Probable involvement of immunoglobulin superfamily genes in most recurrent chromosomal rearrangements from ataxia telangiectasia

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1 Hum Genet (1986) 72 : Springer-Verlag 1986 Probable involvement of immunoglobulin superfamily genes in most recurrent chromosomal rearrangements from ataxia telangiectasia A. Aurias and B. Dutrillaux CNRS - U.A. 620, Structure et Mutagdn6se Chromosomiques, Institut Curie, Pavilion Regaud, 26 rue d'ulm, F Paris Cddex 05, France Summary. From the chromosomal analysis of 9461 lymphocytes from 57 patients affected by ataxia telangiectasia, it is concluded that bands 7p14, 7@5, 14q12, and 14qter, which are frequently recombined in rearrangements are also too frequently involved in rearrangements with a few other chromosome sites. Among these sites, the most frequently involved are bands 2p11, 2p12, 22q12, and 22q13.2, or the proximal parts of adjacent R-bands. The same rearrangements were observed in a large series of control lymphocytes but their frequencies were much lower than in ataxia telangiectasia. All these recurrent sites of rearrangements, except 22q13.2, are known to be near or at immunoglobulin genes or partially homologous genes like T-cell receptor genes and antigen Leu-2/T8. It is supposed that the rearrangements observed correspond to the visualization at the chromosomal level of illegitimate rearrangements between these genes, and by analogy, that another similar structure may exist on band 22q13.2. Introduction In patients affected by ataxia telangiectasia (AT) and, to a lesser degree, in non-affected individuals, a high recurrency of rearrangements involving chromosomes 7 and 14 is well known (Aurias et al. 1980; Welch et al. 1975). These rearrangements occur after breakage at two specific sites on each chromosomes: 7p14, 7q35, 14q12, and 14qter, leading to the formation of inv(7)(p14q35), inv(14)(q12qter), t(7;14) (p14;q12), and t(7;14)(q35;q12) in most of the cases. The analysis of large samples of mitoses from AT and non- AT individuals indicates that these four sites also recurrently exchange with other chromosome sites, especially with two sites on chromosome 2 and two on chromosome 22. It is postulated that these rearrangements are favoured by homologous or partially homologous DNA sequences which could be genes for immunoglobulins and partially homologous genes like those of T cell receptors. Material and methods The analysis of 9461 R-banded mitoses from 57 AT patients was performed using a microscope. All the mitoses with an Offprint requests to: A, Aurias, CNRS - U.A. 620, Structure et Mutagdn~se Chromosomiques, Institut Curie, Pavillou Regaud, 26 rue d'ulm, F Paris Cddex 05, France anomaly were photographed and karyotyped. The results were compared to those obtained in the retrospective study of about 100,000 R-banded mitoses of non-at patients studied at the Institut de Progen6se (Professor Lejeune, Paris) and in the prospective study of 5679 karyotypes from five normal controls. Results In AT patients, 1063 non-clonal rearrangements were detected, among which 876 resulted from two breakpoints at least. The distribution of these rearrangements is the following: (1) 592 involving two of the following bands at least: 7p14, 7q35, 14q12, and/or 14qter; (2) 233 involving none of these bands; (3) 51 involving one of these bands and any other one. In this third type of rearrangement, bands 7p14 were involved 11 times, 7q35 eight times, 14q12 20 times, and 14qter nine times. Among the 51 other breakpoints, 48 could be accurately recognized (Fig. 1). Their distribution is clearly not random since 11 breaks affect the centromeric region of chromosome 2, five the long arm of chromosome 22, and three the centromeric region of chromosome 12 and band 13q13. Thus, almost half of the breaks are concentrated in about 2% of the length of the karyotype. Also on both chromosomes 2 and 22, there are two distinct preferential breakpoints. After the use of R-banding they seem to correspond to the following G- bands: 2pll and 2p12, 22q12 and 22q13.2, but breaks might be located at the junction between these bands and the adjacent R-bands or even at the very proximal parts of these R- bands. Furthermore, six of the nine exchanges with 14qter affect band 2p11, three of the 10 exchanges with 7p14 affect band 13q13, and three of the 23 exchanges with 14q12 affect band 12p11. In addition, eight of these 23 exchanges affect telomeric regions of various chromosomes. In non-at patients, the distribution of the various types of rearrangements is different: (1) 171 occurred between bands 7p14, 7@5, 14q12, and/or 14qter. (2) 206 did not affect any of these bands. (3) 28 occurred between one of these bands and any other site. This distribution is probably biased because of inaccurate detection of many rearrangements in the retrospective study and cannot be directly compared to that observed in AT patients. However, in the first type of rearrangement, it has been shown that inv(14)(q12qter) is the most frequent (Aurias et al. 1985) and this inversion represents 68 of the 171 rearrangements. The two major categories of t(7;14) were also frequently observed as previously described (Aurias et al.

