified. We review here the advances made in identifying these loci, the potential to translate these findings into clinical practice, and future directions needed to advance our understanding of the genetic susceptibility of CLL.
doi:10.1053/j.seminhematol.2013.09.007
PMCID: PMC3834539  PMID: 24246697
CLL; SNP associations; etiology
3.  Precursors to Lymphoproliferative Malignancies 
We review monoclonal B-cell lymphocytosis (MBL) as a precursor to chronic lymphocytic leukemia and monoclonal gammopathy of undetermined significance (MGUS) as a precursor to plasma cell disorders. These conditions are present in the general population and increase with age. These precursors aggregate with lymphoproliferative malignancies in families suggesting shared inheritance. MBL and MGUS may share some of the same risk factors as their related malignancies but data are limited. While these conditions are characterized by enhanced risk for the associated malignancy, the majority of individuals with these conditions do not progress to malignancy. A key focus for current work is to identify markers that predict progression to malignancy.
doi:10.1158/1055-9965.EPI-12-1348
PMCID: PMC3616401  PMID: 23549397
4.  Mapping of the IRF8 gene identifies a 3’ UTR variant associated with risk of chronic lymphocytic leukemia but not other common non-Hodgkin lymphoma subtypes 
Background
Our genome-wide association study (GWAS) of chronic lymphocytic leukemia (CLL) identified 4 highly-correlated intronic variants within the IRF8 gene that were associated with CLL. These results were further supported by a recent meta-analysis of our GWAS with two other GWAS of CLL, supporting the IRF8 gene as a strong candidate for CLL risk.
Methods
To refine the genetic association of CLL risk, we performed Sanger sequencing of IRF8 in 94 CLL cases and 96 controls. We then performed fine-mapping by genotyping 39 variants (of which 10 were identified from sequencing) in 745 CLL cases and 1521 controls. We also assessed these associations with risk of other non-Hodgkin lymphoma (NHL) subtypes.
Results
The strongest association with CLL risk was observed with a common SNP located within the 3’ UTR of IRF8 (rs1044873, log additive odds ratio = 0.7, P=1.81×10−6). This SNP was not associated with the other NHL subtypes (all P>0.05).
Conclusions
We provide evidence that rs1044873 in the IRF8 gene accounts for the initial GWAS signal for CLL risk. This association appears to be unique to CLL with little support for association with other common NHL subtypes. Future work is needed to assess functional role of IRF8 in CLL etiology.
Impact
These data provide support that a functional variant within the 3’ UTR of IRF8 may be driving the GWAS signal seen on 16q24.1 for CLL risk.
doi:10.1158/1055-9965.EPI-12-1217
PMCID: PMC3596428  PMID: 23307532
CLL; NHL; SNPs; IRF8; risk locus
5.  Genome-wide Association Study Identifies Multiple Risk Loci for Chronic Lymphocytic Leukemia 
Berndt, Sonja I. | Skibola, Christine F. | Joseph, Vijai | Camp, Nicola J. | Nieters, Alexandra | Wang, Zhaoming | Cozen, Wendy | Monnereau, Alain | Wang, Sophia S. | Kelly, Rachel S. | Lan, Qing | Teras, Lauren R. | Chatterjee, Nilanjan | Chung, Charles C. | Yeager, Meredith | Brooks-Wilson, Angela R. | Hartge, Patricia | Purdue, Mark P. | Birmann, Brenda M. | Armstrong, Bruce K. | Cocco, Pierluigi | Zhang, Yawei | Severi, Gianluca | Zeleniuch-Jacquotte, Anne | Lawrence, Charles | Burdette, Laurie | Yuenger, Jeffrey | Hutchinson, Amy | Jacobs, Kevin B. | Call, Timothy G. | Shanafelt, Tait D. | Novak, Anne J. | Kay, Neil E. | Liebow, Mark | Wang, Alice H. | Smedby, Karin E | Adami, Hans-Olov | Melbye, Mads | Glimelius, Bengt | Chang, Ellen T. | Glenn, Martha | Curtin, Karen | Cannon-Albright, Lisa A. | Jones, Brandt | Diver, W. Ryan | Link, Brian K. | Weiner, George J. | Conde, Lucia | Bracci, Paige M. | Riby, Jacques | Holly, Elizabeth A. | Smith, Martyn T. | Jackson, Rebecca D. | Tinker, Lesley F. | Benavente, Yolanda | Becker, Nikolaus | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Rabe, Kari G. | Achenbach, Sara J. | Vachon, Celine M. | Goldin, Lynn R | Strom, Sara S. | Lanasa, Mark C. | Spector, Logan G. | Leis, Jose F. | Cunningham, Julie M. | Weinberg, J. Brice | Morrison, Vicki A. | Caporaso, Neil E. | Norman, Aaron D. | Linet, Martha S. | De Roos, Anneclaire J. | Morton, Lindsay M. | Severson, Richard K. | Riboli, Elio | Vineis, Paolo | Kaaks, Rudolph | Trichopoulos, Dimitrios | Masala, Giovanna | Weiderpass, Elisabete | Chirlaque, María-Dolores | Vermeulen, Roel C H | Travis, Ruth C. | Giles, Graham G. | Albanes, Demetrius | Virtamo, Jarmo | Weinstein, Stephanie | Clavel, Jacqueline | Zheng, Tongzhang | Holford, Theodore R | Offit, Kenneth | Zelenetz, Andrew | Klein, Robert J. | Spinelli, John J. | Bertrand, Kimberly A. | Laden, Francine | Giovannucci, Edward | Kraft, Peter | Kricker, Anne | Turner, Jenny | Vajdic, Claire M. | Ennas, Maria Grazia | Ferri, Giovanni M. | Miligi, Lucia | Liang, Liming | Sampson, Joshua | Crouch, Simon | Park, Ju-hyun | North, Kari E. | Cox, Angela | Snowden, John A. | Wright, Josh | Carracedo, Angel | Lopez-Otin, Carlos | Bea, Silvia | Salaverria, Itziar | Martin, David | Campo, Elias | Fraumeni, Joseph F. | de Sanjose, Silvia | Hjalgrim, Henrik | Cerhan, James R. | Chanock, Stephen J. | Rothman, Nathaniel | Slager, Susan L.
