Viggo Jønsson

A high-density SNP genomewide linkage scan for chronic lymphocytic leukemia-susceptibility loci

Chronic lymphocytic leukemia (CLL) and other B-cell lymphoproliferative disorders (LPDs) show clear evidence of familial aggregation, but the inherited basis is largely unknown. To identify a susceptibility gene for CLL, we conducted a genomewide linkage analysis of 115 pedigrees, using a high-density single-nucleotide polymorphism (SNP) array containing 11,560 markers. Multipoint linkage analyses were undertaken using both nonparametric (model-free) and parametric (model-based) methods. Our results confirm that the presence of high linkage disequilibrium (LD) between SNP markers can lead to inflated nonparametric linkage (NPL) and LOD scores. After the removal of high-LD SNPs, we obtained a maximum NPL of 3.14 (P=.0008) on chromosome 11p11. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under both dominant (HLOD 1.95) and recessive (HLOD 2.78) models. In addition, four other chromosomal positions (5q22-23, 6p22, 10q25, and 14q32) displayed HLOD scores >1.15 (which corresponds to a nominal P value <.01). None of the regions coincided with areas of common chromosomal abnormalities frequently observed for CLL. These findings strengthen the argument for an inherited predisposition to CLL and related B-cell LPDs.

Insight into the pathogenesis of chronic lymphocytic leukemia (CLL) through analysis of IgVH gene usage and mutation status in familial CLL

To address the proposition that familial B-cell chronic lymphocytic leukemia (CLL) may exhibit a more restricted phenotype than sporadic CLL with respect to immunoglobulin gene usage or ontogenic development, we compared immunoglobulin (Ig) heavy chain variable region (VH) gene usage and IgVH mutation status in 327 patients with CLL from 214 families with 724 patients with sporadic cases. The frequency of mutated CLL was higher in familial CLL (P < .001), and there was evidence of intrafamilial concordance in mutation status (P < .001). The repertoire and frequency of IgVH usage was, however, not significantly different between familial and sporadic CLL. Furthermore, IgVH usage was not correlated between affected members of the same family. These observations provide evidence that familial CLL is essentially indistinguishable from sporadic CLL, favoring a genetic basis to disease development in general rather than a simple environmental etiology.

Birth order pattern in the inheritance of chronic lymphocytic leukaemia and related lymphoproliferative disease

Rank order of affected offspring in a sibship can inform on epigenetic factors in disease susceptibility. Here we report an analysis of birth order in 32 families segregating chronic lymphocytic leukaemia (CLL) and other B-cell lymphoproliferative disorders. A paternal-offspring, but not a maternal-offspring birth rank order was observed. Cox regression analysis provided relative risks (RR) for paternal and maternal transmission of 3.60 (CI 95%: 1.54 – 8.42; P = 0.0005) and 1.64 (CI 95%: 0.90 – 3.01; P = 0.096), respectively. The significance of paternal and maternal transmission of CLL – CLL pairs employing Haldane and Smiths test were 0.006 and 0.63, respectively. There was no evidence of a relationship between parental age and birth order. The genetic mechanism behind the birth order effect observed is discussed in the light of non-Mendelian imprinting and pregnancy related microchimerism.

Segregation of Malignant Hematological Disease in Families with Malignant Lymphoma

Familial malignant lymphoma, viz. more than two cases of malignant hematological disease in a family of which one diagnosis is malignant lymphoma, was seen in 43 (37 per cent) of the families in our database of familial malignant hematological disease. Genealogical examination of the 43 pedigrees after multiple ascertainment showed an equal amount of vertical transmissions (affected parent-offspring and grandparent-parent-offspring combinations) and non-vertical transmissions (affected uncle, aunt-nephew, niece, cousin combinations) without evident Mendelian pattern and no significant difference between observed and expected patrilineal and matrilineal lines in spite of a marked predominance of males. A marked pleiotropic diversity of involved diagnoses comprised 57 (93 per cent) lymphoproliferative- and 4 (7%) myeloproliferative diseases. Both Hodgkin’s lymphoma, non-Hodgkin’s lymphoma apart from the diffuse large B-cell lymphoma and chronic lymphocytic leukemia had a strong mutual association, and a weaker yet significant association to multiple myeloma and to diffuse large B-cell lymphoma. Compared with the number of patients in the population extracted from the crude age-adjusted incidences, the observed number of patients in familial disease was significantly higher interpreted as a stronger expression of congenic susceptibility among family members with reservations related to different environmental factors. Signs of anticipation in all combinations but no birth order effect were observed. It is discussed that an epigenetic parental genomic imprinting as a modifier for the segregation of linked susceptibility loci theoretically would bring about a similar pattern with male predominance and pleiotrophic diversity of diagnoses away from any Mendelian expectation.

