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No evidence for germlinePTEN mutations in families with breast and brain tumours

1999; Wiley; Volume: 84; Issue: 3 Linguagem: Inglês

10.1002/(sici)1097-0215(19990621)84

1097-0215

Anthony Laug�, C�line Lefebvre, Pierre Laurent‐Puig, Virginie Caux, Sophie Gad, Charis Eng, Michel Longy, Dominique Stoppa‐Lyonnet,

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International Journal of CancerVolume 84, Issue 3 p. 216-219 Human CancerFree Access No evidence for germline PTEN mutations in families with breast and brain tumours Anthony Laugé, Anthony Laugé Unité de Génétique Oncologique, Institut Curie, Paris, FranceSearch for more papers by this authorCéline Lefebvre, Céline Lefebvre Unité de Génétique Oncologique, Institut Curie, Paris, FranceSearch for more papers by this authorPierre Laurent-Puig, Pierre Laurent-Puig Molecular Toxicology Laboratory, Unité INSERM U490, Paris, FranceSearch for more papers by this authorVirginie Caux, Virginie Caux Unité de Génétique Oncologique, Institut Curie, Paris, FranceSearch for more papers by this authorSophie Gad, Sophie Gad Unité de Génétique Oncologique, Institut Curie, Paris, FranceSearch for more papers by this authorCharis Eng, Charis Eng Translational Research Laboratory, Charles A Dana Human Cancer Genetics Unit, Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, and Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge, Cambridge, United KingdomSearch for more papers by this authorMichel Longy, Michel Longy Oncologie Moléculaire, Institut Bergonié, Bordeaux, FranceSearch for more papers by this authorDominique Stoppa-Lyonnet, Corresponding Author Dominique Stoppa-Lyonnet dominique.lyonnet@curie.fr Unité de Génétique Oncologique, Institut Curie, Paris, FranceUnité de Génétique Oncologique, Institut Curie, 26 rue d'Ulm, F-75231 Paris cedex 5, France. Fax: + 33 1 44 32 45 09.Search for more papers by this author Anthony Laugé, Anthony Laugé Unité de Génétique Oncologique, Institut Curie, Paris, FranceSearch for more papers by this authorCéline Lefebvre, Céline Lefebvre Unité de Génétique Oncologique, Institut Curie, Paris, FranceSearch for more papers by this authorPierre Laurent-Puig, Pierre Laurent-Puig Molecular Toxicology Laboratory, Unité INSERM U490, Paris, FranceSearch for more papers by this authorVirginie Caux, Virginie Caux Unité de Génétique Oncologique, Institut Curie, Paris, FranceSearch for more papers by this authorSophie Gad, Sophie Gad Unité de Génétique Oncologique, Institut Curie, Paris, FranceSearch for more papers by this authorCharis Eng, Charis Eng Translational Research Laboratory, Charles A Dana Human Cancer Genetics Unit, Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, and Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge, Cambridge, United KingdomSearch for more papers by this authorMichel Longy, Michel Longy Oncologie Moléculaire, Institut Bergonié, Bordeaux, FranceSearch for more papers by this authorDominique Stoppa-Lyonnet, Corresponding Author Dominique Stoppa-Lyonnet dominique.lyonnet@curie.fr Unité de Génétique Oncologique, Institut Curie, Paris, FranceUnité de Génétique Oncologique, Institut Curie, 26 rue d'Ulm, F-75231 Paris cedex 5, France. Fax: + 33 1 44 32 45 09.Search for more papers by this author First published: 10 November 1999 https://doi.org/10.1002/(SICI)1097-0215(19990621)84:3 3.0.CO;2-ECitations: 15AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Germline mutations of the PTEN gene are involved in Cowden disease, a genetic condition associated with an increased risk of breast cancer. Further somatic PTEN mutations have been found in glioblastomas and to a lesser extent in meningiomas. Therefore, PTEN germline mutations were searched for in a series of 20 unrelated women with breast cancer who also had a personal