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Date: February 12, 2024
by Chaya Venkat
Related Article: Familial CLL
Do you remember the exact moment, the specific place, the particular day you were diagnosed with CLL? How can anything possibly top that, you say. Of course it was the worst day of your life.
For those of us who are parents and grandparents, the day we were diagnosed with CLL will pale in comparison to the day when and if (and hopefully never) we hear one of our children or grandchildren has been diagnosed with CLL. Here, then, is a bitter-sweet valentine to each of you from CLL Topics. This article deals with a difficult subject most of us are too scared to face head on, the subject of inherited predisposition to CLL in families. The technical name for it is "familial CLL". If you are the type that would rather face the monsters that go bump in the night, then read on. If you would rather not know, I understand all too well. I too have been avoiding this subject. For once, I am not even sure that knowledge and information are enough. Perhaps more than the stark facts and figures I can provide, you need wisdom, grace, and courage. I will leave it up each of you to decide that for yourselves.
By now most of us who have been around the CLL block a few times know that many of us get diagnosed with this disease at a given point in time, perhaps because of a blood test that did not look quite right. But in hindsight and going back in our own medical records it often becomes clear that we had been walking around with undiagnosed CLL for several years prior to that. Let us take this a bit further. If we were to pull in people randomly off the street, perfectly healthy looking strangers with no clue what the acronym "CLL" stands for (remember a time when you did not know what it meant?), how many of these people do you think will test positive?
That is exactly what Rawstron et. al. did, a blue-ribbon panel of experts. 910 outpatients who showed up at the hospital for totally unrelated causes, nothing to do with cancer and perfectly normal blood counts, were tested for the tell-tale signs of CLL phenotype. Let me explain that: CLL cells express four characteristic markers, CD19, CD5, CD79B and CD20. By using sophisticated equipment, the researchers looked for any detectable cells that had this particular set of markers. If they found cells with these markers, they further tested to see if they were all identical clones of each other (whether they had the same light chain restriction, a dead giveaway of clonal population). I don't know if they were expecting this result, but I was blown away when I read this article. A whopping 3.5 % of these blissfully oblivious individuals had what can only be termed as CLL.
There were more men than women in this group of undiagnosed CLL cases, more of them were elderly. All of these undiagnosed CLL cases were of the good prognosis variety, looked like the classic "smoldering" variety, they looked like very early stage of an indolent form of CLL. (If you want to learn a bit more about CLL and how it can be subdivided into different prognostic groups, please refer to an earlier article "What Type of CLL Do You Have?" )
My guess would be these folks were all oblivious of their status because the disease had not raised its ugly head above the radar level, it was in small enough numbers and not doing much of anything and therefore had gone undetected. Does this mean each of these people would some day progress to the point where they too will become fully accredited members of the CLL club? Absolutely not! Most of these people will live out their lives without ever having to face that particular "worst day of their lives". A few would progress, the few and lonely CLL cells having grown into much larger clonal populations, large enough to make their presence felt.
Blood. 2024 Jul 15;100(2):635-9.
Monoclonal B lymphocytes with the characteristics of "indolent" chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts.
Rawstron AC, Green MJ, Kuzmicki A, Kennedy B, Fenton JA, Evans PA, O'Connor SJ, Richards SJ, Morgan GJ, Jack AS, Hillmen P.
Haematological Malignancy Diagnostic Service, Academic Unit of Haematology and Oncology, Algernon Firth Building, University of Leeds, United Kingdom.
