Human Molecular Genetics

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Human Molecular Genetics

Pages 1461-1472

©1999 Oxford University Press

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PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome
Introduction
Results
   PTEN mutation scanning in BRR and BRR/CS overlap families
   Genotype-phenotype analyses within the BRR and BRR/CS overlap cohort
   Genotype-phenotype analyses between the CS, BRR/CS and BRR groups
   Hemizygosity analysis in PTEN mutation-negative BRR and BRR/CS
   Fine mapping of 46XY, del(10)(q23.2-q24.1)
Discussion
Materials And Methods
   Patients
   Cultured skin fibroblasts
   DNA preparation
   PTEN mutation scanning
   Intragenic and flanking microsatellite marker analyses
   Genotype-phenotype analyses
Acknowledgements
References

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PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome

Debbie J. Marsh¹, Jennifer B. Kum¹, Kathryn L. Lunetta², Michael J. Bennett³, Robert J. Gorlin⁴, S. Faisal Ahmed⁵, Joann Bodurtha⁶, Carol Crowe⁷, Mary A. Curtis⁸, Majed Dasouki⁹, Teresa Dunn¹⁰, Howard Feit¹¹, Michael T. Geraghty¹², John M. Graham Jr¹³, Shirley V. Hodgson¹⁴, Alasdair Hunter¹⁵, Bruce R. Korf¹⁶, David Manchester¹⁷, Susan Miesfeldt¹⁸, Victoria A. Murday¹⁹, Katherine L. Nathanson²⁰, Melissa Parisi²¹, Barbara Pober²², Corrado Romano²³, John L. Tolmie²⁴, Richard Trembath²⁵, Robin M. Winter²⁶, Elaine H. Zackai²⁰, Roberto T. Zori²⁷, Liang-Ping Weng¹, Patricia L. M. Dahia¹, Charis Eng^{1, 28, *}

¹Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center, 690C Medical Research Facility, 420 West 12th Avenue, Columbus, OH 43210, USA and Charles A. Dana Human Cancer Genetics Unit, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA, ²Department of Biostatistical Science, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA 02115, USA, ³Department of Pathology and Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75235, USA, ⁴Departments of Oral Pathology and Medical Genetics, University of Minnesota, Minneapolis, MN 55455, USA, ⁵Department of Paediatrics, University of Cambridge Clinical School, Cambridge CB2 2QQ, UK, ⁶Clinical Genetics, Children's Hospital, Richmond, VA 23220, USA, ⁷Department of Pediatrics, Metro Health Medical Center, Cleveland, OH 44109, USA, ⁸Clinical Genetics Program, Arkansas Children's Hospital, Little Rock, AR 72202, USA, ⁹Division of Genetics, Vanderbilt University Medical Center, Nashville, TN 37232, USA, ¹⁰Human Genetics, Mount Sinai Medical Center, New York, NY, USA, ¹¹Department of Medical Genetics, Henry Ford Hospital, Detroit, MI 48202, USA, ¹²Department of Medical Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA, ¹³Clinical Genetics and Dysmorphology Service, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA, ¹⁴Medical and Molecular Genetics, United Medical and Dental Schools of Guy's, St Thomas' and King's Hospitals, London, UK, ¹⁵Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, Canada, ¹⁶Clinical Genetics, Children's Hospital, Boston, MA 02114, USA, ¹⁷Clinical Genetics Service, University of Colorado School of Medicine, Denver, CO, USA, ¹⁸Cancer Genetics Program, University of Virginia School of Medicine, Richmond, VA, USA, ¹⁹Clinical Genetics, St George's Hospital Medical School, London SW17 0RE, UK, ²⁰Department of Medical Genetics, Children's Hospital of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia, PA, USA, ²¹Division of Medical Genetics, Children's Hospital and Regional Medical Center, Seattle, WA 98105, USA, ²²Medical Genetics, Yale University School of Medicine, New Haven, CT, USA, ²³Department of Paediatrics and Genetic Counseling Service, Oasi Institute, Troina, Italy, ²⁴Duncan Guthrie Institute of Medical Genetics, Glasgow G3 8SJ, UK, ²⁵Medical Genetics, University of Leicester School of Medicine, Leicester, UK, ²⁶Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust, London WC1N 1EH, UK, ²⁷Clinical Genetics, University of Florida, Gainsville, FL, USA and ²⁸Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge, Cambridge CB2 2QQ, UK

Received February 17, 1999; Revised and Accepted April 30, 1999

Germline mutations in the tumour suppressor gene PTEN have been implicated in two hamartoma syndromes that exhibit some clinical overlap, Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR). PTEN maps to 10q23 and encodes a dual specificity phosphatase, a substrate of which is phosphatidylinositol 3,4,5-triphosphate, a phospholipid in the phosphatidylinositol 3-kinase pathway. CS is characterized by multiple hamartomas and an increased risk of benign and malignant disease of the breast, thyroid and central nervous system, whilst the presence of cancer has not been formally documented in BRR. The partial clinical overlap in these two syndromes is exemplified by the hallmark features of BRR: macrocephaly and multiple lipomas, the latter of which occur in a minority of individuals with CS. Additional features observed in BRR, which may also occur in a minority of CS patients, include Hashimoto's thyroiditis, vascular malformations and mental retardation. Pigmented macules of the glans penis, delayed motor development and neonatal or infant onset are noted only in BRR. In this study, constitutive DNA samples from 43 BRR individuals comprising 16 sporadic and 27 familial cases, 11 of which were families with both CS and BRR, were screened for PTEN mutations. Mutations were identified in 26 of 43 (60%) BRR cases. Genotype-phenotype analyses within the BRR group suggested a number of correlations, including the association of PTEN mutation and cancer or breast fibroadenoma in any given CS, BRR or BRR/CS overlap family (P = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family (P = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in BRR patients (P = 0.028). In contrast to a prior report, no significant difference in mutation status was found in familial versus sporadic cases of BRR (P = 0.113). Comparisons between BRR and a previously studied group of 37 CS families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CS alone or both CS and BRR when compared with BRR alone (P = 0.002). Among CS, BRR and BRR/CS overlap families that are PTEN mutation positive, the mutation spectra appear similar. Thus, PTEN mutation-positive CS and BRR may be different presentations of a single syndrome and, hence, both should receive equal attention with respect to cancer surveillance.

