Meiotic drive in chronic lymphocytic leukemia compared with other malignant blood disorders.

The heredity of the malignant blood disorders, leukemias, lymphomas and myeloma, has so far been largely unknown. The present study comprises genealogical investigations of one hundred and twelve Scandinavian families with unrelated parents and two or more cases of malignant blood disease. For comparison, one large family with related family members and three hundred and forty-one cases of malignant blood disease from the Faroese population was included. The inheritance is non-Mendelian, a combination of genomic parental imprinting and feto-maternal microchimerism. There is significantly more segregation in maternal than in paternal lines, predominance of mother-daughter combinations in maternal lines, and father-son combinations in paternal lines. Chronic lymphocytic leukemia is the most frequent diagnosis in the family material, and chronic lymphocytic leukemia has a transgenerational segregation that is unique in that inheritance of susceptibility to chronic lymphocytic leukemia is predominant in males of paternal lines. Male offspring with chronic lymphocytic leukemia in paternal lines have a birth-order effect, which is manifest by the fact that there are significantly more male patients late in the sibling line. In addition, there is contravariation in chronic lymphocytic leukemia, i.e. lower occurrence than expected in relation to other diagnoses, interpreted in such a way that chronic lymphocytic leukemia remains isolated in the pedigree in relation to other diagnoses of malignant blood disease. Another non-Mendelian function appears in the form of anticipation, i.e. increased intensity of malignancy down through the generations and a lower age at onset of disease than otherwise seen in cases from the Cancer Registers, in acute lymphoblastic leukemia, for example. It is discussed that this non-Mendelian segregation seems to spread the susceptibility genes depending on the gender of the parents and not equally to all children in the sibling line, with some remaining unaffected by susceptibility i.e. "healthy and unaffected", due to a birth order effect. In addition, anticipation is regarded as a non-Mendelian mechanism that can amplify, «preserve¼ these vital susceptibility genes in the family. Perhaps this segregation also results in a sorting of the susceptibility, as the percentage of follicular lymphoma and diffuse large B-cell lymphoma is lower in the family material than in an unselected material. Although leukemias, lymphomas and myelomas are potentially fatal diseases, this non-Mendelian distribution and amplification hardly play any quantitative role in the survival of Homo sapiens, because these diseases mostly occur after fertile age.

Inheritance of Susceptibility to Malignant Blood Disorders.

Malignant blood disorders depend on heritable susceptibility genes and occur in familial aggregations. We suggest a model of transgenerational segregation of the susceptibility genes based on the study of malignant blood disorders in Norwegian and Danish families with unrelated parents, and in the inbred Faroese population with related parents. This model, consisting of parental genomic imprinting and mother-son microchimerism, can explain the male predominance in most of the diseases, the predominance of affected parent-offspring when parents are not related, and the different modes of segregation in males and females. The model displays a specific pattern in the distribution of affected relatives for each diagnosis, viz. a characteristic distribution in the pedigrees of family members with malignant blood disorder related to the proband. Three such patterns, each reflecting a specific transgenerational passage, were identified: (1) alterations in the number of affected relatives in paternal lines alone, e.g. in patterns for probands with multiple myeloma; (2) alterations in the number of affected relatives in both paternal and maternal lines for probands with chronic lymphocytic leukemia; and (3) no alterations in the numbers of male and female affected relatives in the parental lines, e.g. for probands with some types of malignant lymphoma.

Cladribine prolongs progression-free survival and time to second treatment compared to fludarabine and high-dose chlorambucil in chronic lymphocytic leukemia.

We conducted a randomized phase III trial to compare the efficacy and safety of two purine analogs, cladribine and fludarabine, with high-dose chlorambucil, in patients with previously untreated chronic lymphocytic leukemia (CLL). Between 1997 and 2004, 223 patients with CLL were randomly assigned to cladribine, fludarabine or chlorambucil, for six cycles of therapy with frequent health-related quality of life assessments. There was no statistical difference for the primary endpoint of overall response with cladribine (70%), fludarabine (67%) and chlorambucil (59%), or complete remission (12%, 7% and 8%), respectively. However, the median progression-free survival (25, 10, 9 months) and median time to second treatment (40, 22, 21 months) were superior with cladribine. There was no significant difference in overall survival (96, 82 and 91 months), nor in toxicity or HRQoL assessments. Monotherapy with cladribine gives superior PFS and longer response duration than fludarabine and chlorambucil as first-line treatment of CLL.