Molecular and cellular markers associated with malignant disease are frequently identified in healthy individuals. The relationship between these markers and clinical disease is not clear, except where a neoplastic cell population can be identified as in myeloma/monoclonal gammopathies of undetermined significance (MGUS). We have used the distinctive phenotype of chronic lymphocytic leukemia (CLL) cells to determine whether low levels of these cells can be identified in individuals with normal complete blood counts. CLL cells were identified by 4-color flow cytometric analysis of CD19/CD5/CD79b/CD20 expression in 910 outpatients over 40 years old. These outpatients were age- and sex-matched to the general population with normal hematologic parameters and no evident history of malignant disease. CLL phenotype cells were detectable in 3.5% of individuals at low level (median, 0.013; range, 0.002- 1.458 x 10(9) cells/L), and represented a minority of B lymphocytes (median, 11%; range, 3%-95%). Monoclonality was demonstrated by immunoglobulin light-chain restriction in all cases with CLL phenotype cells present and confirmed in a subset of cases by consensus-primer IgH-polymerase chain reaction. As in clinical disease, CLL phenotype cells were detected with a higher frequency in men (male-to-female ratio, 1.9:1) and elderly individuals (2.1% of 40- to 59-year-olds versus 5.0% of 60- to 89-year-olds, P =.01). The neoplastic cells were identical to good-prognosis CLL, being CD5+23+20(wk)79b(wk)11a(-)22(wk)sIg(wk)CD38-, and where assessed had a high degree (4.8%-6.6%) of IgH somatic hypermutation. The monoclonal CLL phenotype cells present in otherwise healthy individuals may represent a very early stage of indolent CLL and should be useful in elucidating the mechanisms of leukemogenesis.
PMID: 12091358
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The next question asked by these researchers was this: how many of the 3.5% of the general walking public with undiagnosed CLL were just random victims, so-called "sporadic cases of CLL", and how many inherited this disease from close blood relatives ("first degree relatives") and therefore cases of "familial CLL"? They examined 59 healthy first-degree relatives of CLL patients in 21 families. Eight out of the 59 (13.5%) of blood relatives of CLL patients had the tell-tale markers. Let me say this another way, if you have never heard of CLL in your family, you may have as much as a 3.5% chance of having an undiagnosed version of it yourself. But if someone close to you, a direct first degree relative has or had CLL, your chances of having the markers for CLL just went up from 3.5% to 13.5%. That is a huge, scary and big jump in the statistics, and leaves no room for doubt. There is a clear familial aspect to CLL. No other blood cancer has a higher risk of being passed along in families in this fashion. CLL was observed in first-degree relatives (between parents, siblings and children) of the patients with CLL, more often than in other relatives. If your second cousin twice removed had CLL, you can breathe a sigh of relief.
Blood. 2024 Oct 1;100(7):2289-90
Inherited predisposition to CLL is detectable as subclinical monoclonal B-lymphocyte expansion.
Rawstron AC, Yuille MR, Fuller J, Cullen M, Kennedy B, Richards SJ, Jack AS, Matutes E, Catovsky D, Hillmen P, Houlston RS.
Academic Unit of Haematology and Oncology, University of Leeds, HMDS, West Yorkshire, Surrey, United Kingdom.
Monoclonal chronic lymphocytic leukemia (CLL)-phenotype cells are detectable in 3.5% of otherwise healthy persons using flow cytometric analysis of CD5/CD20/CD79b expression on CD19-gated B cells. To determine whether detection of such CLL-phenotype cells is indicative of an inherited predisposition, we examined 59 healthy, first-degree relatives of patients from 21 families with CLL. CLL-phenotype cells were detected in 8 of 59 (13.5%) relatives, representing a highly significant increase in risk (P =.00002). CLL-phenotype cell levels were stable with time and had the characteristics of indolent CLL. Indolent and aggressive clinical forms were found in family members, suggesting that initiation and proliferation involves distinct factors. The detection of CLL-phenotype cells provides a surrogate marker of carrier status, potentially facilitating gene identification through mapping in families and direct analysis of isolated CLL-phenotype cells.
PMID: 12239136
____________
Haematologica. 2024 Oct;88(10):1190-1.
Familial chronic lymphocytic leukemia.
Cerny J, Slavickova A, Krepelova A, Trneny M, Karban J, Klener P.
Familial aggregation of chronic lymphocytic leukemia (CLL) has been observed more frequently than familial aggregation of any other type of oncohematologic disorder. The presence of cells with a CLL-like immunophenotype (CLL-like cells) was recently documented in 13.5% healthy first-degree relatives of CLL patients. We present a family with CLL in which 2 brothers, a sister and their mother were affected.
PMID: 14555317
____________
As far as we have been able to sort it out, it appears that there is a strong genetic predisposition to CLL, a susceptibility that may make one more vulnerable to full blown CLL down the road. There are two parts to the puzzle, not every one who has inherited the genetic instability and therefore susceptibility will progress to clinically measurable CLL with symptoms and the whole nine yards. In other words, initiation of CLL may have to do with genetics, but proliferation of the few scarce CLL type cells into full blown disease is a different matter. This is an important difference, one that has big implications for those us worried about our children and grand children, and we will discuss it some more further down.