or familial breast-brain tumour history. Inclusion criteria were 1. family history of breast cancer; 2. absence of germline BRCA1 and p53 mutation; and 3. at least one case of brain tumour (glioblastoma, meningioma, or medulloblastoma) in either the index case or one of their first or second degree relatives. Any stigmata of Cowden disease was an exclusion criteria. Screening of the PTEN gene for point mutations or small rearrangements were performed using the denaturing gradient gel electrophoresis method on the 9 coding exons. No disease-associated mutation of the PTEN gene has been detected in our series. It is, thus, unlikely that PTEN is a significant BRCA predisposing locus. However, one might ask whether breast cancer cases resulting from germline PTEN mutation could occur without any mammary histological feature of Cowden disease. Int. J. Cancer (Pred. Oncol.) 84:216–219, 1999. © 1999 Wiley-Liss, Inc. To date, 3 major and well-established breast cancer predisposing genes, namely BRCA1, BRCA2 and p53, have been identified. Germline BRCA1 and BRCA2 mutations are mostly associated with familial breast and/or ovarian, and with familial site-specific breast cancer history, respectively (Ford et al., 1998, for review), whereas p53 mutations predispose to Li-Fraumeni syndrome characterized by the occurrence of sarcoma, breast, adrenocortical, brain, and hematological tumours in children and young adults (Varley et al., 1997, for review). However, it is now established that other genes must be involved in breast cancer predisposition since several familial cases are not accounted for by the alteration of any of these 3 genes (Ford et al., 1998). The tumour suppressor gene, PTEN/MMAC1/TEP1, is a good candidate since it has been shown that the 10q23 chromosomal region where the PTEN gene is located, is recurrently deleted in gliomas, and to a lesser extent in meningiomas and medulloblastomas (Li et al., 1997; Steck et al., 1997; Rempel et al., 1993; Simon et al., 1995). This gene has been simultaneously cloned using homozygous deleletion mapping in glioblastoma and breast carcinoma cell lines (Li et al., 1997; Steck et al., 1997), and sequence homology with the tyrosine phosphatase motif (Li and Sun, 1997). Apart from dual specificity phosphatase activity, the putative PTEN gene product appears to be involved in cell focal adhesion which might have been predicted because of its homology with tensin (Li et al., 1997; Steck et al., 1997; Li and Sun, 1997; Myers et al., 1997; Tamura et al., 1998). Somatic inactivating mutations of the PTEN gene have been reported in numerous other tumours: endometrium, prostate and to a lesser extent in breast carcinoma (Kong et al., 1997; Cairns et al., 1997; Rhei et al., 1997). Furthermore, germline mutations of the PTEN gene are responsible for Cowden disease (Liaw et al., 1997), a dominantly inherited syndrome characterized by multiple hamartomas of skin, intestine, breast and thyroid, and by an increased risk of breast and thyroid carcinomas; such localized features of the classical Cowden disease might be absent, resulting in an incomplete phenotype (Eng, 1997). PTEN gene alterations have also been reported in Bannayan-Zonana syndrome, mainly characterized by macrocephaly, multiple hemangiomatas and lipomas, highlighting the broad phenotypic heterogeneity of germline PTEN mutations (Marsh et al., 1997). Because germline mutations cause Cowden syndrome, a syndrome which carries a risk for breast cancer and possibly brain tumours, and because somatic mutations in PTEN have been found in glioblastomas and to a lesser extent in meningiomas (Dürr et al.,1998; Peters et al., 1998), we sought to determine whether germline mutation in PTEN could predispose to breast and brain tumours in families without other stigmata of Cowden disease. SUBJECTS AND