Nature genetics  2013;45(8):868-876.
doi:10.1038/ng.2652
PMCID: PMC3729927  PMID: 23770605
6.  Familial Aggregation of Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia with Solid Tumors and Myeloid Malignancies 
Acta Haematologica  2012;127(3):173-177.
Lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM) is a B-cell disorder resulting from the accumulation, predominantly in the bone marrow, of clonally related lymphoplasmacytic cells. LPL/WM is a very rare disease, with an incidence rate of 3–4 cases per million people per year. Currently, the causes of LPL/WM are poorly understood; however, there are emerging data to support a role for immune-related factors in the pathogenesis of LPL/WM. In addition, data show that genetic factors are of importance in the etiology of LPL/WM. In this paper, we will review the current knowledge about familiality of LPL/WM and provide novel data on solid tumors and myeloid malignancies in first-degree relatives of LPL/WM patients.
doi:10.1159/000335618
PMCID: PMC3326274  PMID: 22310551
Autoimmunity; Familial aggregation; Hematological malignancies; Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia; Monoclonal gammopathy of undetermined significance; Solid tumors; Susceptibility
7.  Familial Aggregation of Acute Myeloid Leukemia and Myelodysplastic Syndromes 
Journal of Clinical Oncology  2011;30(2):179-183.
Purpose
Apart from rare pedigrees with multiple cases of acute myeloid leukemia (AML), there is limited data on familial aggregation of AML and myelodysplastic syndromes (MDSs) in the population.
Patients and Methods
Swedish population-based registry data were used to evaluate risk of AML, MDS, and other malignancies among 24,573 first-degree relatives of 6,962 patients with AML and 1,388 patients with MDS compared with 106,224 first-degree relatives of matched controls. We used a marginal survival model to calculate familial aggregation.
Results
AML and/or MDS did not aggregate significantly in relatives of patients with AML. There was a modest risk ratio (RR, 1.3; 95% CI, 0.9 to 1.8) in myeloproliferative/myeloid malignancies combined. The risks for any hematologic or any solid tumor were modestly but significantly increased. Relatives of patients with MDS did not show an increased risk for any hematologic tumors. In contrast, we found a significantly increased risk (RR, 6.5; 95% CI, 1.1 to 38.0) of AML/MDS and of all myeloid malignancies combined (RR, 3.1; 95% CI, 1.0 to 9.8) among relatives of patients diagnosed at younger than age 21 years.
Conclusion
We did not find evidence for familial aggregation of the severe end of the spectrum of myeloid malignancies (AML and MDS). The risks of myeloproliferative neoplasms were modestly increased with trends toward significance, suggesting a possible role of inheritance. In contrast, although limited in sample size, relatives of young patients with AML were at increased risk of AML/MDS, suggesting that germline genes may play a stronger role in these patients. The increased risk of all hematologic malignancies and of solid tumors among relatives of patients with AML suggests that genes for malignancy in general and/or other environmental factors may be shared.
doi:10.1200/JCO.2011.37.1203
PMCID: PMC3255562  PMID: 22162584
8.  Detectable clonal mosaicism from birth to old age and its relationship to cancer 
Laurie, Cathy C. | Laurie, Cecelia A. | Rice, Kenneth | Doheny, Kimberly F. | Zelnick, Leila R. | McHugh, Caitlin P. | Ling, Hua | Hetrick, Kurt N. | Pugh, Elizabeth W. | Amos, Chris | Wei, Qingyi | Wang, Li-e | Lee, Jeffrey E. | Barnes, Kathleen C. | Hansel, Nadia N. | Mathias, Rasika | Daley, Denise | Beaty, Terri H. | Scott, Alan F. | Ruczinski, Ingo | Scharpf, Rob B. | Bierut, Laura J. | Hartz, Sarah M. | Landi, Maria Teresa | Freedman, Neal D. | Goldin, Lynn R. | Ginsburg, David | Li, Jun | Desch, Karl C. | Strom, Sara S. | Blot, William J. | Signorello, Lisa B. | Ingles, Sue A. | Chanock, Stephen J. | Berndt, Sonja I. | Le Marchand, Loic | Henderson, Brian E. | Monroe, Kristine R | Heit, John A. | de Andrade, Mariza | Armasu, Sebastian M. | Regnier, Cynthia | Lowe, William L. | Hayes, M. Geoffrey | Marazita, Mary L. | Feingold, Eleanor | Murray, Jeffrey C. | Melbye, Mads | Feenstra, Bjarke | Kang, Jae H. | Wiggs, Janey L. | Jarvik, Gail P. | McDavid, Andrew N. | Seshan, Venkatraman E. | Mirel, Daniel B. | Crenshaw, Andrew | Sharopova, Nataliya | Wise, Anastasia | Shen, Jess | Crosslin, David R. | Levine, David M. | Zheng, Xiuwen | Udren, Jenna I | Bennett, Siiri | Nelson, Sarah C. | Gogarten, Stephanie M. | Conomos, Matthew P. | Heagerty, Patrick | Manolio, Teri | Pasquale, Louis R. | Haiman, Christopher A. | Caporaso, Neil | Weir, Bruce S.