By now you are aware of the importance of knowing the exact chromosomal aberration that is responsible for your CLL. If you are new to this site and do not know what I am talking about, perhaps you should go to our section on prognostics, bring yourself up to speed. Interphase FISH has become one of the most important tests to classify CLL patients into different risk categories. 13q, trisomy 12, 11q and 17p are the four common aberrations, 6q is a little less common aberration in CLL patients. When Goldin et al looked at 94 people in 18 families, they found that a surprising number of them had instabilities associated with 6q, 13q, 12 and 17p regions, the same regions where CLL patients develop chromosomal deletions and mutations. Surprisingly enough, 11q deletion (deletion of the important ATM gene) did not figure in this list. It appears at this point in time that ATM mutations are rare in familial CLL, this seems to be one genetic defect that does not seem to be involved in inherited predisposition to CLL.
Br J Haematol. 2024 Jun;121(6):866-73.
A genome scan of 18 families with chronic lymphocytic leukaemia.
Goldin LR, Ishibe N, Sgambati M, Marti GE, Fontaine L, Lee MP, Kelley JM, Scherpbier T, Buetow KH, Caporaso NE.
Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute/NIH, Bethesda, MD
Chronic lymphocytic leukaemia (CLL) accounts for about 30% of all leukaemias and is most prevalent in older individuals. Significant familial aggregation has been demonstrated but the mode of inheritance is unknown. Recurrent cytogenetic abnormalities are frequently found in CLL tumour cells but no susceptibility genes have been confirmed. We have collected clinical data and biospecimens on families ascertained for having at least two living patients with CLL. The current study included DNA samples from 94 individuals (38 affected patients) in 18 families. We have carried out a genome scan using the ABI 28-panel medium density linkage mapping set (average spacing of 10 cM and average heterozygosity of 80%). Genotypes for 359 markers were scored. Multipoint limit of detection (lod) scores were calculated, assuming both dominant and recessive inheritance and allowing for increased penetrance with age and genetic heterogeneity. Non-parametric linkage scores were also calculated. Lod scores of 1.0 or greater were found on regions of chromosomes 1, 3, 6, 12, 13 and 17, but none of these loci achieved statistical significance. Four of these six regions (6q, 13q, 12 and 17p) coincide with areas where cytogenetic abnormalities are frequently observed in CLL tumour cells and are, therefore, strong candidate regions for containing germ line changes.
PMID: 12786797
____________
Blood. 2024 Jul 15;100(2):603-9.
ATM mutations are rare in familial chronic lymphocytic leukemia.
Yuille MR, Condie A, Hudson CD, Bradshaw PS, Stone EM, Matutes E, Catovsky D, Houlston RS.
Academic Department of Haematology and Cytogenetics, Institute of Cancer Research, Sutton, Surrey, United Kingdom.
It is now recognized that a subset of B-cell chronic lymphocytic leukemia (CLL) is familial. The genetic basis of familial CLL is poorly understood, but recently germ line mutations in the Ataxia Telangiectasia (ATM) gene have been proposed to confer susceptibility to CLL. The evidence for this notion is, however, not unequivocal. To examine this proposition further we have screened the ATM gene for mutations in CLLs from 61 individuals in 29 families. Truncating ATM mutations, including a known ATM mutation, were detected in 2 affected individuals, but the mutations did not cosegregate with CLL in the families. In addition, 3 novel ATM missense mutations were detected. Common ATM missense mutations were not overrepresented. The data support previous observations that ATM mutation is associated with B-CLL. However, ATM mutations do not account for familial clustering of the disease.
PMID: 12091354
____________
The majority of CLL patients are fifty years or older at diagnosis. But this general rule of thumb breaks down when we talk about familial CLL. It appears that when CLL does strike different generations in a given family, it is diagnosed at earlier and earlier age in subsequent generations. Just a couple of weeks ago I came across a mother and daughter who were both diagnosed with CLL for the first time, within a few weeks of each other. The age difference between the two of them was more than 25 years. This aspect of inherited CLL, where the child may be diagnosed at an earlier age compared to the parent, is called "anticipation". To put it in terms that will get you where you live, if you are a CLL patient in your fifties, your children are likely to be of an age when they are at risk, even though they are in just barely in their thirties! There is also a hint that the disease is of a more aggressive variety if it strikes in the next generation.