INTRODUCTION

Bannayan-Riley-Ruvalcaba (BRR) syndrome and Cowden syndrome (CS) are two hamartoma syndromes displaying both clinical and genetic overlap. Hamartomas are developmentally disorganized, benign growths and occur in multiple organ systems in CS including the breast, thyroid, skin, central nervous system and gastrointestinal tract (1-5). Trichilemmomas, benign tumours of the hair follicle infundibulum, as well as mucocutaneous papules are hallmark hamartomas of CS, occurring in 99% of CS patients (2-5), but are not considered to be true components of BRR. Other hamartomas occurring frequently in CS include breast fibroadenomas (70% of affected females), thyroid adenomas and multinodular goitre (40-60% of all CS patients), and gastrointestinal polyps (35-40% of affected individuals). Thirty-eight per cent of CS patients have megencephaly or macrocephaly. CS patients also have an increased lifetime risk of developing breast and thyroid cancer. Breast cancer develops in 25-50% of affected females and thyroid cancer in 3-10% of all affected individuals (4,5). Malignant and benign disease is also seen in the central nervous system in ~40% of cases (4). Lhermitte-Duclos disease (LDD), also a feature of CS, describes dysplastic gangliocytoma of the cerebellum which manifests as seizures, tremors and poor coordination (6-9).

BRR is characterized by the classic triad of macrocephaly, lipomatosis and pigmented macules of the glans penis (speckled penis) (10-12). Some features of BRR, such as pigmented macules of the glans penis and very early age of onset, have never been reported in CS. Other BRR component features such as macrocephaly, lipomatosis, haemangiomas, Hashimoto's thyroiditis, mental and developmental delay can be quite common in BRR but occur only in the minority of CS patients. It is of note that an increased risk of malignancy has not been formally documented in BRR.

Germline mutations in the tumour suppressor PTEN have been found in 13-81% of CS patients (13-16) and 57-60% of BRR cases (16,17). PTEN maps to 10q23 and encodes a dual-specificity phosphatase which has homology to the focal adhesion molecules tensin and auxilin (18-21). A classic phosphatase (PTPase) core motif is encoded within exon 5 of this gene. One of PTEN's major endogenous substrates is phosphotidylinositol 3,4,5-triphosphate [Ptd-Ins(3,4,5)P₃], a phospholipid in the phosphatidylinositol 3-kinase (PI-3 kinase) pathway (22-24) which previously has been established to be important in cell growth signalling (25). In this pathway, PTEN may act as a 3-phosphatase to dephosphorylate Ptd-Ins(3,4,5)P₃ to Ptd-Ins(4,5)P₂. Mutant or decreased PTEN leads to the accumulation of Ptd-Ins(3,4,5)P₃, which is required for activation of protein kinase B (PKB)/Akt, a known cell survival factor (22-24,26).

In the present study, we have performed PTEN mutation analysis in 43 unrelated BRR cases, including a subset of 11 families with both BRR and CS, and compared these data with those found in a previous study of 37 CS families (16). Genotype-phenotype correlations were sought both within the BRR group and between the CS and BRR groups in an attempt to identify trends unique to either group or alternatively which support the hypothesis that BRR and CS are different presentations of the same syndrome.

RESULTS

PTEN mutation scanning in BRR and BRR/CS overlap families

Constitutive DNA from 43 unrelated patients with BRR (32 with BRR alone and 11 with both BRR and CS) were screened for germline PTEN mutations using denaturing gradient gel electrophoresis (DGGE). DGGE variants were then sequenced. Germline PTEN mutations, including point missense or nonsense mutations, insertions, deletions, deletion-insertions, splice site mutations, gross deletion and a balanced translocation were identified in 60% (26 of 43) of BRR cases (Table 1). Where possible, the screening of both affected and unaffected relatives showed that these mutations segregated with the disease phenotype. These mutations were observed along the entirety of the gene, with the exception of exons 1, 4 and 9 (Fig. 1A), a very similar mutation spectrum to that found in 37 CS families (16) (Fig. 1B). No significant difference was observed between the presence of mutations in the apparently sporadic cases of BRR (seven of 16, 44%) compared with that in familial cases of BRR (19 of 27, 70%) (P = 0.113). Ten of the 11 (91%) BRR/CS overlap families were shown to have germline PTEN mutation.

A

B

Figure 1. (A) PTEN mutations in BRR and BRR/CS overlap families. The PTPase core motif is indicated in exon 5. Truncating-type mutations are recorded in the lower portion of the figure and missense mutations in the upper portion. The presence of a phenotype is indicated by a shaded box in one of six positions as described in the figure. (B) PTEN mutations in CS families. Truncating-type mutations are presented in the lower portion of the figure and missense in the upper portion.