Nature genetics  2012;44(6):642-650.
Clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) was detected using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells (>5–10%) with the same abnormal karyotype (presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rises rapidly to 2–3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions that pinpoint the locations of genes previously associated with hematological cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer prior to DNA sampling, those without a prior diagnosis have an estimated 10-fold higher risk of a subsequent hematological cancer (95% confidence interval = 6–18).
doi:10.1038/ng.2271
PMCID: PMC3366033  PMID: 22561516
9.  Detectable clonal mosaicism and its relationship to aging and cancer 
Jacobs, Kevin B | Yeager, Meredith | Zhou, Weiyin | Wacholder, Sholom | Wang, Zhaoming | Rodriguez-Santiago, Benjamin | Hutchinson, Amy | Deng, Xiang | Liu, Chenwei | Horner, Marie-Josephe | Cullen, Michael | Epstein, Caroline G | Burdett, Laurie | Dean, Michael C | Chatterjee, Nilanjan | Sampson, Joshua | Chung, Charles C | Kovaks, Joseph | Gapstur, Susan M | Stevens, Victoria L | Teras, Lauren T | Gaudet, Mia M | Albanes, Demetrius | Weinstein, Stephanie J | Virtamo, Jarmo | Taylor, Philip R | Freedman, Neal D | Abnet, Christian C | Goldstein, Alisa M | Hu, Nan | Yu, Kai | Yuan, Jian-Min | Liao, Linda | Ding, Ti | Qiao, You-Lin | Gao, Yu-Tang | Koh, Woon-Puay | Xiang, Yong-Bing | Tang, Ze-Zhong | Fan, Jin-Hu | Aldrich, Melinda C | Amos, Christopher | Blot, William J | Bock, Cathryn H | Gillanders, Elizabeth M | Harris, Curtis C | Haiman, Christopher A | Henderson, Brian E | Kolonel, Laurence N | Le Marchand, Loic | McNeill, Lorna H | Rybicki, Benjamin A | Schwartz, Ann G | Signorello, Lisa B | Spitz, Margaret R | Wiencke, John K | Wrensch, Margaret | Wu, Xifeng | Zanetti, Krista A | Ziegler, Regina G | Figueroa, Jonine D | Garcia-Closas, Montserrat | Malats, Nuria | Marenne, Gaelle | Prokunina-Olsson, Ludmila | Baris, Dalsu | Schwenn, Molly | Johnson, Alison | Landi, Maria Teresa | Goldin, Lynn | Consonni, Dario | Bertazzi, Pier Alberto | Rotunno, Melissa | Rajaraman, Preetha | Andersson, Ulrika | Freeman, Laura E Beane | Berg, Christine D | Buring, Julie E | Butler, Mary A | Carreon, Tania | Feychting, Maria | Ahlbom, Anders | Gaziano, J Michael | Giles, Graham G | Hallmans, Goran | Hankinson, Susan E | Hartge, Patricia | Henriksson, Roger | Inskip, Peter D | Johansen, Christoffer | Landgren, Annelie | McKean-Cowdin, Roberta | Michaud, Dominique S | Melin, Beatrice S | Peters, Ulrike | Ruder, Avima M | Sesso, Howard D | Severi, Gianluca | Shu, Xiao-Ou | Visvanathan, Kala | White, Emily | Wolk, Alicja | Zeleniuch-Jacquotte, Anne | Zheng, Wei | Silverman, Debra T | Kogevinas, Manolis | Gonzalez, Juan R | Villa, Olaya | Li, Donghui | Duell, Eric J | Risch, Harvey A | Olson, Sara H | Kooperberg, Charles | Wolpin, Brian M | Jiao, Li | Hassan, Manal | Wheeler, William | Arslan, Alan A | Bas Bueno-de-Mesquita, H | Fuchs, Charles S | Gallinger, Steven | Gross, Myron D | Holly, Elizabeth A | Klein, Alison P | LaCroix, Andrea | Mandelson, Margaret T | Petersen, Gloria | Boutron-Ruault, Marie-Christine | Bracci, Paige M | Canzian, Federico | Chang, Kenneth | Cotterchio, Michelle | Giovannucci, Edward L | Goggins, Michael | Bolton, Judith A Hoffman | Jenab, Mazda | Khaw, Kay-Tee | Krogh, Vittorio | Kurtz, Robert C | McWilliams, Robert R | Mendelsohn, Julie B | Rabe, Kari G | Riboli, Elio | Tjønneland, Anne | Tobias, Geoffrey S | Trichopoulos, Dimitrios | Elena, Joanne W | Yu, Herbert | Amundadottir, Laufey | Stolzenberg-Solomon, Rachael Z | Kraft, Peter | Schumacher, Fredrick | Stram, Daniel | Savage, Sharon A | Mirabello, Lisa | Andrulis, Irene L | Wunder, Jay S | García, Ana Patiño | Sierrasesúmaga, Luis | Barkauskas, Donald A | Gorlick, Richard G | Purdue, Mark | Chow, Wong-Ho | Moore, Lee E | Schwartz, Kendra L | Davis, Faith G | Hsing, Ann W | Berndt, Sonja I | Black, Amanda | Wentzensen, Nicolas | Brinton, Louise A | Lissowska, Jolanta | Peplonska, Beata | McGlynn, Katherine A | Cook, Michael B | Graubard, Barry I | Kratz, Christian P | Greene, Mark H | Erickson, Ralph L | Hunter, David J | Thomas, Gilles | Hoover, Robert N | Real, Francisco X | Fraumeni, Joseph F | Caporaso, Neil E | Tucker, Margaret | Rothman, Nathaniel | Pérez-Jurado, Luis A | Chanock, Stephen J