2 211 Fill~ :-I,, =,,~,:lt 'lt,~';f! i:*:fl * =1:*!.. 1,4,'~=t,*~.o =l,,,=~ '1,~ i/ 'l~t ;~',,~.,.,., :,,,,,~,,~-,;~,,~.,,5,~? I'.,e =11~,! ~l,+,f! I'1,'~'~ 14 ~, i,_1,, }1,' ~ i~s,e 41]z If 1,4,:11 i,~ il 14~ 11 leo,ill "~ h-p,, =[] 217,t~ ' I~-~'.J~L I~4', $ _,,-l~,sli i=_~ ii x,,,:'" 1~' 1-~Z I~ 4 'I:":P I'~ I,-I':i ~ :I i t! I,~,,_~,I;~:ls I.,.n,l,,.l~ I,~ I'd,= ~ 11= ~-~.1=5=, :zt ' 0 " s:ti =l,':"ij.-,~.. [] ~i il &&& I s jll.fl r,4~i 11?I~-I,',U 14 l,*.li i 15 1H z ~ly~,,'~ I,-i'3,iii ~i~: =s: 21~ doo,l~"ff [] o3--i~ It 1 I,",u 19 i 11N42~ 0 21,~.: u III~,:U " " lirn[]a 'J'= ft 1! Y IS4 0: i 6 ee I:s o~,m X Fig. 1. Distribution of the breakpoints involved in rearrangements with bands 7p14 (triangles), 7q35 (stars), 14q12 (squares), and 14qter (circles) in AT patients (dark) and in controls (open)

3 212 Fig.2. Translocations t(2;7)(p12;q35), t(7;22)(p14;q12), t(2;14) (p12;q12), t(2;14)(p11;qter), t(14;22)(q12;q13.2), and t(14;22) (qter;q12). In each pair, rearranged chromosomes, shown in R-banding, are on the right 1980). The breakpoints of the 28 rearrangements of the third type could be accurately located. For chromosomes 7 and 14, they were at band 7p14 six times, 7q35 eight times, 14q12 ten times, and 14qter four times. The distribution of the 28 other breakpoints, indicated in Fig. 1, is more dispersed than in AT lymphocytes, but six are observed at bands 2p11, 2p12, 22q12, and 22q13.2. The rearrangements resulting from these six breakpoints are identical to those observed in AT lymphocytes. Finally, after pooling AT and non-at samples, the following rearrangements are observed at least twice (Fig. 2): - t(2;14)(pll;qter) : 7times - t(14;22)(q12;q13.2) : 4 times - t(2;7)(p12;q35) : 3 times - t(7;13)(p14;q13) : 3 times - t(12;14)(p11;q12) : 3 times - t(6;14)(p22;q12) : 2times - t(14;15)(q12;qter) : 2times - t(14;22)(qter;q12) : 2times - t(14;17)(q12;q24) : 2times - t(14;17)(q12;p12) : 2times - t(14;19)(q12;pter) : 2times and six sites are affected three times at least; 2pll seven times; 2p12 and 22q13.2 five times; 12p11, 13q13, and 22q12 three times. D i s c u s s i o n It is now well established that four sites located on chromosomes 7 and 14 are frequently involved in acquired rearrange- merits observed in human nonmalignant lymphocytes. This propensity is dramatically increased in lymphocytes from patients affected by ataxia telangiectasia (approximately 25- fold). These four sites are usually involved in exchanges between themselves, the most frequent being inv(14)(q12qter) in non-at and inv(7)(p14q35) in AT lymphocytes (Aurias et al. 1980). In this report, we show that these sites are also more frequently involved in rearrangements than by mere chance with other chromosome sites. After exclusion of rearrangements affecting them only, they correspond to about one tenth of the breakpoints although they should correspond to about one hundredth, assuming a random distribution of breaks along the karyotypes. The specificity of the rearrangements involving these sites is still more striking when the chromosome sites exchanging with them are considered: 20 out of 74 breakpoints are located at the proximal region of the short arm of chromosome 2 and in the long arm of chromosome 22 (Fig. 1). A meticolous analysis of the rearrangements leads us to conclude that two sites exist both in chromosome 2 (2pll and 2p12) and in chromosome 22 (22q12 and 22q13.2) (Fig.2). Possibly other recurrent sites exist like 12p11.1 and 13q13 but the size of our sample is too small to demonstrate this. It would be of interest to determine if this specificity is related to either the structure or the function, or both, of genes located at these sites. Indeed, an obvious relationship can be proposed with immunoglobulin and T-cell receptor genes. On chromosome 14, the genes for IgH have been assigned to the more distal band, i.e., very close to 14qter (Kirsch et al. 1982) and more recently, those for c~-chain of T-cell receptor to 