Table 1. PTEN mutations in BRR and BRR/CS overlap patients

Family identifier	Phenotype	Familial/sporadic	Mutation	Exon/IVS
Ban1	BRR	sporadic	A34D	exon 2
Ban2	BRR	sporadic	Y68H	exon 3
Ban3 (BSNa)	BRR	sporadic	IVS3+1G->A	IVS3
Ban4	BRR	sporadic	C105Y	exon 5
B/CS1	BRR/CS	familial	Q110X	exon 5
Ban5	BRR	familial	c.324delG	exon 5
B/CS2	BRR/CS	familial	R130X	exon 5
B/CS3	BRR/CS	familial	R130X	exon 5
Ban6 (B322/B383a)	BRR	familial	R130X	exon 5
Ban7	BRR	familial	I135V	exon 5
B/CS4	BRR/CS	familial	c.441insAdelGG	exon 5
Ban8	BRR	familial	S170R	exon 5
Ban9	BRR	familial	c.520-544del25	exon 6
B/CS5	BRR/CS	familial	IVS6-1G->C	IVS6
Ban10	BRR	familial	IVS6+5G->T	IVS6
Ban11	BRR	familial	R233X	exon 7
Ban12	BRR	sporadic	R233X	exon 7
Ban13 (B172/B173/B1016a)	BRR	familial	P246L	exon 7
B/CS6	BRR/CS	familial	IVS7-4insT	IVS7
Ban14	BRR	sporadic	c.866insCT	exon 8
Ban15	BRR	familial	c.950-953delTACT	exon 8
B/CS7	BRR/CS	familial	c.987-990delTAAA	exon 8
B/CS8	BRR/CS	familial	R335X	exon 8
Ban16	BRR	sporadic	IVS8-8G->A	IVS8
Ban17	BRR	sporadic	46XY, del(10)(q23.3-q24.1)	gross deletion
Ban18	BRR	sporadic	46XY, t(10;13)(q23.2;q33)	balanced translocation
B/CS9	BRR/CS	familial	no mutation	-
Ban19	BRR	familial	no mutation	-
Ban20	BRR	sporadic	no mutation	-
Ban21	BRR	sporadic	no mutation	-
Ban22	BRR	familial	no mutation	-
Ban23	BRR	sporadic	no mutation	-
Ban24	BRR	familial	no mutation	-
Ban25	BRR	familial	no mutation	-
Ban26	BRR	sporadic	no mutation	-
Ban27	BRR	familial	no mutation	-
Ban28	BRR	familial	no mutation	-
Ban29	BRR	sporadic	no mutation	-
Ban30	BRR	sporadic	no mutation	-
Ban31	BRR	sporadic	no mutation	-
Ban32	BRR	sporadic	no mutation	-
Ban33	BRR	familial	no mutation	-
Ban34 (B85a)	BRR	sporadic	no mutation	-

^aMutation analysis was performed on DNA extracted from cultured skin fibroblasts.

Four nonsense point mutations were common to both CS and BRR or BRR/CS overlap families. These were Q110X (one CS, one BRR/CS), R130X (two CS, two BRR/CS, one BRR), R233X (two CS, two BRR) and R335X (one CS, one BRR/CS). Interestingly, while both gross deletion, 46XY, del(10)(q23.2-q24.1), and balanced translocation, 46XY, t(10;13)(q23.2;q33), were observed in BRR, such gross genetic abnormalities were not seen in CS.

Genotype-phenotype analyses within the BRR and BRR/CS overlap cohort

A number of genotype-phenotype associations were identified within and between the BRR and BRR/CS groups. Compared with the BRR-only group, the distinguishing features in the 11 BRR/CS families were a minimum of one individual with BRR, and an individual(s) with either cancer or breast fibroadenomas in conjunction with trichilemmomas or papillomatous papules [i.e. a CS (4) rather than BRR phenotype]. Within the BRR and BRR/CS group, the presence of a germline PTEN mutation was associated with lipomatosis (P = 0.028, Table 2). It is of note that in the combined BRR and BRR/CS group, the presence of a PTEN mutation was associated with the presence of either cancer or breast fibroadenoma (i.e. traditionally, a CS phenotype) in any given family (P = 0.014). Similarly, a correlation between truncating PTEN mutations and the presence of cancer or breast fibroadenoma was identified (P = 0.024, Table 2).

Table 2. Correlations between BRR and BRR/CS phenotypes and PTEN mutations

Phenotype	Mutation	No mutation	P-valuea
Cancer or breast fibroadenoma present	11	1
Cancer or breast fibroadenoma absent	15	16 (n = 43)	0.014
Lipoma(s) present	25	12
Lipoma(s) absent	1	5 (n = 43)	0.028
Sporadic BRR	7	9
Familial BRR	19	8 (n = 43)	0.113
Phenotype	Truncating mutation	Non-truncating mutation
Cancer or breast fibroadenoma present	10	0
Cancer or breast fibroadenoma absent	8	6 (n = 24)	0.024
Phenotype	Mutation frequencies (%)
CS	81
BRR	60
BRR/CS	91

^aDetermined by Fisher's exact test (two-tailed).

Correlations were not identified between the presence of a PTEN mutation and intestinal polyps, speckled penis or café-au-lait spots, thyroid involvement or haemangiomas (P = 0.154-1.000). With the exception of cancer and breast fibroadenomas (see above), no additional correlations could be made between phenotype and mutation position (5[prime] of or within the PTPase core motif versus 3[prime] of the core motif) or type (truncating or non-truncating) in the mutation-positive BRR and BRR/CS cases (P = 0.166-1.000).

Genotype-phenotype analyses between the CS, BRR/CS and BRR groups

Prior to making comparisons across the three groups, four hypotheses were generated. The first hypothesis was that there would be a statistically significant difference in the frequency of PTEN mutations in CS patients compared with BRR patients. The mutation frequencies in the CS only series (81%, n = 37) and the CS/BRR overlap cases (91%, n = 11) were similar and, hence, were grouped together to test our first hypothesis. A significant difference was observed in mutation frequency between the grouped CS plus BRR/CS families (83%, n = 48) and the entire BRR-only set (50%, n = 32) (P = 0.002, Table 3). Similarly, the mutation frequency of the combined CS plus BRR/CS group was also different from that of the familial BRR-only set (P = 0.041, Table 3).