METHODS Women affected with invasive breast cancer have been ascertained from the family cancer clinic of the Institut Curie according to the following criteria: 1. a family history of breast cancer, 2.the absence of detected germline BRCA1 and p53 mutation, and 3. the diagnosis of primary brain tumour or the presence of at least one case of brain tumour in a first or second degree relative of a breast cancer case. Patients and families were excluded if the following were present: 1. any facial and acral signs, thyroid adenoma and goiter or mammary polyfibroadenomatosis suggestive of Cowden disease in each index case; and 2. Cowden disease cases in the family history report. Patients were informed about the aims and limits of genetic testing for breast cancer predisposition in 2 separate genetic counselling sessions. With their written informed consent, a blood sample was collected. Twenty unrelated women were ascertained according to the above criteria. Moreover, 11 cases have been tested negative for mutation of BRCA2 (Table I). Breast cancer could be verified histologically for all index cases and for 49% of the relatives. The brain tumour histological records have been verified in 14/23 cases (Table I): glial tumours (8/14) (including 4 glioblastomas, 3 astrocytomas and 1 low grade glioma), medulloblastomas (2/14) and meningiomas (4/14). Four women were affected both with brain tumour and breast carcinoma (Table I). Table I. TUMOUR SITE(S) OR HISTOLOGICAL DIAGNOSIS OF BRAIN TUMOUR AND AGE AT DIAGNOSIS IN INDEX CASES AND THEIR FIRST OR SECOND DEGREE RELATIVES OF THE SAME PARENTAL LINEAGE Family Index case First and second- Breast cancer predisposing number degree relatives genes tested/not involved F36 Breast 41 Medulloblastoma 12, Breast 63 BRCA1, BRCA2, p53 F68 Breast 60/glio- Breast 48, Breast 55 BRCA1, BRCA2, p53 blastoma 6911 A slash indicates that the individual was affected with 2 or 3 tumours. F182 Breast 41 Glioma 9, Breast 36, breast 42, breast 70 BRCA1, BRCA2, p53 F332 Breast 33 Brain 45, Breast 38, breast 50 BRCA1, p53 F479 Breast 44 Glioblastoma 55, Breast 52, breast 55 BRCA1, BRCA2, p53 F544 Meningioma 41/ Meningioma 46/breast 55/Meningioma 56 BRCA1, p53 breast 52/ breast 53 F567 Breast 57 Brain 32, Breast 48, breast 54, breast 60 BRCA1, p53 F496 Breast 41 Medulloblastoma 4, Breast 38 BRCA1, p53 F583 Breast 43 Breast 47/astrocytoma 55, Breast 45, ovary 67 BRCA1, BRCA2, p53 F585 Breast 44 Brain 37, Breast 44, breast 46, Melanoma 56, Larynx 52 BRCA1, p53 F612 Breast 31 Astrocytoma 39, Breast 41, breast 46 BRCA1, BRCA2, p53 F659 Breast 49/ Brain 20, Breast 34, breast 60, breast 63, Breast 68, Prostate 76 BRCA1, BRCA2, p53 breast 54 F681 Breast 28 Meningioma 43, Breast 31, breast 43, breast 53, Kidney 63 BRCA1, p53 F707 Breast 38 Brain 8, Breast 35, breast 42, breast 53, Ovary 43 BRCA1, BRCA2, p53 F752 Breast 45 Brain 46, Breast 45/breast 80 BRCA1, p53 F806 Breast 29 Glioblastoma 67 BRCA1, p53 F859 Breast 70 Astrocytoma 42, Breast 47 BRCA1, p53 F1008 Breast 44 Brain 56, Breast 45, breast 49, breast 51, Testis 47, stomach 50 BRCA1, BRCA2, p53 F1063 Breast 41 Brain 45, Breast 26, breast 48, breast 56, Ovary 65 BRCA1, BRCA2, p53 F1074 Breast 61 Glioblastoma 32, brain 5, Breast 41, Choroid melanoma 59 BRCA1, BRCA2, p53 1 A slash indicates that the individual was affected with 2 or 3 tumours. Screening of the PTEN gene for point mutations or small rearrangements was performed by analysis of genomic DNA with the denaturating gradient gel electrophoresis method (DGGE). The 9 coding exons and the flanking intron exon junctions were studied with the exception of the intron 7-exon 8 junction and the first 43 nucleotides of exon 8, where no PCR primers could be chosen. Sequence of primers, PCR and electrophoretic conditions are presented in Table II. DNA extractions were performed