Nature genetics  2012;44(6):651-658.
In an analysis of 31,717 cancer cases and 26,136 cancer-free controls drawn from 13 genome-wide association studies (GWAS), we observed large chromosomal abnormalities in a subset of clones from DNA obtained from blood or buccal samples. Mosaic chromosomal abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of size >2 Mb were observed in autosomes of 517 individuals (0.89%) with abnormal cell proportions between 7% and 95%. In cancer-free individuals, the frequency increased with age; 0.23% under 50 and 1.91% between 75 and 79 (p=4.8×10−8). Mosaic abnormalities were more frequent in individuals with solid-tumors (0.97% versus 0.74% in cancer-free individuals, OR=1.25, p=0.016), with a stronger association for cases who had DNA collected prior to diagnosis or treatment (OR=1.45, p=0.0005). Detectable clonal mosaicism was common in individuals for whom DNA was collected at least one year prior to diagnosis of leukemia compared to cancer-free individuals (OR=35.4, p=3.8×10−11). These findings underscore the importance of the role and time-dependent nature of somatic events in the etiology of cancer and other late-onset diseases.
doi:10.1038/ng.2270
PMCID: PMC3372921  PMID: 22561519
10.  Mood Disorders and Risk of Lung Cancer in the EAGLE Case-Control Study and in the U.S. Veterans Affairs Inpatient Cohort 
PLoS ONE  2012;7(8):e42945.
Background
Mood disorders may affect lung cancer risk. We evaluated this hypothesis in two large studies.
Methodology/Principal Findings
We examined 1,939 lung cancer cases and 2,102 controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) case-control study conducted in Italy (2002–2005), and 82,945 inpatients with a lung cancer diagnosis and 3,586,299 person-years without a lung cancer diagnosis in the U.S. Veterans Affairs Inpatient Cohort (VA study), composed of veterans with a VA hospital admission (1969–1996). In EAGLE, we calculated odds ratios (ORs) and 95% confidence intervals (CI), with extensive adjustment for tobacco smoking and multiple lifestyle factors. In the VA study, we estimated lung cancer relative risks (RRs) and 95% CIs with time-dependent Poisson regression, adjusting for attained age, calendar year, hospital visits, time within the study, and related previous medical diagnoses. In EAGLE, we found decreased lung cancer risk in subjects with a personal history of mood disorders (OR: 0.59, 95% CI: 0.44–0.79, based on 121 lung cancer incident cases and 192 controls) and family history of mood disorders (OR: 0.62, 95% CI: 0.50–0.77, based on 223 lung cancer cases and 345 controls). The VA study analyses yielded similar results (RR: 0.74, 95% CI: 0.71–0.77, based on 2,304 incident lung cancer cases and 177,267 non-cancer person-years) in men with discharge diagnoses for mood disorders. History of mood disorders was associated with nicotine dependence, alcohol and substance use and psychometric scales of depressive and anxiety symptoms in controls for these studies.
Conclusions/Significance
The consistent finding of a relationship between mood disorders and lung cancer risk across two large studies calls for further research into the complex interplay of risk factors associated with these two widespread and debilitating diseases. Although we adjusted for smoking effects in EAGLE, residual confounding of the results by smoking cannot be ruled out.
doi:10.1371/journal.pone.0042945
PMCID: PMC3413657  PMID: 22880133
11.  Chronic Immune Stimulation Might Act As a Trigger for the Development of Acute Myeloid Leukemia or Myelodysplastic Syndromes 
Journal of Clinical Oncology  2011;29(21):2897-2903.