It sort of makes sense. If you have CLL as a result of genetic predisposition, and that genetic predisposition is passed on to your children, they may be likely to come down with it sooner, perhaps with more chromosomal aberrations than you have. I wonder how many of us diagnosed with CLL in our fifties and sixties can go back and look at the medical histories of our parents, who might have had undiagnosed CLL in their seventies and eighties. Perhaps the level of medical technology in those days may not even have detected it, it may have been written off as just old age problems. Are you the first one in your family with CLL, or was the true origin of this disease in your family with your father or mother ? If it has struck your parent and you, are your kids next in line?
Leuk Lymphoma. 2024 Jun;42(1-2):99-108.
Clinical characteristics of familial B-CLL in the National Cancer Institute Familial Registry.
Ishibe N, Sgambati MT, Fontaine L, Goldin LR, Jain N, Weissman N, Marti GE, Caporaso NE.
Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute/NIH, Rockville, MD
In an ongoing study, families with two or more living cases of B-CLL in first-degree relatives have been recruited through physician and self-referral. Since 1967, 28 kindreds with 73 cases of B-CLL have been enrolled within the National Cancer Institute (NCI) Familial B-CLL Registry. Medical, clinical, and demographic information have been obtained from private physicians, patient interview, hospital records, and death certificates. We used SEER Registry data to compare characteristics of sporadic B-CLL to familial B-CLL. The mean age at diagnosis was approximately 10 years younger among familial cases (57.9 +/- 12.1) than that observed in sporadic cases (70.1 +/- 11.9). A higher percentage of second primary tumors among familial CLL cases compared to reports in sporadic was also observed (16% vs. 8.8%). However, the transformation rate to non-Hodgkin's lymphoma does not appear to be different from that reported for sporadic cases. In conclusion, we observed some differences between familial and sporadic cases; whether any of these characteristics affect survival time or severity of disease is unknown. The study of families with multiple B-CLL cases will aid in delineating the genes and environmental factors that may play a role in the development of both forms of B-CLL.
PMID: 11699227
____________
Br J Haematol. 2024 May;113(2):407-14.
Anticipation in familial chronic lymphocytic leukaemia.
Wiernik PH, Ashwin M, Hu XP, Paietta E, Brown K.
Comprehensive Cancer Center, Our Lady of Mercy Medical Center, New York Medical College, Bronx, NY, USA.
Anticipation, a phenomenon in which an inherited disease is diagnosed at an earlier age in each successive generation of a family, has been demonstrated in certain heritable neurological disorders and in multiple myeloma, non-Hodgkin's lymphoma and other haematological neoplasms. The present study was conducted to determine whether anticipation occurs in familial chronic lymphocytic leukaemia (CLL). Fourteen published reports of multigenerational familial CLL were analysed for anticipation, together with 10 previously unreported families with familial CLL, and the difference in disease-free survival between generations was determined. The difference between age at onset for each affected parent-child pair was tested against the null hypothesis that there was no difference in age at onset. The age at onset of the studied cases was also compared with that of the Surveillance Epidemiology and End Results (SEER) Program of the U.S. National Cancer Institute. The median ages at onset in the child and parent generations of all families (51.0 and 72.0 years respectively) were significantly different (P < 0.000001), and the null hypothesis was rejected (P < 0.000001). A significant difference was observed between the ages of onset of the child generation and the SEER population (P < 0.00001), but not between the parent generation and the SEER population. Anticipation characterizes familial CLL.
PMID: 11380406
____________
Leukemia. 1998 Nov;12(11):1696-8.
Anticipation in familial chronic lymphocytic leukaemia.
Yuille MR, Houlston RS, Catovsky D.
Academic Department of Haematology and Cytogenetics, Institute of Cancer Research, Sutton, UK.