Familiær forekomst av kronisk lymfatisk leukemi i Norge

BACKGROUNDnThe only known risk factor for chronic lymphocytic leukaemia (CLL) is occurrence of the disease in close relatives. The aim of this study was to determine the frequency of familial chronic lymphocytic leukaemia.nnnMATERIAL AND METHODnAll patients with chronic lymphocytic leukaemia notified to the Cancer Registry in the period 1.10.2007-31.12.2009 were asked to report occurrences of malignant disease in siblings, parents, grandparents and children. The information about malignant haematological disease was verified with the Cancer Registry.nnnRESULTSnWe found malignant haematological disease in close relatives of 42 of the 236 included patients (18%). CLL and lymphoma were the most common diagnoses. On average, 16 family members were identified in each family. The relative risk of developing CLL was six times higher in those who had close relatives with the disease (16 of a total of 3,776 family members) than among those who did not have close relatives who were affected (76 cases among 107,223 family members of 38,159 control subjects). The increased risk of disease was also associated with other lymphoproliferative diseases. With patrilinear, but not matrilinear inheritance, we found a birth order effect, with affection of younger men in a group of siblings, while the eldest escaped.nnnINTERPRETATIONnMalignant haematological disease is common in the family members of patients with CLL. CLL is the most common disease, but there is extensive pleiotropy.

Possible Imprinting and Microchimerism in Chronic Lymphocytic Leukemia and Related Lymphoproliferative Disorders

Based on the concept that the tumorogenesis in chronic lymphocytic leukaemia comprises both an initial, inherited mutation and subsequent somatic mutations, the pleiotypic diversity of familial chronic lymphocytic leukaemia and related malignant lymphoproliferative disorders is generally explained by a repertoire of monoallelic polygenes in the initial mutation. Epigenetic genomic imprinting is a likely mechanism behind of the asynchroneous replicating monoallelic polygenes which is discussed in the light of pleiotrophy and birth order effect. Furthermore, it is discussed that one possible mechanism available for the epigenetic transfer of these genes could be the physiological pregnancy-related microchimerism between mother and fetus.

Chronic Lymphocytic Leukemia, Advantages of Monoclones?

From a basic biological point of view, genetic traits from the human genome have been selected during a long evolution in the fight for fitness. Since the susceptibility for CLL has a genotype, a theoretical question about its advantage is relevant. This is a question about mutated monoclones and whether they are an advantage to man. We suggest that the genetic capability to provide such monoclones could be explained as reminiscence from the fetal life like a “Bad for the postnates, good for the prenates” principle. Some examples are described, e.g. the fetomaternal processing of endogenous retrovirus in the production of placenta-specific transcripts of several genes in a ceasefire balance with potential infectious exogenous retrovirus. The regulation of some cytokine reactions affected lymphocytes and monocytes around the trophoblasts, which clearly has a specific clonal pattern. Feto-maternal microchimerism with longstanding implanting of clonal maternal stem cells or lymphocytes in the offspring is yet another example giving rise to later autoimmune reactions both in the mother and in the adult life of the offspring. Based on the clinical association between CLL and the other malignant hematological disorders, seen as an increased frequency of the diagnoses in affected families, a genetic linking of their susceptibility seems likely. This entity of clonal disorders may then perhaps be seen as a previous feto-maternal genetic repertoire.

Anticipation in Families with Chronic Lymphocytic Leukemia and Other Lymphoproliferative Disorders

Fifty-one parent-offspring pairs with chronic lymphocytic leukemia (CLL) or other lymphoproliferative disorders (nonCLL) such as malignant lymphoma, multiple myeloma, or other types of lymphocytic leukemia than CLL were ascertained independently in 38 families. There were 30 CLL-CLL parent-offspring pairs and 21 pairs with nonCLL in parents and/or in offspring. The median age of onset of disease was 13 years lower in the offspring than in the parents when comparing all 51 pairs (P < 0.001). This difference was mainly caused by a significantly lower age at onset in offspring with parental nonCLL (P < 0.001) where paternal disease was transferred especially to sons, while affected offspring to parents with CLL have the same age at debut of disease than their parents (P = 0.130) and a nearly equal transfer to sons and daughters. The low-malignant follicular small B-cell lymphoma was the predominant diagnosis within nonCLL. Anticipation is pointed out as one likely mechanism behind the lower age at onset of disease in offspring than in parents, even if a part of this difference is ascribed to a generally earlier diagnosis with modern technology in offspring than in parents.

Looking for CLL genes

We learn from the article of Sellick et al. [1] that germ line mutations in the RAD (51, 51AP1, 51B, C, D, 52 and 54L) sequences are most probably not related to the genetics of CLL. The investigation was based on the fact that these RAD sequences master homologous recombination, including that of IgJ and IgH, which relates to CLL susceptibility. To achieve the strongest possible signal, Sellick et al. used cases of familial CLL and not sporadic CLL for their investigation. However, the findings were negative throughout, adding these mutated RAD sequences to the long list of unlikely candidate genes for inherited CLL [2,3]. How do we interpret the many negative findings from a considerable number of published studies on linking and screening? Is there any systematic paradigm and what are the options?

High frequency of unrecognized indolent hematological disorders among HLA-matched siblings of patients with lymphoproliferative malignancies eligible for allo-SCT

High frequency of unrecognized indolent hematological disorders among HLA-matched siblings of patients with lymphoproliferative malignancies eligible for allo-SCT