Purpose
Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) often present with infections, but there are little data to assess whether a personal history of selected infections may act as pathogenic triggers. To additionally expand our knowledge on the role of immune stimulation in the causation of AML and MDS, we have conducted a large, population-based study to evaluate the risk of AML and MDS associated with a prior history of a broad range of infections or autoimmune diseases.
Patients and Methods
By using population-based central registries in Sweden, we included 9,219 patients with AML, 1,662 patients with MDS, and 42,878 matched controls. We used logistic regression to calculate odds ratios (ORs) and 95% CIs for the association of AML or MDS with infectious and/or autoimmune diseases.
Results
Overall, a history of any infectious disease was associated with a significantly increased risk of both AML (OR, 1.3; 95% CI, 1.2 to 1.4) and MDS (OR, 1.3; 95% CI, 1.1 to 1.5). These associations were significant even when we limited infections to those occurring 3 or more years before AML/MDS. A previous history of any autoimmune disease was associated with a 1.7-fold (95% CI, 1.5 to 1.9) increased risk for AML and 2.1-fold (95% CI, 1.7 to 2.6) increased risk for MDS. A large range of conditions were each significantly associated with AML and MDS.
Conclusion
Our novel findings indicate that chronic immune stimulation acts as a trigger for AML/MDS development. The underlying mechanisms may also be due to a common genetic predisposition or an effect of treatment for infections/autoimmune conditions.
doi:10.1200/JCO.2011.34.8540
PMCID: PMC3138717  PMID: 21690473
12.  Treatment-Related Risk Factors for Transformation to Acute Myeloid Leukemia and Myelodysplastic Syndromes in Myeloproliferative Neoplasms 
Journal of Clinical Oncology  2011;29(17):2410-2415.
Purpose
Patients with myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to develop acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). Using population-based data from Sweden, we assessed the role of MPN treatment and subsequent AML/MDS risk with special focus on the leukemogenic potential of hydroxyurea (HU).
Methods
On the basis of a nationwide MPN cohort (N = 11,039), we conducted a nested case-control study, including 162 patients (153 and nine with subsequent AML and MDS diagnosis, respectively) and 242 matched controls. We obtained clinical and MPN treatment data for all patients. Using logistic regression, we calculated odds ratios (ORs) as measures of AML/MDS risk.
Results
Forty-one (25%) of 162 patients with MPNs with AML/MDS development were never exposed to alkylating agents, radioactive phosphorous (P32), or HU. Compared with patients with who were not exposed to HU, the ORs for 1 to 499 g, 500 to 999 g, more than 1,000 g of HU were 1.5 (95% CI, 0.6 to 2.4), 1.4 (95% CI, 0.6 to 3.4), and 1.3 (95% CI, 0.5 to 3.3), respectively, for AML/MDS development (not significant). Patients with MPNs who received P32 greater than 1,000 MBq and alkylators greater than 1 g had a 4.6-fold (95% CI, 2.1 to 9.8; P = .002) and 3.4-fold (95% CI, 1.1 to 10.6; P = .015) increased risk of AML/MDS, respectively. Patients receiving two or more cytoreductive treatments had a 2.9-fold (95% CI, 1.4 to 5.9) increased risk of transformation.
Conclusion
The risk of AML/MDS development after MPN diagnosis was significantly associated with high exposures of P32 and alkylators but not with HU treatment. Twenty-five percent of patients with MPNs who developed AML/MDS were not exposed to cytotoxic therapy, supporting a major role for nontreatment-related factors.
doi:10.1200/JCO.2011.34.7542
PMCID: PMC3107755  PMID: 21537037
13.  Immnuophenotypic and Gene Expression Analysis of Monoclonal B Cell Lymphocytosis Shows Biologic Characteristics Associated With Good Prognosis CLL 
Monoclonal B cell lymphocytosis (MBL) is a hematologic condition wherein small B cell clones can be detected in the blood of asymptomatic individuals. Most MBL have an immunophenotype similar to chronic lymphocytic leukemia (CLL), and “CLL-like” MBL is a precursor to CLL. We used flow cytometry to identify MBL from unaffected members of CLL kindreds. We identified 101 MBL cases from 622 study subjects; of these, 82 individuals with MBL were further characterized. Ninety-one unique MBL clones were detected: 73 CLL-like MBL (CD5+CD20dimsIgdim), 11 atypical MBL (CD5+CD20+sIg+), and 7 CD5neg MBL (CD5negCD20+sIgneg). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b, and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70, and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on 7 CLL-like MBL, and showed activation of B cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders.
doi:10.1038/leu.2011.117
PMCID: PMC3164475  PMID: 21617698
15.  Lymphoma risk following celiac disease diagnosed in Sweden from the mid-1970s to the early 21st Century 
Gastroenterology  2008;136(1):91-98.
Background
Celiac disease (CD), a common digestive disease, is well-known to be associated with excess non-Hodgkin lymphoma (NHL) risk. However, there are only limited data on risk in the current era of serologic testing and human leukocytes antigen (HLA) typing to screen for CD. Also, there is no information on the role of family history of CD in relation to lymphoma risk.
