Henry T. Lynch, M.D., Kelly Ferrara, M.S., Bart Barlogie, M.D., Ph.D., Elizabeth A. Coleman, Ph.D., Jane F. Lynch, B.S.N., Dennis Weisenburger, M.D., Warren Sanger, Ph.D., Patrice Watson, Ph.D., Henry Nipper, Ph.D., Vinetta Witt, Ph.D., and Stephan Thomé, M.D.
We describe a family with five cases of multiple myeloma, threecases of monoclonal gammopathy of undetermined significance(MGUS), and five cases of prostate cancer in two generations.The putative progenitor had progeny with two female partners.The progeny had prostate cancer, multiple myeloma, and MGUS.
Multiple myeloma accounts for approximately 10% of all hematologiccancers and is most frequent in persons over 65 years of age;only 2% of patients are younger than 40 years of age.1,2,3 Thecharacteristic feature of the disease is a clonal proliferationof malignant plasma cells, which produce a monoclonal protein(M protein) and cause lytic bone lesions. Multiple myeloma canevolve from MGUS, but the factors that contribute to the evolutionof MGUS into multiple myeloma are unknown.4 Extensive chromosomalabnormalities are detectable in the plasma cells of most patientswith multiple myeloma, and similar changes are also presentin MGUS. Persons with MGUS usually have a serum concentrationof M protein of less than 30 g per liter and less than 10% bonemarrow plasma cells. MGUS is differentiated from multiple myelomaby the absence of renal failure, anemia, and bone lesions.5IgG is the most common isotype of the M protein in MGUS.6
The cause of multiple myeloma is unknown.2,3 A small but unknownfraction of patients have familial disease. There is evidenceof a higher incidence of the disease in blacks than in whites.7In a study of 39 families with several cases of multiple myeloma,some family members had MGUS, other types of hematologic cancers,or solid tumors.8 We report on a black family in which therewere five cases of multiple myeloma, three of MGUS, and fiveof prostate cancer.
Materials and Methods
The study was approved by the institutional review board ofCreighton University. Our multiple myeloma–prone familywas studied at the University of Arkansas for Medical Sciencesand the Creighton University School of Medicine. The methodsfor developing the family pedigree were the same as those usedin our previous study.8 A detailed genealogic compilation ofthe family's medical history was obtained with the use of questionnairesand personal interviews that included questions about cancerat all anatomical sites. Individual histories of cancer wereconfirmed by review of original pathology reports or death certificateswhenever possible. Offspring and siblings of myeloma-affectedfamily members were recruited for evaluation of MGUS, as werefirst-degree relatives of the identical twin of a myeloma-affectedfamily member. A family information service9 was organized withthe assistance of key family members. Twenty blood relativesattended, as well as four of the authors. During this 1-daymeeting, the family was educated about multiple myeloma, withparticular emphasis on its epidemiologic and genetic risk factors.They were told about the pertinent aspects of our investigation,and consenting first-degree relatives of a myeloma-affectedfamily member provided fresh urine and blood samples to aidthe investigation of the possibility of MGUS.
