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Somatic Loss of Maternal Chromosome 11 Causes Parent-Of-Origin-Dependent Inheritance in SDHD-Linked Paraganglioma and Phaeochromocytoma Families

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Somatic Loss of Maternal Chromosome 11 Causes Parent-Of-Origin-Dependent Inheritance in SDHD-Linked Paraganglioma and Phaeochromocytoma Families Oncogene (2004) 23, 4076–4083 & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $25.00 www.nature.com/onc Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families Erik F Hensen1,2, Ekaterina S Jordanova2, Ivonne JHM van Minderhout3, Pancras CW Hogendoorn2, Peter EM Taschner3, AndelGL van der Mey 1, Peter Devilee2,3 and Cees J Cornelisse*,2 1Department of Otolaryngology and Head and Neck Surgery, Leiden University Medical Centre, Albinusdreef 2, H4Q, 2333 ZA, Leiden, The Netherlands; 2Department of Pathology, Leiden University Medical Center, Albinusdreef 2, L1Q, 2333 ZA, Leiden, The Netherlands; 3Department of Human Genetics, Wassenaarseweg 72, 2333 AL, Leiden University Medical Center, Leiden, The Netherlands Germline mutations in succinate dehydrogenase subunits Introduction B, C and D (SDHB, SDHC and SDHD), genes encoding subunits of mitochondrial complex II, cause hereditary Paragangliomas (PGL) of the head and neck are paragangliomas and phaeochromocytomas. In SDHB neuroendocrine tumours arising in branchiomeric and (1p36)- and SDHC (1q21)-linked families, disease in- intravagalparaganglia.They are rare, highlyvascular, heritance is autosomal dominant. In SDHD (11q23)- mostly benign tumours usually characterized by an linked families, the disease phenotype is expressed only indolent growth pattern. Paragangliomas, like normal upon paternal transmission of the mutation, consistent paraganglia, consist of two cell types: the type I or chief with maternal imprinting. However, SDHD shows bialle- cells, which represent the neoplastic population in lic expression in brain, kidney and lymphoid tissues paragangliomas (van Schothorst et al., 1998a), and the (Baysal et al., 2000). Moreover, consistent loss of the type II or sustentacular cells. The most common site is wild-type (wt) maternal allele in SDHD-linked tumours the carotid body, a chemoreceptive organ in the suggests expression of the maternal SDHD allele in bifurcation of the carotid artery that senses oxygen normal paraganglia. Here we demonstrate exclusive loss levels in peripheral blood in a way that is not yet fully of the entire maternal chromosome 11 in SDHD-linked understood. Most paragangliomas appear to be spora- paragangliomas and phaeochromocytomas, suggesting dic, but a significant minority of the cases (10–50%) has that combined loss of the wt SDHD allele and maternal been shown to be familial. Recently, several genes have 11p region is essential for tumorigenesis. We hypothesize been implicated in these familial forms of the disease. that this is driven by selective loss of one or more Analysis of families carrying the PGL1 gene revealed imprinted genes in the 11p15 region. In paternally, but not germline mutations in the succinate dehydrogenase in maternally derived SDHD mutation carriers, this can complex-subunit D (SDHD) gene on 11q23 (Baysal be achieved by a single event, that is, non-disjunctional et al., 2000). This gene encodes a mitochondrialprotein, loss of the maternal chromosome 11. Thus, the exclusive an anchoring subunit of the mitochondrialrespiratory paternal transmission of the disease can be explained by a chain complex II. Subsequently, mutations in other somatic genetic mechanism targeting both the SDHD subunits of the same mitochondrial complex II were also gene on 11q23 and a paternally imprinted gene on found to be associated with hereditary paraganglioma. 11p15.5, rather than imprinting of SDHD. The SDHB gene (1p36.1–p35) encodes a catalytic Oncogene (2004) 23, 4076–4083. doi:10.1038/sj.onc.1207591 subunit of mitochondrialcomplexII and has been Published online 5 April 2004 implicated in familial paraganglioma of the head and neck as well as in familial paraganglioma of the adrenal Keywords: paraganglioma; phaeochromocytoma; im- medulla, better known as pheochromocytoma (Astuti printing; SDHD; inheritance; monosomy 11 et al., 2001). Both SDHD and SDHB appear to act as tumour-suppressor genes in hereditary paraganglioma. The SDHC gene (1q21) encodes the second anchoring subunit of the mitochondrialcomplexII and mutations in this gene have recently been shown to cause hereditary paraganglioma as well (Niemann and Muller, 2000). Furthermore, a hereditary paraganglioma family *Correspondence: CJ Cornelisse; E-mail: [email protected] with linkage to a region on 11q13.1, the PGL2 locus, has Received 22 October 2003; revised 23 January 2004; accepted 30 January been described (Mariman et al., 1993). However, no 2004; Published online 5 April 2004 mitochondrial complex II genes are known to be located Somatic loss of chromosome 11 mimics imprinting of SDHD EF Hensen et al 4077 in this region. Interestingly, strikingly different inheri- tance patterns have been found for paragangliomas of different genetic background. Whereas SDHB-and SDHC-linked pedigrees show autosomal dominant inheritance, SDHD- and PGL2-linked pedigrees exhibit a clear parent-of-origin