Familial occurrence of chronic lymphocytic leukaemia in Norway.

BACKGROUND: The 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. MATERIAL AND METHOD: All 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. RESULTS: We 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. INTERPRETATION: Malignant haematological disease is common in the family members of patients with CLL. CLL is the most common disease, but there is extensive pleiotropy.

Chronic lymphocytic leukaemia in Norway--incidence and prognostic markers at diagnosis.

BACKGROUND: The clinical courses of chronic lymphocytic leukaemia (CLL) are very heterogeneous. Biological markers that provide good prognostic information at the time of diagnosis are available. The aim of the study was to determine the prevalence of these markers in a population-based material. MATERIAL AND METHOD: Biological markers were examined using standard laboratory methods after obtaining an informed consent statement from patients diagnosed with chronic lymphocytic leukaemia in the period 1.10.2007-31.12.2009. RESULTS: There were 388 new cases of chronic lymphocytic leukaemia during the study period, and 236 patients (61%) were included in the study. Of 222 patients, 178 (80%) were in Binet's stage A, 26 (12%) in stage B and 18 (8%) in stage C. The V(H) gene was mutated in 69% and unmutated in 31% of cases. Cytogenetic aberrations were found in 68%: del(13q14) in 48%, trisomy 12 in 13%, del(11q22) in 10% and del(17p13) in 7%. CD38-positive disease was found in 28% of the patients. The V(H) gene was mutated in 67% of the patients in Binet's stage A, and in the majority of these a mutated V(H) gene was associated with non-expression of CD38 and del(13q14). INTERPRETATION: At the time of diagnosis, most patients are asymptomatic and do not need treatment. The biological markers that indicate a favourable prognosis occur most frequently in this group. Markers that indicate a poor prognosis occur more frequently in the group that has symptoms at the time of diagnosis.

[A woman in her 60s with multifactorial anaemia]. / En kvinne i 60-årene med kombinert anemi.

Anaemia may be multifactorial in origin. We present a woman with autoimmune hepatitis and secondary warm autoimmune haemolytic anaemia and most likely also concomitant anaemia of chronic disease. A relapse of autoimmune haemolysis was successfully treated with steroids and high-dose intravenous immunoglobulin. At the same time, bleeding from angiodysplasia in the coecum was masked by unauthorised perorally administrated iron. No other cause of bleeding was found. During that period, she required extensive blood transfusions, up to several times per month. Surgical or endoscopic treatment of the bleeding angiodysplasia was not possible. Alloimmunisation developed as a complication to the large number of transfusions, despite the use of steroids. Treatment with somatostatin analogue markedly reduced the need of our patient for blood transfusions for a follow-up period of more than one year, and she has not experienced any side effects. We do not know how long the haemostasis achieved will last, however, we believe that this treatment may be an alternative for other patients as bleeding from angiodysplasia is not uncommon and is often difficult to eradicate.

Familial Hodgkin's lymphoma in Scandinavia.

From 2005 to 2010, eight families with clustering of Hodgkin's lymphoma and other lymphoproliferative disorders were found: Hodgkin's lymphoma 9 cases, chronic lymphocytic leukemia 8, non-Hodgkin's lymphoma 3, and multiple myeloma 1 case. Seven cases of Hodgkin's lymphoma, all males, were seen in pleiotropic pairs of affected family members from two successive generations; two patients were sisters. Five of the seven pairs showed sign of anticipation. The 7 males with Hodgkin's lymphoma were found in 5 patrilineal pairs and 2 matrilineal pairs; 6 parent-offspring pairs and 1 uncle-nephew pair. In contrast to the matrilineal pairs, all patrilineal pairs, apart from one family with an only child, had healthy older siblings in accordance with a birth-order effect. The association among Hodgkin's lymphoma, males, and other lymphoproliferative disorders undoubtedly reflects genotypic traits of the susceptibility. A non-Mendelian segregation is discussed comprising genomic parental imprinting and incomplete penetrance susceptibility in both familial and solitary cases.

Familial chronic lymphocytic leukemia in Norway and Denmark. Comments on pleiotropy and birth order.