Serum and urine protein electrophoreses were performed withthe Paragon electrophoresis system and an Appraise densitometer(Beckman Coulter) with the use of agarose gel (1.0%) in 1.2%barbital buffer (pH 8.6) on flexible plastic backing. The gelswere stained with Paragon blue, consisting of 0.5% (wt/vol)8-amino-7-(3-nitrophenylazo)-2-(phenylazo)-1-naphthol-3,6-disulfonicacid disodium salt in 5% acetic acid solution (Beckman Coulter).Urine samples were concentrated by a factor of more than 100with the use of a Minicon concentrator (Millipore). Proteinimmunofixation electrophoresis on serum or urine was performedwith the use of the gels provided with the Paragon electrophoresissystem, consisting of 1.0% agarose in a 1.2% TRIS barbital aspartatebuffer. The antiserum specimens used were goat IgG fractionsagainst human IgG, IgA, and IgM and the kappa and lambda lightchains (Beckman Coulter). After electrophoresis and fixationon the gel, the proteins were stained with Paragon blue. Theprocedures specified in the manufacturer's instructions werefollowed after validation in our laboratory.10 All the testswere performed in the Special Chemistry Laboratory at CreightonMedical Laboratories. Serum kappa and lambda free light chainswere measured at ARUP Laboratories by a standard method.11
The number of cases meeting the criteria for MGUS in this familywas compared with the expected number of cases, which was calculatedfrom published age- and sex-specific prevalence estimates.6Figures for Olmsted County, Minnesota,6 were multiplied by threeon the basis of the observation that the prevalence of MGUSwas higher by a factor of three in blacks than in whites ina large series of cases.7 Because data on prevalence among personsunder the age of 50 years are not available, in this study weused rates among persons 50 to 60 years of age for the youngerage groups. In Ghana, the prevalence in black men is twice thatin white men,12 which suggests that our expected number is aconservative estimate. On the assumption that the prevalenceis lower in younger persons, this approach will overestimatethe expected number of cases and thus result in a more conservativestatistical test. The observed number was compared with theexpected number with the use of Byar's approximation of thePoisson test.13
Results and Discussion
Table 1 shows the results from 11 first-degree relatives whowere evaluated for MGUS with the use of the free light-chaintest. In a cohort of this size with this distribution of agesand sexes, less than 1 case of MGUS (0.7 case) would be expected;we found 3 cases (Family Members II-11, III-1, and III-6). Mproteins were also found by serum protein electrophoresis patternsin these three family members and were characterized by immunofixationas IgG- in Family Members II-11 and III-1 and as IgG- in III-6.The serum levels of M proteins in Family Members III-1 and III-6were too low to be measured. The serum level of M proteins inFamily Member II-11 was higher (7.8 g per liter), and the levelof the other immunoglobulins was reduced (2.4 g per liter).Figure 1 shows the results of assays for serum free light chain.Urine studies of all 11 family members tested yielded no evidenceof M proteins or monoclonal free light chains.
Figure 1. New Cases of Monoclonal Gammopathy of Undetermined Significance (MGUS) in Clinically Unaffected Family Members II-11 (Panel A), III-1 (Panel B), and III-6 (Panel C), Documented by Serum Protein Electrophoresis (SPE) and Serum Immunofixation.
The cases were detected as a result of investigation by the study's family information service. The graphs on the left side of each panel show densitometric tracings of the total serum proteins. Albumin is the largest single-protein peak; the alpha 1, alpha 2, beta, and gamma peaks contain multiple globulins. Small peaks in the gamma fraction indicate the presence of M proteins (a single immunoglobulin produced in excessive quantities from a single plasma-cell clone). In a normal electrophoretic pattern, the gamma fraction is broad because of the polyclonal nature of the many different immunoglobulins produced by many different plasma cells. An abnormal electrophoretic pattern has a tall, narrow peak indicating the presence of an M protein. The columns on the right side of each panel depict immunofixation of serum proteins on agarose gels. The first column shows all serum proteins, and the other columns show specific immunoglobulin subtypes (IgG, IgA, IgM, and kappa and lambda light chains), as identified by immunofixation to specific antiserum. The bands indicate subtypes of monoclonal proteins (M proteins). The arrowheads indicate the presence of monoclonal proteins, as detected in the densitometric tracing, that are identified by immunofixation. Plus and minus signs indicate the positions of the positive and negative electrodes.
The pedigree (Figure 2) shows the five family members with multiplemyeloma and the three with MGUS. Family Member I-2 is the putativeprogenitor. He died of colon cancer at the age of 88 years.Multiple myeloma developed in his progeny from two women: inII-12, his daughter from his first partner, and in II-1, II-5,and II-8, his children from his second partner. In the thirdgeneration, the proband (III-3) had multiple myeloma, and twoother family members had MGUS. All these persons were in thedirect line of descent from the putative progenitor. FamilyMember II-2 died at the age of 50 years of pancreatic cancer,and her identical twin (II-1) had multiple myeloma. The daughterof II-2 (III-6) has MGUS. Family Member II-8 was found to haveprostate cancer at the age of 69 years and multiple myelomaat the age of 72 years. That man's brother, II-11, had prostatecancer at 64 years of age and MGUS at 73 years of age. FamilyMember II-11 has two sons, III-19 and III-20, who received adiagnosis of prostate cancer at 44 and 41 years of age, respectively.