Methods
We identified 37,869 NHL, 8323 Hodgkin lymphoma (HL), 13,842 chronic lymphocytic leukemia (CLL) patients diagnosed in Sweden 1965-2004, 236,408 matched controls, and 613,961 first-degree relatives. Using logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) as measures of risks adjusted for matching factors.
Results
Overall we found persons with a hospital discharge diagnosis of CD to have a 5.35-fold (95%CI=3.56-8.06) increased NHL risk. Risk of HL was borderline increased (OR=2.54, 95%CI=0.99-6.56); however, there was no excess CLL risk. Persons diagnosed with CD in 1975-1984, 1985-1994, and 1995-2004 had a 13.2-fold (95%CI=3.63-48.0), 7.90-fold (95%CI=3.38-18.5), and 3.84-fold (95%CI=2.28-6.45) increased risk of NHL, respectively (Ptrend<0.0001). Individuals with a sibling affected with CD had a 2.03-fold (95%CI=1.29-3.19) increased NHL risk.
Conclusions
Persons with CD have an increased NHL risk; however, the excess risk has tapered off substantially in the last four decades. The observed excess NHL risk among individuals with a sibling affected with CD suggests shared susceptibility. Future studies are needed to explore the roles of gluten intake, secondary intestinal inflammation, and susceptibility genes in relation to subsequent risk of developing lymphoma.
doi:10.1053/j.gastro.2008.09.031
PMCID: PMC3227529  PMID: 18950631
Celiac disease; secular trend; family history; risk; lymphoma; shared susceptibility
16.  Common Occurrence of Monoclonal B-cell Lymphocytosis Among Members of High-Risk CLL Families 
British journal of haematology  2010;151(2):152-158.
Summary
Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic haematological condition characterized by low absolute levels of B-cell clones with a surface immunophenotype similar to that of chronic lymphocytic leukaemia (CLL). In the general population, MBL increases with age with a prevalence of 5–9% in individuals over age 60 years. It has been reported to be higher among first-degree relatives from CLL families. We report results of multi-parameter flow cytometry among 505 first-degree relatives with no personal history of lymphoproliferative disease from 140 families having at least two cases of CLL. Seventeen percent of relatives had MBL. Age was the most important determinant where the probability for developing MBL by age 90 years was 61%. MBL clustered in certain families but clustering was independent of the number of known CLL cases in a family. As is the case with CLL, males had a significantly higher risk for MBL than did females (p=0.04). MBL patients had significantly higher mean absolute lymphocyte counts (2.4 × 109/l) and B-cell counts (0.53 × 109/l) than those with a normal B-cell immunophenotype. Our findings show that MBL occurs at a very high rate in high risk CLL families. Both the age and gender distribution of MBL are parallel to CLL, implying a shared inherited risk.
doi:10.1111/j.1365-2141.2010.08339.x
PMCID: PMC2966536  PMID: 20738309
chronic lymphocytic leukaemia; high risk families; monoclonal B-cell lymphocytosis; flow cytometry
17.  Familial Chronic Lymphocytic Leukemia 
Current opinion in hematology  2010;17(4):350-355.
Purpose of Review
Families with multiple individuals affected with chronic lymphocytic leukemia (CLL) and other related B-cell tumors have been described in the literature and strong familial aggregation has been seen in population studies. However, predisposing germ line mutations have not been identified. We will discuss the spectrum of conditions associated with CLL in families and the advances in identifying the underlying susceptibility genes.
Recent Findings
Familial CLL does not appear to differ substantially from sporadic CLL in terms of prognostic markers and clinical outcome, although it may be associated with more indolent disease. The precursor condition, monoclonal B-cell lymphocytosis (MBL) also aggregates in CLL families. Linkage studies have been conducted in high-risk CLL families to screen the whole genome for susceptibility loci but no gene mutations have yet been identified by this method. Association studies of candidate genes have implicated several genes as being important in CLL but more studies are needed. Results from whole genome association studies are promising.
Summary
The ability to conduct large scale genomic studies in unrelated CLL cases and in high risk CLL families will play an important role in detecting susceptibility genes for CLL over the next few years and thereby help to delineate etiologic pathways.
doi:10.1097/MOH.0b013e328338cd99
PMCID: PMC2891437  PMID: 20389242
chronic lymphocytic leukemia; monoclonal b-cell lymphocytosis; familial; germ line genes
18.  Immune-Related and Inflammatory Conditions and Risk of Lymphoplasmacytic Lymphoma or Waldenström Macroglobulinemia 
Background
Chronic immune stimulation appears to be associated with lymphoplasmacytic lymphoma (LPL)-Waldenström macroglobulinemia (WM); however, available information is sparse. We conducted, to our knowledge, the most comprehensive study to date to evaluate associations between a personal or family history of many immune-related and/or inflammatory disorders and the subsequent risk of LPL-WM.
Methods
We used Swedish population-based registries to identify 2470 case patients with LPL-WM, 9698 matched control subjects, and almost 30 000 first-degree relatives of either case patients or control subjects. We evaluated a wide range of autoimmune, infectious, allergic, and inflammatory conditions. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for each condition by use of logistic regression.