AIM: To investigate the genetics of chronic lymphocytic leukemia (CLL). MATERIALS AND METHODS: In 56 (7%) out of 800 CLL patients with concomitant malignant hematological disease, 51 families and 141 cases were ascertained. RESULT: 106 cases (75%) of CLL, 27 cases (19%) of nonCLL and 8 cases (6%) of myeloproliferative disorders. Paternal disease was transmitted primarily to the youngest sons in the sibship while maternal disease was transmitted equally to all sibs, demonstrated by means of matrix conjugation and confirmed with Cox regression on parity and birth order (maternal-offspring combination: relative risk (RR), 95% confidence interval (CI)=1.47 (0.89 - 2.43), p=0.12, compared with paternal-offspring combination: RR=3.25, 95% CI=(1.57-6.72), p<0.001). The B-cell expression in familial and sporadic CLL was indistinguishable. CONCLUSION: Parental genomic imprinting is pointed out as one possible mechanism behind this non-Mendelian genomic output.

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.

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.

Pleiotropía en familias con leucemia linfocítica crónica / Pleiotropy in families with chronic lymphocytic leukemia

La pleiotropía de la leucemia linfocítica crónica (LLC) indica la aparición de otros tipos de enfermedades linfoproliferativas en ancestros del probando. En 35 pares de padres-descendientes con LLC en los padres, 27 pares (77%) tenían también LLC. en los descendientes, igual en herencia materna y paterna. En 8 descendientes (23%) sin LLC, hubo 6 casos con otra enfermedad linfoproliferativa y dos casos con plicitemia vera. Por ende, la pleitropía de la LLC comprende tanto trastornos linfoproliferativos como mieloproliferativos. En relación con la anticipación, no se observó ninguna diferencia en la edad al inicio de la enfermedad entre padres e hijos. Se debate que estos hallazgos puedan estar de acuerdo con un modo no mendeliano de transmisión de la LLC con muchos alelos de bajo riesgo que confieren un pequeño riesgo fenotípico de LLC. Además, la transmisión de los genes no alélicos refleja la impronta (silenciamiento) materna de los genes paternos como consecuencia del microquimerismo relacionado con el embarazo.

Pleiotropía en familias con leucemia linfocítica crónica / Pleiotropy in families with chronic lymphocytic leukemia

La pleiotropía de la leucemia linfocítica crónica (LLC) indica la aparición de otros tipos de enfermedades linfoproliferativas en ancestros del probando. En 35 pares de padres-descendientes con LLC en los padres, 27 pares (77%) tenían también LLC. en los descendientes, igual en herencia materna y paterna. En 8 descendientes (23%) sin LLC, hubo 6 casos con otra enfermedad linfoproliferativa y dos casos con plicitemia vera. Por ende, la pleitropía de la LLC comprende tanto trastornos linfoproliferativos como mieloproliferativos. En relación con la anticipación, no se observó ninguna diferencia en la edad al inicio de la enfermedad entre padres e hijos. Se debate que estos hallazgos puedan estar de acuerdo con un modo no mendeliano de transmisión de la LLC con muchos alelos de bajo riesgo que confieren un pequeño riesgo fenotípico de LLC. Además, la transmisión de los genes no alélicos refleja la impronta (silenciamiento) materna de los genes paternos como consecuencia del microquimerismo relacionado con el embarazo.(AU)

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.

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 Smith's 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.

The influence of pregnancy on the development of autoimmunity in chronic lymphocytic leukemia.

To examine whether pregnancy influences the development of autoimmunity in chronic lymphocytic leukemia (CLL), we studied 591 consecutive CLL patients (202 post-menopausal women and 389 men). The mean observation time for all patients was 3.8 years, corresponding to approximately 2200 person-years of follow-up. Autoimmune manifestations were analyzed in 194 women with known obstetric history and known number of long-term sexual partners, and in the 389 male CLL patients for comparison. One hundred and fifty-nine of the CLL patients exhibited autoimmune manifestations, 38% in females and 21% in men. In female CLL patients, the frequency of autoimmunity and the number of pregnancies and the number of partners were strongly correlated. Each of the major autoimmune types approximately doubled in frequency for each additional pregnancy. The impact of pregnancy on expressed autoimmunity increased with each additional sexual partner (the odds of autoimmunity increased 11 times with each long-term sexual partner). The average numbers of pregnancies in female CLL patients with and without autoimmunity were 4.92 and 2.24, respectively (P < 0.001). Coombs' positive autoimmune anemia, a gastric ulcer with parietal cell autoantibodies and idiopathic thrombocytopenic purpura were equally common in women and men, whereas autoimmune thyroiditis, Sjögren's syndrome, rheumatoid arthritis and systemic lupus erythematosus were seen in higher rates in women than in men. The spectrum of autoimmunity suggests that pregnancy-related alloimmunization may be involved in the development of autoimmunity in CLL.