Figure 2. Pedigree Showing Family Members with Multiple Myeloma or Monoclonal Gammopathy of Undetermined Significance (MGUS) in a Pattern Consistent with Autosomal Dominant Transmission.
The pedigree shows a decrease in the age of onset of prostate cancer, MGUS, and multiple myeloma from generation II to generation III. The arrow indicates the proband. The double horizontal line between Family Members II-1 and II-2 indicates that they are identical twins.
We previously reported another family that included a sibshipof seven, of whom three had multiple myeloma and two had MGUS.14One sibling had two primary cancers (prostate cancer and multiplemyeloma), and systemic amyloidosis developed in one siblingwho had MGUS; the father of this sibship also had prostate cancer.8These observations led us to investigate additional instancesof familial multiple myeloma.8
The overall risk of multiple myeloma in first-degree relativesof persons with multiple myeloma is reported to be increasedby a factor of two to four.15 The risk of hematologic and solidcancers, especially chronic lymphocytic leukemia, non-Hodgkin'slymphoma,4 prostate cancer, and endometrial cancer,8,14,16,17also appears to be higher in relatives of persons with multiplemyeloma.8 Brown et al.18 reported an increased risk of multiplemyeloma associated with a family history of any hematologiccancer (odds ratio, 1.7) but did not find a significant increasein the rate of solid cancers in white or black families in theUnited States. Eriksson and Hallberg,16 however, in a smallerstudy of Swedish families with various cancers, identified anincreased risk of prostate cancer in first-degree relativesof persons with multiple myeloma (relative risk, 3.11).16
Evidence of an increased risk of multiple myeloma in relativesof carriers of the BRCA1 or BRCA2 mutation has also been reported.19In addition, Dilworth et al.20 described a melanoma-prone familyin which one member with multiple myeloma had a germ-line mutationof the CDKN2A (p16) gene. To determine whether the CDKN2A mutationwas responsible for multiple myeloma, these investigators searchedfor loss of heterozygosity and found that the wild-type CDKN2Aallele was lost in the malignant plasma cells, a result suggestingthat germ-line mutations of CDKN2A may confer an increased susceptibilityto multiple myeloma as well as to melanoma and pancreatic cancer.21
In conclusion, this myeloma-prone family merits long-term medicaland genetic follow-up, including formal linkage analysis, insearch of a cancer-susceptibility locus.
Supported by revenue from Nebraska cigarette taxes awarded toCreighton University by the Nebraska Department of Health andHuman Services and by a grant from the National Institutes ofHealth (1U01 CA 86389). Dr. Lynch's work is supported in partby the Charles F. and Mary C. Heider Chair in Cancer Research,which he holds at Creighton University.
No potential conflict of interest relevant to this article wasreported.
The views expressed are those of the authors and do not necessarilyrepresent the official views of the State of Nebraska or theNebraska Department of Health and Human Services.
Source Information
From Creighton University School of Medicine (H.T.L., K.F., J.F.L., P.W., S.T.); Nebraska Medical Center (D.W., W.S.); and Creighton University Medical Center (H.N.) — all in Omaha; the University of Arkansas for Medical Sciences, Little Rock (B.B., E.A.C.); and Newberry College, Newberry, SC (V.W.).
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Familial Myeloma
Camp N. J., Werner T. L., Cannon-Albright L. A., Lynch H. T., Thomé S.
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in Family Members II-11 and III-1 and as IgG-
in III-6. The serum levels of M proteins in Family Members III-1 and III-6 were too low to be measured. The serum level of M proteins in Family Member II-11 was higher (7.8 g per liter), and the level of the other immunoglobulins was reduced (2.4 g per liter). Figure 1 shows the results of assays for serum free light chain. Urine studies of all 11 family members tested yielded no evidence of M proteins or monoclonal free light chains. 
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