14q11-14q12 (Croce et al. 1985). On chromosome 7, the genes for 13- and 7-chains of T-cell receptor have been assigned to 7q35 and 7p14 respectively (Isobe et al. 1985; Morton et al. 1985; Le Beau et al. 1985; Mure et al. 1985). It is known that each of these clusters of genes undergoes intrinsic rearrangements in relation to immunological maturation. However, although many analogies of composition and structure exist, no rearrangements are known to occur be- Table 1. Postulated rearrangements of immunoglobulin superfamily genes in recurrent chromosomal rearrangements Observed chromosomal rearrangement t(7;7)(p14;q35) ~/7 inv(7) (p14q35) [~/7 inv(14) (ql2qter) a/h t(7;14) (p14;q12) 7/c~ t(7;14)(q35;q12) I~/a t(7;14) (p14;qter) 7/H t (7;14)(q35;qter) 13/H t(14;14)(ql2;qter) cdh t (2;7)(p12;q35) T8/13 t(2;7)(p12;p14) T8/7 t (2; 14) (pl 1 ;qter) K/H t(2;14) (p12;q12) T8/a t(7;22) (p14;q12) 7/;~ t(7;22) (p14;q13.2) 7/? t(14;22) (q12;q13.2) c~/? t (14;22)(qter;ql2) I-I/L Postulated molecular rearrangement

4 213 Fig.3. Chromosomal locations of immunoglobulin superfamily genes tween these clusters at the molecular level. The recurrent rearrangements between bands 7p14, 7q35, 14q12, and 14qter leading to inv(7), inv(14) and various t(7;14) could correspond to illegitimate rearrangements between two different clusters, exhibited at the chromosomal level. For instance, the inv(14), recurrent both in AT and non-at lymphocytes, may correspond to rearrangements between IgH and a-chain of T- cell receptor genes, the inv(7), specially recurrent in AT lymphocytes, to rearrangements between genes of [3- and y-chains of T-cell receptor, and t(7;14), recurrent both in AT and non- AT lymphocytes, to rearrangements between genes of [3- and a- (t(7;14)(q35;q12)) or 7- and a-chains of T-cell receptor (t(7;14)(p14;q12)). Other rearrangements between these genes may occur although more rarely since various other translocations have been occasionally observed: t(7;14) (q35;qter), rearrangement 13/H; t(7;14)(p14;qter), rearrangement 7/H; and t(14;14)(q12;qter), rearrangement a/h. These data are summarized in Table 1. Interestingly, K genes have been assigned to the very proximal region of the short arm of chromosome 2 (Malcolm et al. 1982) and )~ genes to the proximal region of the long arm of chromosome 22 (De la Chapelle et al. 1984). These two regions are precisely those which are the most recurrently involved in rearrangements with bands 7p14, 7@5, 14q12, and 14qter, and it can be expected that these translocations correspond to rearrangements between K or )~ genes and those for IgH and T-cell receptor (Table 1). Recently another gene, coding for T-cell differentiation antigen Leu-2/T8, was found homologous to immunoglobulin and T-cell receptor variable regions and was mapped to the short arm of chromosome 2, near IgK genes, and slightly more distally (Sukhatme et al. 1985). Finally, on chromosome 2, the two sites recurrently involved in translocations that we have found: 2pll and 2p12, may correspond to K and T8 genes respectively. All translocations involving 2pll result from an exchange with band 14qter and could correspond to a rearrangement between K and IgH genes, and all translocations involving 2p12, and thus presumably T8 gene, result from an exchange with either 7p14, 7q35, or 14q12 which all may correspond to T-cell receptor chains locus (Table 1). Up to now, except for Ig)~ genes located in band 22q11.2, no other gene presenting homologies with Ig or T-cell receptor genes have been assigned to chromosome 22. However, as for chromosome 2, 7, and 14, we find two sites of recurrent translocations on this chromosome. The more proximal one may correspond to the )~ gene locus. The more distal one, located at or near 22q13.2, is involved in several translocations with 14q12 and 7p14 and by analogy with chromosomes 2, 7, and 14; it can be expected that it carries a gene presenting homologies with Ig and T-cell receptor genes. To summarize, we