by using QIAamp blood kit (Qiagen, Hilden, Germany) according to the manufacturer's instructions. DGGE electrophoretic conditions (gradient and run time) were determined by use of Meltmap and SQHTX softwares. PCR and DGGE were performed according to the methods described by Stoppa-Lyonnet et al. (1997). PCR products showing an electrophoretic variant pattern were directly sequenced on both strands by the fluorometric method with automated sequencing procedures (dRhodamine Terminator Cycle Sequencing Ready Reaction and ABI377 DNA sequencer; Applied Biosystems, Foster City, CA). Table II. PRIMERS AND EXPERIMENTAL CONDITIONS FOR PTEN GENE SCREENING WITH DGGE Amplicon Forward primer 5′ → 3′ Reverse primer 5′ → 3′ Annealing DMSO (5%)/ Size Gradient Run time temperature (°C) MgCl2 (mM) (bp) (%) (hr:min) exon 1 F(GC) CCA TCT CTC TCC TCC TTT TTC TTC GCA TCC GTC TAC TCC CAC 57 Yes/1.5 253 30–80 05:00 exon 2 GTT TGA TTG CTG CAT ATT TCA R(GC) TCT AAA TGA AAA CAC AAC ATG 57 No/1.5 253 10–60 02:00 exon 3 ATT TCA AAT GTT AGC TCA TTT TG R(GC) TTT AGA AGA TAT TTC AAG CAT AC 57 No/2 196 10–60 02:00 exon 4 F(GC) CAT TAT AAA GAT TCA GGC AAT G GAC AGT AAG ATA CAG TCT ATC 57 Yes/1.5 264 10–60 02:00 exon 5 ACC TGT TAA GTT TGT ATG CAA R(GC) TCC AGG AAG AGG AAA GGA AA 55 No/1.5 431 20–70 05:30 exon 6 F(GC) CAT AGC AAT TTA GTG AAA TAA CT GAT ATG GTT AAG AAA ACT GTT C 55 No/1.5 333 20–70 02:00 exon 7 CAG TTA AAG GCA TTT CCT GTG R(GC) GGA TAT TTC TCC CAA TGA AAG 57 No/1 303 10–60 05:00 exon 8 F(GC) GGG TAA ATA CAT TCT TCA TAC CAG G TGT CAA GCA AGT TCT TCA TCA GC 55 Yes/1.5 362 20–70 05:00 exon 9 F(GC) AGA TGA GTC ATA TTT GTG GG ATT TTC ATG GTG TTT TAT CCC TC 57 Yes/2 330 10–60 05:00 GC clamp F(GC): CCC CGC CCG GCC CGC CCC GCC CCC CGC CCC CCC TCC CGG CCC GCC CCC CTG GCG CCC CGC R(GC): CCC CAC GCC ACC CGA CGC CCC AGC CCG ACC CCC CCG CGC CCG GCG CCC CCG C RESULTS Migration patterns of PTEN gene amplicons are shown in Figure 1, as well as mutant control DNAs for amplicons 2–8. A variant pattern detected in amplicon 5 (family F68) led to the detection of the insertion of a T in intron 4 (IVS4–29insT, Fig. 1). The variation did not co-segregate with the breast cancer phenotype in the family and was detected in 4/80 unrelated individuals (5%); this change was thus regarded as a rare polymorphism. A T to G transition was detected in intron 8 at position +32 after sequencing of variant migration patterns. The heterozygozity was 52% in our set (Fig. 1). This was in accordance with previous results indicating that the IVS8+32T/G variant is a common polymorphism (Dahia et al., 1997). In summary, therefore, no disease-associated mutations of the PTEN gene has been detected in our series of 20 breast cancer patients with breast-brain tumour family history. Figure 1Open in figure viewerPowerPoint Normal and variant electrophoretic DGGE profiles of the 9 PTEN gene coding exons and the flanking intron-exon junctions analysed through 9 amplicons. N: normal; C: control (heterozygous mutant); V: variant (heterozygous variant); P: polymorphism;. C2: 962ins4; C3: IVS3+5G/A; C4: IVS4+1G/T; V5: IVS4–29insT; C5: 1108insT; C6: 1369delA; C7: 1527insTT; PA: IVS8+32T (homozygous); PB: IVS8+32G (homozygous), PAB: IVS8+32T/G (heterozygous); C8: 1785delA and IVS8+32T/G. DISCUSSION Focused analysis of a subset of familial breast cancer families may be useful in identifying new predisposing genes as this strategy might decrease the genetic heterogeneity and therefore increase the power of studies looking for candidate genes. Given the existing germline and somatic PTEN data in Cowden syndrome and sporadic brain tumours, PTEN was a plausible candidate gene for families and individuals with breast and brain tumours. However, our results show hat germline PTEN gene alterations are not likely to be involved in breast-brain tumour familial cases