Results
An increased risk of LPL-WM was associated with a personal history of the following autoimmune diseases: systemic sclerosis (OR = 4.7, 95% CI = 1.4 to 15.3), Sjögren syndrome (OR = 12.1, 95% CI = 3.3 to 45.0), autoimmune hemolytic anemia (OR = 24.2, 95% CI = 5.4 to 108.2), polymyalgia rheumatica (OR = 2.9, 95% CI = 1.6 to 5.2), and giant cell arteritis (OR = 8.3, 95% CI = 2.1 to 33.1). An increased risk of LPL-WM was associated with a personal history of the following infectious diseases: pneumonia (OR = 1.4, 95% CI = 1.1 to 1.7), septicemia (OR = 2.4, 95% CI = 1.2 to 4.3), pyelonephritis (OR = 1.7, 95% CI = 1.1 to 2.5), sinusitis (OR = 2.7, 95% CI = 1.4 to 4.9), herpes zoster (OR = 3.4, 95% CI = 2.0 to 5.6), and influenza (OR = 2.9, 95% CI = 1.7 to 5.0). An increased risk of LPL-WM was associated with a family history of the following autoimmune or infectious diseases: Sjögren syndrome (OR = 5.0, 95% CI = 2.1 to 12.0), autoimmune hemolytic anemia (OR = 3.8, 95% CI = 1.1 to 13.2), Guillain–Barré syndrome (OR = 4.1, 95% CI = 1.8 to 9.4), cytomegalovirus (OR = 2.7, 95% CI = 1.4 to 5.3), gingivitis and periodontitis (OR = 1.9, 95% CI = 1.3 to 2.7), and chronic prostatitis (OR = 4.3, 95% CI = 1.7 to 11.1).
Conclusions
Personal history of certain immune-related and/or infectious conditions was strongly associated with increased risk of LPL-WM. The association of both personal and family history of Sjögren syndrome and autoimmune hemolytic anemia with risk of LPL-WM indicates the potential for shared susceptibility for these conditions.
doi:10.1093/jnci/djq043
PMCID: PMC2857799  PMID: 20181958
19.  Genetic susceptibility variants for chronic lymphocytic leukemia 
Background
There is strong and consistent evidence that a genetic component contributes to the etiology of chronic lymphocytic leukemia (CLL). A recent genome-wide association study (GWAS) of CLL identified 7 genetic variants that increased the risk of CLL within a European population.
Methods
We evaluated the association of these variants, or variants in linkage disequilibrium (LD) with these variants, with CLL risk in an independent sample of 438 CLL cases and 328 controls.
Results
Of these 7 SNPs, 6 had p-trend < 0.05 and had estimated odds ratios (ORs) that were strikingly comparable to those of the previous study. Associations were seen for rs9378805 (OR = 1.47, 95% CI: 1.19, 1.80, p-trend = 0.0003) near IRF4 and rs735665 near GRAMD1B (OR= 1.47; 95% CI: 1.14, 1.89; p-trend = 0.003). However, no associations (P> 0.05) were found for rs11083846, nor were any found for any SNPs in LD with rs11083846.
Conclusions
Our results confirm the previous findings and further support the role of a genetic basis in the etiology of CLL; however, more research is needed to elucidate the causal SNP(s) and the potential manner in which these SNPs or linked SNPs function in CLL pathogenesis.
doi:10.1158/1055-9965.EPI-09-1217
PMCID: PMC2852480  PMID: 20332261
IRF4; CLL; genetic association
20.  Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32 
Nature genetics  2010;42(8):661-664.
To identify susceptibility loci for non-Hodgkin lymphoma (NHL) subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma (FL) in 1,465 FL cases/6,958 controls at 6p21.32 (rs10484561, rs7755224, r2=1.0; combined p-values=1.12×10-29, 2.00×10-19), providing further support that MHC genetic variation influences FL susceptibility. Confirmatory evidence of a previously reported association was also found between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined p-value=4.24×10-9).
doi:10.1038/ng.626
PMCID: PMC2913472  PMID: 20639881
21.  Familial Aspects of Chronic Lymphocytic Leukemia, Monoclonal B-Cell Lymphocytosis (MBL), and Related Lymphomas 
Families with multiple individuals affected with chronic lymphocytic leukemia (CLL) and other related B-cell tumors have been described in the literature. Familial CLL does not appear to differ from sporadic CLL in terms of prognostic markers and clinical outcome. While some environmental factors (such as farming related exposures and occupational chemicals) may increase risk of CLL, results of epidemiological studies have been generally inconsistent inconsistent and well-defined extrinsic risk factors are unknown. Large, population-based case-control and cohort studies have also shown significant familial aggregation of CLL and related conditions including non-Hodgkin lymphomas, especially other indolent lymphomas. The precursor condition, monoclonal B-cell lymphocytosis (MBL) also aggregates in CLL families. However because the baseline population risks for CLL and other indolent lymphomas are low, the absolute risk to a first-degree relative for developing CLL or a related disease is also low. Linkage studies have been conducted in high-risk CLL families to screen the whole genome for loci that contribute to susceptibility but no gene mutations have yet been identified by this method. Association studies of candidate genes have implicated several genes as being important in CLL but more studies are needed to verify these findings. Results from whole genome association are promising. The ability to conduct large scale genomic studies will play an important role in detecting susceptibility genes for CLL over the next few years and thereby help to delineate etiologic pathways.