conclude that there may be eight chromosomal sites, two located together on chromosomes 2, 7, 14, and 22, presenting homologies favouring their rearrangements detectable at the chromosomal level. Seven out of these eight sites may correspond to Ig and T-cell receptor genes previously mapped and we suppose that the eighth presents homologies with them (Fig. 3). Some of these rearrangements like inv(7) (p14q35), inv(14) (q12qter), t(7;14)(p14;q12), and t(7;14)(q35;q12) are much more recurrent than others like t(7;7)(p14;q35), t(14;14) (ql2;qter), t(7;14)(p14;qter), t(7;14)(q35;qter), t(2;14) (pll;qter), t(14;22)(q12;q13.2) etc... but all are too frequently observed to have occurred by chance. The frequency of some of these rearrangements, like inv(7), being much higher in AT than in non-at lymphocytes, it seems that their occurrence is not only related to the degree of homologies of the involved structures, but also probably to the different selective advantages of the carrier cells. Acknowledgements. This research was supported by grants from Electricit6 de France, EURATOM, Ligue Nationale Fran~aise contre le Cancer. The authors are grateful to their colleagues from the Institut de Progen6se and UA 620 du CNRS for their help in the analysis of control cells, and to Drs. C. Griselli, E. Vilmer, J.Aicardi, M.F. Croquette, and J. P. Nuyts for providing the blood samples of AT patients. References Aurias A, Dutrillaux B, Buriot D, Lejeune J (1980) High frequencies of inversions and translocations of chromosomes 7 and 14 in ataxia telangiectasia. Mutat Res 69 : Aurias A, Couturier J, Dutrillaux AM, Dutrillaux B, Herpin F, Lamoliatte E, Lombard M, Muleris M, Paravatou M, Prieur M, Prod'Homme M, Sportes M, Viegas-Pequignot E, Volobouev V (1985) Inversion (14)(ql2qter) or (qll.2q32.3): the most frequently acquired rearrangement in lymphocytes. Hum Genet 71 : Croce CM, Isobe M, Palumbo A, Puck J, Ming J, Tweardy D, Erikson J, Davis M, Rovera G (1985) Gene for or-chain of human T-cell receptor: location on chromosome 14 region involved in T-cell neoplasms. Science 227 : De La Chapelle A, Lenoir G, Bou6 J, Bou6 A, Gallano C, Huerre C, Jeanpierre M, Kaplan JC (1984) Lambda Ig constant region is localized in band 22qll and translocated to chromosome 8 in Burkitt's lymphoma with t(8;22). In: Human gene mapping 7, 7th International Workshop on Human Gene Mapping. Cytogenet Cell Genet 37 : 436

5 214 Isobe M, Erikson J, Emanuel BS, Nowell PC, Croce C (1985) Location of gene for [3 subunit of human T-cell receptor at band 7q35, a region prone to rearrangements in T-cells. Science 228 : Kirsch IR, Morton CC, Nakahara K, Leder P (1982) Human immunoglobulin heavy chain genes map to a region of translocations in malignant B lymphocytes. Science 216 : Le Beau MM, Diaz MO, Rowley JD, Mak TW (1985) Chromosomal localization of the human T-cell receptor [3-chain genes. Cell 41 : 335 Malcolm S, Barton P, Murphy C, Ferguson-Smith MA, Bentley DL, Rabbits TH (1982) Localization of human immunoglobulin K light chain variable region genes to the short arm of chromosome 2 by in situ hybridization. Proc Natl Acad Sci USA 79 : Morton CC, Duby AD, Eddy RL, Shows TB, Seidman JG (1985) Genes for ~ chain of human T-cell antigen receptor map to regions of chromosomal rearrangement in T-cells. Science 228: Mure C, Waldmann RA, Morton CC, Bongiovanni KF, Waldmann TA, Shows TB, Seidman JG (1985) Human 7-chain genes are rearranged in leukaemic T cells and map to the short arm of chromosome 7. Nature 316: Sukhatme VP, Volmer AC, Erikson J, Isobe M, Croce C, Parnes JR (1985) Gene for the human T-cell differentiation antigen Leu-2/T8 is closely linked to the K light chain locus on chromosome 2. J Exp Med 161 : Welch JP, Lee CLY, Beatty-Desana JW, Hoggard MS, Cooledge JW, Hecht F, Kaiser McCaw B, Peakman D, Robinson A (1975) Nonrandom occurrence of 7-14 translocations in human lymphocytes cultures. Nature 255 : Received October 2, 1985 / Revised November 18, 1985