without clinical features of Cowden disease. Both the abnormal migration patterns of mutant controls for amplicons 2–8, and the known efficiency of DGGE detection of point mutations and small gene alterations, exclude the possibility that the DGGE could have missed numerous mutations (Grompe, 1993). It may be noticed, however, that large rearrangements would have escaped our mutation detection strategy but this is no more so than any PCR-based technology, even gold standard sequencing. Moreover, the small number of cases, 20, and the histological heterogeneity of brain tumours in our series might have led to limited detection of a relatively small proportion of germline PTEN gene mutations in breast cancer predisposition associated with brain tumours. Even with 20 families, if 15% of such families carried germline PTEN mutations, the power to detect at least one mutation in our set, is as high as 0.96. At 10%, the power is still 0.88. Nonetheless, it would be desirable to perform analysis of a larger family set and the restriction of inclusion criteria to glioblastoma which is the brain tumour in which the PTEN gene is most frequently inactivated, and could be helpful for accurately estimating the proportion of PTEN gene alterations in breast-brain tumour family cases. One could also ask whether breast cancer may occur in women carrying a germline PTEN mutation without the severe polyfibroadenomatosis which is the architectural abnormality characteristic of breast tissue in Cowden disease. The homology between PTEN and tensin proteins suggests that PTEN might play a role in cell-cell interactions and, therefore, in correct glandular tissues development. The germlinealteration of a single PTEN allele might be sufficient to disrupt the normal pattern of architectural development in breast, skin and thyroid tissues, tissues often involved in Cowden disease. Indeed, loss of heterozygosity (LOH) at the PTEN locus is quite rare in hamartomas from Cowden patient (20%, Marsh et al., 1998b). Conversely, alteration of both PTEN alleles resulting in complete inactivation of the phosphatase activity of the PTEN protein, might be required for carcinogenic progression, thus fitting the classic tumour suppressor gene model (Haber and Harlow, 1997). Therefore, in tissues where PTEN haplo-insufficiency pertains (breast, thyroid and colonic), malignant development would be expected in hamartomatosis tissues only. Such hypothesis appears to be confirmed by 2 recent studies of the PTEN gene in breast cancer families where PTEN gene mutations were detected only in families with Cowden disease features (Tsou et al., 1997; Lynch et al., 1997), although a single family (2%) with breast carcinoma, thyroid disease and endometrial carcinoma, without other Cowden features, was found to have an occult germline PTEN mutation (Marsh et al., 1998a). Complementary studies of the PTEN gene in women with isolated severe mammary fibrocystic disease may allow us to estimate the contribution of PTEN gene mutations in such disease and consequently to breast cancer predisposition in the general population. Acknowledgements We thank the patients for their cooperation, Dr. L.S. Lerman for providing Melt87 and SQHTX computer program and Mr. S. Tsakas for his help in software installation. We thank Drs. P. Kerbrat, L. Desjardins and the Institut Curie Breast Cancer Group for referring patients. CE is the Lawrence and Susan Marx Investigator in Human Cancer Genetics and a Barr investigator. This work complies with the French bioethics law (July 1994). REFERENCES Cairns, P., Okami, K., Halachmi, S., Halachmi, N., Estellet, M., Herman, J.G., Jen, J., Isaacs, W.B., Bova, G.S., and Sidransky, D., Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res., 57, 4997– 5000 (1997). 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