Table 3. Correlations between PTEN mutation and the alternative family groupings of CS-only versus BRR/CS versus BRR-only

Test 1. Mutation present/absent
Phenotype grouping	Present	Absent	P-valuea
Test 1a
CS	30	7
BRR/CS	10	1
BRR (familial only)	9	7 (n = 64)	0.086
BRR (familial + sporadic)	16	16 (n = 80)	0.005
Test 1b
CS and CS/BRR	40	8
BRR (familial only)	9	7 (n = 64)	0.041
BRR (familial + sporadic)	18	16 (n = 80)	0.002
Test 1c
CS	30	7
BRR/CS + BRR (familial)	19	8 (n = 64)	0.378
BRR/CS + BRR (familial + sporadic)	26	17 (n = 80)	0.053
Test 2. Mutation type (truncating/non-truncating)
Phenotype grouping	Truncating	Non-truncating	P-valuea
Test 2a
CS	24	6
BRR/CS	10	0
BRR (familial only)	6	3 (n = 49)	0.142
BRR (familial + sporadic)	8	6 (n = 54)	0.050
Test 2b
CS + CS/BRR	34	6
BRR (familial only)	6	3 (n = 49)	0.336
BRR (familial + sporadic)	8	6 (n = 54)	0.057
Test 2c
CS	24	6
BRR/CS + BRR (familial only)	16	3 (n = 49)	1.000
BRR/CS + BRR (familial + sporadic)	18	6 (n = 54)	0.748
Test 3. Mutation position relative to core (5[prime] and within core/3[prime] of core)
Phenotype grouping	5[prime] and within core	3[prime] of core	P-valuea
Test 3a
CS	16	14
BRR/CS	3	7
BRR (familial only)	2	7 (n = 49)	0.182
BRR (familial + sporadic)	7	8 (n = 55)	0.477
Test 3b
CS + CS/BRR	19	21
BRR (familial only)	2	7 (n = 49)	0.267
BRR (familial + sporadic)	7	8 (n = 55)	1.000
Test 3c
CS	16	14
BRR/CS + BRR (familial only)	5	14 (n = 49)	0.081
BRR/CS + BRR (familial + sporadic)	10	15 (n = 55)	0.419
Test 4. Mutations within the motif
Phenotype grouping	Point nonsense	Point missense	P-valuea
CS	CS	2
All BRR	0	3 (n = 10)	0.167

^aDetermined by Fisher's exact test (two-tailed).

The second and third hypotheses were based on genotypic differences between CS and BRR, i.e. that there would be different mutational spectra (truncating versus non-truncating, and 5[prime] versus 3[prime] of the core motif) between these two syndromes. Independently of the patient groupings, i.e. whether the BRR/CS patients were analysed as a separate group or included with familial BRR, familial and sporadic BRR or CS alone, the mutational spectra based on position and type of mutation were not significantly different (P > 0.05, Table 3).

The fourth hypothesis relates to mutations within the core motif. Of the 26 mutations identified in BRR patients, only three cases (two BRR/CS and one BRR family) representing 12% of mutations identified were located in the PTPase core motif. All three of these families had the nonsense mutation R130X. In the previous CS study, 23% of mutations, both nonsense (five) and missense (two) point mutations, were found in the core motif (Fig. 1B). Although the numbers were small, the difference between point missense and nonsense mutations in the core motif in CS versus BRR was not found to be significant (P = 0.167, Table 3).

Hemizygosity analysis in PTEN mutation-negative BRR and BRR/CS

Rare BRR patients have been found to have gross deletion of 10q23 including PTEN. Thus, all PTEN mutation-negative probands were analysed for the possibility of germline whole gene deletion. In order to assess for hemizygosity at this locus, three flanking dinucleotide repeat markers and five intragenic polymorphic markers were used to amplify constitutive DNA from the affected individuals (Fig. 2A). Heterozygosity at a particular marker was used as the exclusion criterion for hemizygosity. The order of the five intragenic markers in relation to each other has not been clarified. Two of these polymorphic markers, IVS4+109insTCTTA and IVS8+32T/G, have been identified previously in intervening sequences (IVS) 4 and 8, respectively (27,28). The microsatellite marker AFMa086wg9 had been mapped to IVS2 (20). Two additional intragenic microsatellite markers, D10S2491 and D10S2492, were isolated and noted to be within PTEN (29) although their precise location with respect to the three previous markers was unknown. To determine more precisely where these markers are, genomic DNA from the glioblastoma cell line A172, which had been shown to contain only the first two PTEN exons (20), was utilized as a template. Using previously described PCR conditions (30,31), only D10S2491 was able to be amplified from A172, placing this marker 5[prime] of, or centromeric to, AFMa086wg9. Hence, D10S2492 must be located 3[prime] of IVS2 but centromeric to the 3[prime] end of PTEN although its precise location could not be determined with the resources available (data not shown). Thus, the most likely order of these PTEN intragenic markers is D10S2491-AFMa086wg9-IVS4+109insTCTTA-D10S2492/IVS8+32T/G.

A

B

Figure 2. (A) Hemizygosity analysis of eight polymorphic markers within 10q22-24 in PTEN mutation-negative BRR cases. Hatched circles, heterozygosity, i.e. confirmation of the presence of two alleles, at a particular marker site; open circles, homozygosity; ND, marker has not been analysed due to technical difficulties. (B) Fine structure mapping of the interstitial deletion 46XY, del(10)(q23.2-q24.1). Retention of heterozygosity is observed at D10S219 in the proband. The markers D10S1687 and D10S579 immediately telomeric are non-informative. Thus, the centromeric breakpoint of this deletion is telomeric of D10S219. The deleted paternal chromosome is indicated by a dotted line box.

Using this panel of eight polymorphic markers, both flanking and within the PTEN locus, we found that all of the 17 PTEN mutation-negative BRR cases displayed retention of heterozygosity in at least one of these markers, and 13 of 17 (76%) also showed retention of heterozygosity in at least one intragenic marker (Fig. 2A).