effect: inheritance of paragan- glioma occurs in an autosomal dominant way only when paternally transmitted, while no phenotype develops after maternaltransmission. This pattern is consistent in all SDHD- linked pedigrees, and suggests sex-specific epigenetic modification of the maternal SDHD allele, consistent with genomic imprinting (van der Mey et al., 1989). However, no evidence of a physicalimprint, for example, methylation of the 11q22.1–23 region, has been found. Furthermore, the SDHD gene is biallelicly expressed in human brain, kidney and lymphoid tissue (Baysal et al., 2000). It has been suggested that the imprinting of SDHD is restricted to the paraganglia cells, but loss of the maternal SDHD allele is frequently observed in paraganglioma from SDHD-mutation carriers, an event that is unlikely to promote tumour growth when the maternal allele is already silenced by an imprint (Baysal et al., 1997, 2000; Dannenberg et al., 2001). We hypothesized that somatic, selective loss of the whole maternal chromosome 11 could explain the exclusive paternal inheritance of the disease, mimicking maternalimprinting of the SDHD gene. We performed fluorescent in situ hybridisation (FISH) studies on 23 SDHD-linked tumours using different probe sets in order to test for loss of chromosome 11, and loss of heterozygosity (LOH) analysis using several microsatel- lite markers to determine the parental origin of the lost chromosome. Complete loss of a chromosome 11 copy was found in all tumours, and LOH analysis on a subset of seven tumours from patients for whom parental DNA samples were available revealed the exclusive Figure 1 Results obtained from interphase FISH analysis of maternalorigin of the lostchromosome. We propose paraffin-embedded sections of five SDHD-linked paragangliomas that the selective loss of the maternal chromosome 11 (P1–5). (a) Frequency distribution of signals obtained with the centromere 1 (PUC1.77) probe (upper panel) and the centromere copy is driven by the allelic phasing of the SDHD 11 (pLC11A) (lower panel). Compared to chromosome 1, there is a germline mutation and a paternally imprinted tumour- clear loss of chromosome 11 centromere signals. More than two suppressor gene on 11p15. chromosome 1 signals are observed in 9–17% of the nuclei, indicating aneuploidy or tetraploidy. (b) Loss of centromere 11 relative to centromere 1 signals (red and orange) is observed in 46– 65% of the nuclei. Loss of centromere 1 signals relative to centromere 11 (‘other combinations’) is 2–11% Results We started with FISH experiments on tissue sections from five paragangliomas from D92Y carriers. The signals for chromosome 11, whereas of the nuclei with rationale for initially choosing sections rather than cell only one signal for chromosome 1, 0–7% had no signals suspensions was the expectation that this would facil- for chromosome 11. itate the visual selection of nuclei of the type I (chief) To exclude the possibility that loss of signals due to cells. The sections were hybridized with centromere tissue sectioning could have interfered with the results, probes for chromosomes 11 and 1, the latter chromo- we next hybridized isolated whole nuclei of 10 para- some serving as a ploidy reference. Loss of centromere gangliomas, three of which were also studied in the first 11 relative to centromere 1 was found in all tumours, in study. Whereas the use of suspensions precluded the 45–65% of nuclei (Figure 1). Of the nuclei with three selection of type I cells, evaluation of an unselected signals for chromosome 1, 13–54% had two signals for sample of 200 nuclei still demonstrated the relative loss chromosome 11, 5–54% had one signalfor chromosome of centromere 11 in all samples in 35–63% of nuclei 11 and 5–32% had no signals for chromosome 11. Of (Figure 2). To discriminate between loss of the entire the nuclei with two signals for chromosome 1, 44–66% chromosome and subchromosomal loss due to complex had one signalfor chromosome 11 and 8–31% had no rearrangements, we next analysed isolated whole nuclei Oncogene Somatic loss of chromosome 11 mimics imprinting of SDHD EF Hensen et al 4078 Figure 2 Interphase FISH results from isolated whole nuclei of 10 SDHD-linked paragangliomas (P1–10). (a) Frequency distribution of signals obtained with the centromere 1 (PUC1.77) probe (upper panel) and the centromere 11 (pLC11A) probe (lower panel). Compared to chromosome 1, there is a clear loss of chromosome 11 centromere signals. More than two chromosome 1 signals are observed in 12–40% of the nuclei, indicating aneuploidy or tetraploidy. (b) Loss of centromere 11 relative to centromere 1 signals (red and orange) is observed in 35–63% of the nuclei. Loss of centromere 1 signals relative to centromere 11 (‘other combinations’) is negligible (0–1%) of nine paragangliomas and two pheochromocytomas of paraganglioma and 31–62% of pheochromocytoma from D92Y mutation carriers that were not used in the nuclei (Figure 4a). previous studies, using a triple colour FISH technique. Next, we used BAC probes for the subtelomeric This allows simultaneous detection of two probes on regions of 11p and 11q, with the centromere 1 probe as a chromosome 11 and one probe on centromere 1 reference (Figure 3b and d).
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