PMCID: PMC3010372  PMID: 21191471
chronic lymphocytic leukemia; monoclonal b-cell lymphocytosis; familial risk; germ line susceptibility; environmental risk factors
22.  Patterns of hematologic malignancies and solid tumors among 37,838 first-degree relatives of 13,896 multiple myeloma patients in Sweden 
There are emerging data to suggest a role for genetic factors in the pathogenesis of multiple myeloma (MM). Based on small numbers, certain solid tumors have been reported to occur more frequently among blood relatives of MM patients. Using population-based data, we assessed risks for hematologic malignancies, monoclonal gammopathy of undetermined significance (MGUS), and solid tumors among first-degree relatives of MM patients. We included 13,896 MM patients and 54,365 matched controls. Also we identified first-degree relatives of MM patients (n=37,838) and controls (n=151,068). Using a marginal survival model, we estimated relative risks (RRs) and 95% confidence intervals (CIs) for hematologic and solid tumors among family members of MM patients and controls as measures of familial aggregation. Compared to relatives of controls, relatives of MM patients had an increased risk of developing MM (RR=2.1; 95% CI 1.6–2.9), MGUS (2.1; 1.5–3.1), acute lymphoblastic leukemia (ALL) (2.1; 1.0–4.2), any solid tumor (1.1; 1.0–1.1), and bladder cancer (1.3; 1.0–1.5). No significantly increased risk was found for other hematologic or solid malignancies. Our findings support a role for a shared susceptibility (genetic, environmental, or both) that predisposes to MM, MGUS, ALL, and bladder cancer.
doi:10.1002/ijc.24514
PMCID: PMC2737604  PMID: 19582882
multiple myeloma; MGUS; solid tumors; bladder cancer; familial aggregation; susceptibility
23.  Common Genetic Variants in Candidate Genes and Risk of Familial Lymphoid Malignancies 
British journal of haematology  2009;146(4):418-423.
Summary
Familial aggregation, linkage, and case-control studies support the role of germline genes in the etiology of lymphoid malignancies. To further examine the role of genetic variation underlying susceptibility, we analyzed 1536 SNPs in 152 genes involved in apoptosis, DNA repair, immune response, and oxidative stress pathways among a unique sample of 165 unrelated familial cases including patients with chronic lymphocytic leukemia (CLL), Waldenström's (WM), and Hodgkin lymphoma (HL), and 107 spouse controls. We confirmed previous studies showing a polymorphism in the IL10 promoter (rs1800890/-3575T>A) to be associated with non-Hodgkin lymphoma since we found this allele to be associated with both CLL and WM. We also confirmed the role of IL6 variation to be associated with HL. Polymorphisms in the TRAIL gene were associated with both CLL and WM. Future replication and functional studies are needed to clarify the role of these genetic variants. Finally, our data further support the close association of WM and CLL.
doi:10.1111/j.1365-2141.2009.07790.x
PMCID: PMC2890251  PMID: 19573080
Candidate genes; association; familial; lymphoid malignancies; chronic lymphocytic leukemia; Waldenström's macroglobulinemia; Hodgkin lymphoma
24.  Highly increased familial risks for specific lymphoma subtypes 
British journal of haematology  2009;146(1):91-94.
SUMMARY
Studies have shown that familial risk contributes to etiology of lymphomas. Using large population registries from Sweden, we evaluated risk of lymphoma subtypes among first-degree relatives of 2668 follicular lymphoma (FL) patients, 2517 diffuse large B-cell lymphoma (DLBCL) patients, and 6963 Hodgkin lymphoma (HL) patients compared to first-degree relatives of controls. Relatives were at the highest risk for developing the same lymphoma subtype as the case. DLBCL was 10-fold increased among relatives of DLBCL patients, FL was 4-fold increased among relatives of FL patients and HL was 4-fold increased among relatives of HL patients. These results imply that germline susceptibility genes are specific to lymphoma subtype.
doi:10.1111/j.1365-2141.2009.07721.x
PMCID: PMC2702464  PMID: 19438470
non-Hodgkin lymphoma; DLBCL; FL; Hodgkin lymphoma; familial risk
25.  Germline and somatic JAK2 mutations and susceptibility to chronic myeloproliferative neoplasms 
Genome Medicine  2009;1(5):55.
Myeloproliferative neoplasms (MPNs) are a group of closely related stem-cell-derived clonal proliferative diseases. Most cases are sporadic but first-degree relatives of MPN patients have a five- to seven-fold increased risk for developing an MPN. The tumors of most patients carry a mutation in the Janus kinase 2 gene (JAK2V617F). Recently, three groups have described a strong association of JAK2 germline polymorphisms with MPN in patients positive for JAK2V617F. The somatic mutation occurs primarily on one particular germline JAK2 haplotype, which may account for as much as 50% of the risk to first-degree relatives. This finding provides new directions for unraveling the pathogenesis of MPN.
doi:10.1186/gm55
PMCID: PMC2689447  PMID: 19490586

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