Fine mapping of 46XY, del(10)(q23.2-q24.1)

The peripheral blood karyotype of a patient with sporadic BRR had previously shown a region of interstitial deletion on 10q encompassing PTEN, 46XY, del(10)(q23.2-q24.1) (32). The patient's parents were shown to have normal chromosome complements (32). Fine structure mapping using the proband's and both parents' germline DNA and the above panel of polymorphic markers was performed to define at least one end of this deletion and to assign the parent of origin (Fig. 2B). Retention of heterozygosity was observed at D10S219, the most centromeric marker used, while clear hemizygosity was observed for D10S2491 and D10S541. The marker D10S579 was non-informative; thus, the centromeric breakpoint of this deletion is distal to DI0S219 and might even be defined by D10S2491 (Fig. 2B). Inspection of the alleles inherited from both parents demonstrated a paternal origin for this deletion (Fig. 2B).

DISCUSSION

Twenty-six of 43 (60%) unrelated individuals with BRR were found to have a germline PTEN mutation. These mutations were found scattered along the length of PTEN, with the exception of exons 1, 4 and 9, and included point missense and nonsense mutations, deletions, insertions, deletion-insertions, splice site mutations, a balanced translocation and a gross deletion (Table 1 and Fig. 1A). Of the 17 BRR cases where mutations were not detected, hemizygosity analysis encompassing PTEN excluded whole-gene and whole-region deletion. These results would suggest that gross gene deletion was an unlikely mechanism of PTEN inactivation in these cases. However, other possible mechanisms of PTEN inactivation, including mutations in the promoter region, mutations deep within an intron or methylation of promoter sequences, cannot be excluded, although the latter has yet to be described as a germline mechanism of gene regulation in syndromes where imprinting is not involved.

While two anecdotal cases of gross deletion of the 10q23 region encompassing PTEN have been reported (32,33), no CS cases have been found to carry a germline hemizygous PTEN deletion or chromosomal rearrangement. In this series, only two of 43 (5%) unrelated BRR cases have a gross chromosomal abnormality. In the case with 46XY, del(10)(q23.2-q24.1) (32), we found that this deletion originated on the paternal allele. Interestingly, this patient does not seem to have a more `severe' phenotype, from a neoplastic point of view, presenting with lipomas, hemangiomas and intestinal polyps without known malignancy (32). However, this patient suffered severe morbidity from his polyposis, which necessitated a total colectomy for control of anaemia and malnutrition (M.T. Geraghty and C. Eng, unpublished data). Together with the fact that germline intragenic PTEN mutations are aetiologic for a proportion of BRR, the observation that gross alteration of PTEN probably results in haploinsufficiency argues for gross PTEN deletion causing BRR as well. These three chromosomal aberration cases (two reported here), especially the deletions, provide an approximate human equivalent of the Pten^+/- mouse models (22,34,35). Interestingly, neither of these mouse models developed the characteristic tumours of CS, including breast, brain or thyroid cancer. The major tumour of the first model (22,34) was T cell lymphoma. Lymphoma is only rarely known to be associated with CS (36) and it is difficult to determine whether this is a true association or chance occurrence. However, more reminiscent of both BRR and CS, this murine model had microscopic hamartomatous polyps of the colon (34). The other phenotypic features found in the second model (35), such as prostate abnormalities, colon adenocarcinomas and papillary thyroid carcinoma, are atypical of the human syndromes. These cancers are not component to BRR, while papillary thyroid carcinoma is very rarely seen in CS, except in germline PTEN mutation-negative and PTEN deletion-negative cases (16; C. Eng, unpublished data).

It is of considerable interest that loss of the wild-type PTEN allele was reported in thymic lymphomas from the first mouse model (34), while the wild-type allele was retained in various tumours from the second mouse model (35). Our finding of germline deletion in the two BRR patients in the absence of an additional identifiable somatic PTEN mutation in their tumours (data not shown) would appear to be in concordance with the second model suggesting that PTEN haploinsufficiency alone may cause developmental defects and tumour formation. However, whilst point mutations could not be identified in the remaining allele in these patients, disruption of the function of wild-type PTEN by alternative mechanisms such as transcriptional inactivation was not excluded. From a phenotypic standpoint based on very small numbers, it would appear that the two gross deletion cases are associated with much more severe gastrointestinal symptoms and mental retardation than those with intragenic mutation. Whether the severity of symptoms in PTEN deletion-related BRR is a result of PTEN haploinsufficiency or loss of sequence flanking PTEN is not known.

Of the 43 BRR cases studied, 16 were sporadic and 27 were familial. Germline PTEN mutations were identified in both groups. In contrast to an earlier report that was unable to detect PTEN mutations or deletions in sporadic cases of BRR (37), our data suggest that it is equally likely to be able to identify germline PTEN mutations in both sporadic and familial BRR. The small sample size, n = 3, of this earlier report may explain this apparent discrepancy. Thus, our results would suggest that the genetic aetiologies of sporadic and familial BRR are similar.

Genotype-phenotype correlation analyses revealed three putative associations. First, in the BRR cohort as a whole, the presence of a germline PTEN mutation was correlated with the presence of lipomatosis (P = 0.028). Lipomas occur only rarely in CS, unlike in BRR where they are common, thus the association of lipoma and PTEN mutation in CS could not be assessed (16). It is possible that BRR may also be caused by additional, as yet unidentified, genes. Our data suggest that, in fact, this may be true in 40% of cases. Unfortunately, the PTEN mutation-negative BRR families in the current study are too small effectively to exclude linkage to 10q23 and thus provide further evidence of genetic heterogeneity in BRR. However, it is possible that if BRR in some cases does develop along alternative pathways to those influenced by a PTEN mutation, then these pathways do not favour the growth of lipomas.