A recent analysis of literature reports of familial clusters of chronic lymphocytic leukaemia (CLL) suggested that affected offspring are diagnosed at an age 21 years less than CLL parents. Such an analysis risks sampling bias. We avoided these potential sources of bias by systematic ascertainment of CLL families. Statistical analysis of 10 such families showed a significant decline of 22 years between the mean ages at diagnosis of disease in parents and offspring. This confirms the analysis of literature reports and provides the first systematic investigation of a phenomenon which, if familial clustering of CLL cases is considered due to genetic effects, points to familial CLL manifesting anticipation.
PMID: 9823943
____________
Tohoku J Exp Med. 1994 May;173(1):133-40.
Genetic predisposition of autoimmune disease and B-cell chronic lymphocytic leukemia (B-CLL).
Shirai T., Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan.
Autoimmune disease is a polygenic disease in which various genetic factors play crucial roles. The familial clustering and the association of HLA haplotypes have been well-recognized. There is a close association between chronic lymphocytic leukemia (CLL) and autoimmune disease. Like autoimmune diseases, CLL is the type of leukemia most often occurring among close relatives. The patients with CLL frequently share common HLA haplotypes with relatives with autoimmune disease. As the majority of CLL is of CD5+ B-cell type, and as CD5+ B cells are suggested to be involved in autoimmunity, certain regulatory abnormalities in the proliferation and differentiation of CD5 B cells may be involved in both B-CLL and autoimmune disease. I discuss here the possibility that different, but related, MHC haplotypes would predispose either to autoimmune disease or to B-CLL, based on our findings obtained from MHC (H-2)-congenic New Zealand mouse strains.
PMID: 7528945
___________
Hematol Cell Ther. 1997 Nov;39 Suppl 1:S5-11.
The search for genetic clues in chronic lymphocytic leukemia.
Catovsky D.
Academic Department of Haematology & Cytogenetics, Royal Marsden NHS Trust, London, United Kingdom.
Research on the genetic basis of CLL is progressing at a rapid pace. The development of new techniques such as FISH, comparative genomic hybridisation (CGH) and a whole range of molecular methods is being applied to identify abnormalities in this relatively common B-cell leukaemia. The abnormalities may be of a different nature. There are some which are clearly associated with particular forms of the disease and usually with aggressive characteristics. The best examples are deletions at 11q23 seen in younger patients with generalised lymphadenopathy and inferior prognosis; trisomy 12, commonly associated with an increased proportion of prolymphocytes (CLL/PL) and more progressive disease; 17p abnormalities, chiefly mutations and deletions of p53, although rare, seem to be associated with transformation such as Richter syndrome, with CLL/PL and poor response to therapy. Abnormalities at 13q, though not correlated with particular clinical syndromes, are the subject of intense interest due to the possibility that one or more tumour suppressor genes relevant to the pathogenesis of CLL may be identified. Two areas in which work is being focused are 13q14 and 13q12. Finally, the incidence of familial cases of CLL, which has been known for a number of years, will lead to an international effort to collect familial cases, which ultimately will allow a genetic linkage study to discover a CLL "susceptibility gene". The presentations at the IWCLL were up-to-date, stimulating and pointed the way forward to further rapid progress in this exciting field.
PMID: 9471056
___________
If you have CLL, and you have children and grandchildren you love dearly, should you get them tested to see if they have the tell-tale markers of CLL? That is a tough question to answer, and I am sure I do not have any better handle on it than you. But here are some points to consider.
It seems to me that there are a lot of factors to consider before you pick up that phone and make arrangements to have your minor child tested for potential worries about CLL down the road. Siblings are another matter, since in most cases they are full-fledged adults and can make the decisions for themselves. It is not really your call to make. The same is true of grown children as well. You can provide your advice, but the decision is not yours to make.
Here are some unequivocal and clear-cut things you can do to help your children. The very fact that there is a significant inherited component to this cancer means that the secrets and solutions for CLL also reside in the genetic information that can be culled from familial CLL research. If you already have a familial CLL situation diagnosed in your family, make the effort to register your data with the CLL researchers. Write to us at the email address at the bottom of this page if you need help in registering your data. We can get you the contact information. Learn as much as you can about this disease, be proactive in finding a cure for it. Even if the cure does not come in time to be of much help to you, perhaps it will be available soon enough for your children. True, we are a small community compared to the AIDS or breast cancer or prostate cancer patient groups. But our voices can be heard and we can have an impact if we are determined and mobilized.
A bitter-sweet valentine, from my family to yours.
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