Secondly, the presence of germline PTEN mutation in the BRR cohort, including BRR/CS overlap families, showed an association with any cancer or breast fibroadenoma (i.e. a CS phenotype) (P = 0.014). Thirdly, an association was observed in the entire BRR cohort between the presence of truncating PTEN mutations and cancer or breast fibroadenoma (P = 0.024). Perhaps, a parallel correlation observed in CS alone is the presence of PTEN mutation and the development of breast carcinoma in a given CS family (16). Continuing this parallel, it may be possible to conclude that the presence of a PTEN mutation, whether it be in CS, BRR or BRR/CS families, predisposes to the presence of tumours. However, it would appear that mutation-positive status in BRR predisposes to benign tumours, i.e. lipomas, compared with malignant tumours, i.e. breast or uterine carcinoma, in CS or BRR/CS overlap families. Nonetheless, the associative trend of mutation positivity and tumour in BRR should alert the clinician that cancer might be a formal component of BRR, especially in mutation-positive cases, and specifically in BRR/CS overlap families. As the presence of neoplasms in CS does not appear to occur much earlier than in non-CS cancer-affected individuals, it is possible that a similar phenomenon occurs with BRR. Thus, perhaps longer follow-up periods are required for the diagnosis of neoplasia to be made in this group.

The mutation-positive-any tumour association, together with our observation of 11 BRR/CS overlap families, 10 of which are PTEN mutation positive, the similar but not identical mutational spectra of CS and BRR and the four mutations common to both syndromes lead us to suggest that CS and BRR constitute a single syndrome with broad clinical expression. There is little doubt that, at least in the instances of the four identical mutations, Q110X, R130X, R233X and R335X, found in CS-only, BRR-only and BRR/CS overlap families, other genetic and/or epigenetic factors, such as modifier loci, are involved. In the case of BRR, these unknown factors would seem to favour the development of benign tumours; whereas in the case of CS, malignancy, especially breast carcinoma, is favoured. However, for some of the other mutations that are, to date, unique to each group, it is plausible that differences might occur by differentially triggering various signalling pathways. Evidence supporting this theory already exists. While some mutants have been shown to have loss of phosphatase activity against in vitro protein substrates (18) and Ptd-Ins(3,4,5)P₃, an endogenous substrate, the CS mutation G129E had normal phosphatase activity against non-phospholipid substrates both in vitro (23) and in cell lines (38) but had no phosphatase activity against Ptd-Ins(3,4,5)P₃. Thus, it would seem likely that PTEN will have multiple substrates including both phospholipids and proteins. It is possible that CS- and BRR-specific mutations may differentially affect PTEN activity towards phospholipid versus proteic substrates and that this may occur in a cell- or tissue-specific manner.

Finally, the overlap of a number of clinical features, the sharing of identical PTEN mutations, in addition to the presence of BRR/CS overlap families, are all highly suggestive that BRR and CS are different presentations of a single syndrome and suggest that anticipation may pertain in this syndrome as well. The clinical implications of such a conclusion would be that known affected BRR and CS patients, as well as their at-risk relatives, should receive equal attention with respect to cancer surveillance. This is especially true in the case of PTEN mutation-positive BRR and CS. Thus, we believe that PTEN mutation-positive CS and BRR can now be grouped together for clinical purposes and classified as the `PTEN hamartoma-tumour syndrome' (PHTS).

MATERIALS AND METHODS

Patients

Forty-three unrelated BRR patients and, where possible, their affected and unaffected family members, were identified and blood samples collected for PTEN mutation screening. The diagnosis of BRR was made with the minimum standard criteria that included at least three of the following four features: macrocephaly, lipomatosis, haemangiomas and pigmented macules of the glans penis (speckled penis) in males. With the exception of one BRR/CS overlap family, B/CSBORD, all BRR cases in this study had macrocephaly. In seven cases, BSN, B85, B172, B173, B1016, B383 and B322, PTEN mutation screening was performed on fibroblast lines generated from skin punch biopsies from BRR patients. Of the 43 BRR cases collected, 16 represented sporadic cases of BRR based on clinical history and 27 were familial. Of the 27 familial cases of BRR, 11 were classified as BRR/CS overlap families. Each of these BRR/CS families comprised a minimum of one individual with BRR and one other related member with at least one major feature of CS (4), including breast fibroadenoma, trichilemmomas, papillomatous papules, uterine cancer or breast carcinoma. The comparison cohort of CS-only families had been collected and analysed previously for germline PTEN mutation (16). The results of PTEN mutation screening in this CS cohort were used for comparison with those of the BRR group in an attempt to identify mutations specific for either CS or BRR.

Cultured skin fibroblasts

Cultured skin fibroblasts were available from seven BRR patients. B172, B173 and B1016 are affected individuals from the same family, as are B322 and B383. All cells were grown in Dulbecco's modified Eagle's medium supplemented with 10% heat-inactivated fetal calf serum, 1× minimum essential medium sodium pyruvate solution, penicillin/streptomycin, 10 mM HEPES buffer solution and 4.4 mM L-glutamine (all from Gibco-BRL Life Technologies, Gaithersburg, MD).

DNA preparation

Constitutional DNA was extracted from blood leucocytes using standard techniques (39). DNA was extracted from fibroblast cell lines using the QIAam Tissue kit (Qiagen, Chatsworth, CA)

PTEN mutation scanning

A combination of DGGE and temporal temperature gel electrophoresis was used to screen the nine PTEN exons and flanking intronic sequences in germline genomic DNA extracted from blood leucocytes or cultured skin fibroblasts. Primer sequences, PCR and gel conditions have been described previously (40-42).

Intragenic and flanking microsatellite marker analyses

To exclude the possibility of gross deletion in PTEN mutation-negative BRR and BRR/CS patients, eight polymorphic markers spanning a physical distance of ~9 cM flanking and within PTEN were analysed for hemizygosity. The markers are ordered from centromeric to telomeric and reflect the integrated genetic and physical map of chromosome arm 10q (http://www-genome.wi.mit.edu ): D10S219-D10S579-D10S2491-AFMa086wg9-IVS4+109insTCTTA-D10S2492/IVS8+32T/G-D10S541. These markers were also used for analysis of a BRR patient and his parents, the proband known to have the karyotype 46XY, del(10)(q23.2-q24.1). The five markers D10S2491-IVS8+32T/G lie within PTEN itself. The IVS8+32G/T polymorphism was screened for by digestion with HincII under the manufacturer's guidelines (New England Biolabs, Beverly, MA) as described previously (16,28). The IVS4+109insTCTTA polymorphism was detected by sequence analysis. PCR conditions for the microsatellite markers have been described previously (31,40).

Genotype-phenotype analyses

Genotype-phenotype analyses were carried out on a family-as-a-unit basis (16,43,44). Associations were tested for both within the BRR and BRR/CS overlap group as well as between the BRR-only, BRR/CS overlap group and the CS-only group previously analysed (16). Initially, associations were sought between the presence or absence of PTEN mutation and the phenotypic classification of BRR alone, BRR/CS overlap or CS alone. Possible differences between the presence or absence of PTEN mutation in sporadic and familial BRR and BRR/CS overlap were also assessed. Mutation type (truncating, non-truncating, gross deletion or translocation) and mutation location (5[prime] of ,and within, the PTPase core motif versus 3[prime] of the PTPase core motif) was also considered, both within the BRR and BRR/CS overlap group and between this group and the CS cohort.

The genotypic information generated by DGGE screening was then cross-tabulated with known phenotype. Firstly, correlations were sought within the entire BRR and BRR/CS overlap group between the presence of a PTEN mutation and that of any cancer, skin manifestations or breast fibroadenomas that would be diagnostic of CS, lipomas, intestinal polyps, pigmented macules of the glans penis or café-au-lait spots, thyroid involvement (Hashimoto's thyroiditis, multinodular goitre, follicular thyroid carcinoma or hypothyroidism), or haemangiomas. Secondly, the mutation type (truncating or non-truncating) was cross-tabulated with the BRR phenotypes listed. Thirdly, the mutation position (5[prime] of, or within, the PTPase core motif or 3[prime] of the core motif) was assessed in relation to BRR phenotype.

Comparisons were then made between the CS-only, BRR/CS and BRR-only groups in an attempt to identify trends that may be associated specifically with one or other of these groups. The correlations sought when comparing these three groups included presence or absence of PTEN mutation, the mutation type (truncating or non-truncating) and the mutation position (5[prime] of, and within, the PTPase core motif versus 3[prime] of the PTPase core motif). Based on observed differences of the mutation type in the PTPase core motif between the BRR-only and BRR/CS overlap groups and CS-only (Fig. 1), a statistically significant correlation was sought.

For all analyses, the statistical significance of differences between genotype groups was calculated using the two-tailed Fisher's exact test (45,46).

ACKNOWLEDGEMENTS

We are grateful to the patients, their families, clinicians and genetics counsellors, especially Dr L. Hudgins, Dr C.E. Jackson, B. Poling, A. Chittenden, H. Hampel, S. Jones, N. Petrucelli and K. Schneider for their invaluable assistance. We thank A. Satterfield for assistance with sample collection and data management, and the Dana-Farber Cancer Institute Molecular Biology Core Facility, Boston, MA, for running sequencing and Genescan gels. This study was partially supported by National Cancer Institute grant P30 CA16058 (Ohio State University Comprehensive Cancer Center), American Cancer Society grants RPG-97-064-01 and RPG-98-211-01-CCE, US Army Research Medical and Material Command Breast Cancer Research Program grant DAMD17-98-1-8058 and the Concert for the Cure (to C.E.). P.L.M.D. is a postdoctoral fellow of the Susan G. Komen Breast Cancer Research Foundation.

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*To whom correspondence should be addressed at: Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center, 690C Medical Research Facility, 420 West 12th Avenue, Columbus, OH 43210, USA. Tel: +1 614 688 4508; Fax: +1 614 688 3582; Email: eng-1{at}medctr.osu.edu

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				B. Li, V. G. Krishnan, M. E. Mort, F. Xin, K. K. Kamati, D. N. Cooper, S. D. Mooney, and P. Radivojac Automated inference of molecular mechanisms of disease from amino acid substitutions Bioinformatics, November 1, 2009; 25(21): 2744 - 2750. [Abstract] [Full Text] [PDF]

				B. Markman, F. Atzori, J. Perez-Garcia, J. Tabernero, and J. Baselga Status of PI3K inhibition and biomarker development in cancer therapeutics Ann. Onc., August 27, 2009; (2009) mdp347v1. [Abstract] [Full Text] [PDF]

				J. Zhou, J. Blundell, S. Ogawa, C.-H. Kwon, W. Zhang, C. Sinton, C. M. Powell, and L. F. Parada Pharmacological Inhibition of mTORC1 Suppresses Anatomical, Cellular, and Behavioral Abnormalities in Neural-Specific Pten Knock-Out Mice J. Neurosci., February 11, 2009; 29(6): 1773 - 1783. [Abstract] [Full Text] [PDF]

				J. G. Schwab, L. Pena, D. Waggoner, and P. Pytel Two Children with Macrocephaly, Developmental Delay, and PTEN Mutation Clinical Pediatrics, January 1, 2009; 48(1): 89 - 92. [PDF]

				F Chibon, C Primois, J-M Bressieux, D Lacombe, C Lok, L Mauriac, A Taieb, and M Longy Contribution of PTEN large rearrangements in Cowden disease: a multiplex amplifiable probe hybridisation (MAPH) screening approach J. Med. Genet., October 1, 2008; 45(10): 657 - 665. [Abstract] [Full Text] [PDF]

				N. J. Oviedo, B. J. Pearson, M. Levin, and A. Sanchez Alvarado Planarian PTEN homologs regulate stem cells and regeneration through TOR signaling Dis. Model. Mech., September 1, 2008; 1(2-3): 131 - 143. [Abstract] [Full Text] [PDF]

				D. C. Allain Genetic Counseling and Testing for Common Hereditary Breast Cancer Syndromes: A Paper from the 2007 William Beaumont Hospital Symposium on Molecular Pathology J. Mol. Diagn., September 1, 2008; 10(5): 383 - 395. [Abstract] [Full Text] [PDF]

				R. E. Teresi, S. M. Planchon, K. A. Waite, and C. Eng Regulation of the PTEN promoter by statins and SREBP Hum. Mol. Genet., April 1, 2008; 17(7): 919 - 928. [Abstract] [Full Text] [PDF]

				M. R. Sharma, E. M. Petty, and M. M. Lesperance Airway Obstruction Caused by PTEN Hamartoma (Bannayan-Riley-Ruvalcaba) Syndrome Arch Otolaryngol Head Neck Surg, November 1, 2007; 133(11): 1157 - 1160. [Full Text] [PDF]

				A. Andres-Pons, I. Rodriguez-Escudero, A. Gil, A. Blanco, A. Vega, M. Molina, R. Pulido, and V. J. Cid In vivo Functional Analysis of the Counterbalance of Hyperactive Phosphatidylinositol 3-Kinase p110 Catalytic Oncoproteins by the Tumor Suppressor PTEN Cancer Res., October 15, 2007; 67(20): 9731 - 9739. [Abstract] [Full Text] [PDF]

				W.-H. Tan, H. N Baris, P. E Burrows, C. D Robson, A. I Alomari, J. B Mulliken, S. J Fishman, and M. B Irons The spectrum of vascular anomalies in patients with PTEN mutations: implications for diagnosis and management J. Med. Genet., September 1, 2007; 44(9): 594 - 602. [Abstract] [Full Text] [PDF]

				K L Lachlan, A M Lucassen, D Bunyan, and I K Temple Cowden syndrome and Bannayan Riley Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers J. Med. Genet., September 1, 2007; 44(9): 579 - 585. [Abstract] [Full Text] [PDF]

				C. Blanco-Aparicio, O. Renner, J. F.M. Leal, and A. Carnero PTEN, more than the AKT pathway Carcinogenesis, July 1, 2007; 28(7): 1379 - 1386. [Abstract] [Full Text] [PDF]

				W I Al-Daraji, H M Ramsay, and R B M Ali Storiform collagenoma as a clue for Cowden disease or PTEN hamartoma tumour syndrome J. Clin. Pathol., July 1, 2007; 60(7): 840 - 842. [Full Text] [PDF]

				C. A. Alvarez-Breckenridge, K. A. Waite, and C. Eng PTEN regulates phospholipase D and phospholipase C Hum. Mol. Genet., May 15, 2007; 16(10): 1157 - 1163. [Abstract] [Full Text] [PDF]

				M. G. Pezzolesi, K. M. Zbuk, K. A. Waite, and C. Eng Comparative genomic and functional analyses reveal a novel cis-acting PTEN regulatory element as a highly conserved functional E-box motif deleted in Cowden syndrome Hum. Mol. Genet., May 1, 2007; 16(9): 1058 - 1071. [Abstract] [Full Text] [PDF]

				K. Suphapeetiporn, P. Kongkam, J. Tantivatana, T. Sinthuwiwat, S. Tongkobpetch, and V. Shotelersuk PTEN c.511C>T Nonsense Mutation in a BRRS Family Disrupts a Potential Exonic Splicing Enhancer and Causes Exon Skipping Jpn. J. Clin. Oncol., December 1, 2006; 36(12): 814 - 821. [Abstract] [Full Text] [PDF]

				R.N. Srinivasa and P.E. Burrows Dural Arteriovenous Malformation in a Child with Bannayan-Riley-Ruvalcaba Syndrome. AJNR Am. J. Neuroradiol., October 1, 2006; 27(9): 1927 - 1929. [Abstract] [Full Text] [PDF]

				D. Freeman, R. Lesche, N. Kertesz, S. Wang, G. Li, J. Gao, M. Groszer, H. Martinez-Diaz, N. Rozengurt, G. Thomas, et al. Genetic Background Controls Tumor Development in Pten-Deficient Mice. Cancer Res., July 1, 2006; 66(13): 6492 - 6496. [Abstract] [Full Text] [PDF]

				Y. Tang and C. Eng p53 Down-Regulates Phosphatase and Tensin Homologue Deleted on Chromosome 10 Protein Stability Partially through Caspase-Mediated Degradation in Cells with Proteasome Dysfunction. Cancer Res., June 15, 2006; 66(12): 6139 - 6148. [Abstract] [Full Text] [PDF]

				J. V. Schaffer, H. Kamino, A. Witkiewicz, J. M. McNiff, and S. J. Orlow Mucocutaneous Neuromas: An Underrecognized Manifestation of PTEN Hamartoma-Tumor Syndrome. Arch Dermatol, May 1, 2006; 142(5): 625 - 632. [Abstract] [Full Text] [PDF]

				S. Agrawal and C. Eng Differential expression of novel naturally occurring splice variants of PTEN and their functional consequences in Cowden syndrome and sporadic breast cancer Hum. Mol. Genet., March 1, 2006; 15(5): 777 - 787. [Abstract] [Full Text] [PDF]

				X Cao, K W Eu, M P Kumarasinghe, H H Li, C Loi, and P Y Cheah Mapping of hereditary mixed polyposis syndrome (HMPS) to chromosome 10q23 by genomewide high-density single nucleotide polymorphism (SNP) scan and identification of BMPR1A loss of function. J. Med. Genet., March 1, 2006; 43(3): e13 - e13. [Abstract] [Full Text] [PDF]

				A. R. Patterson, A. M. Leitch, P. Weatherall, X.-P. Zhou, C. Eng, and G. E. Tomlinson CASE 4. Fibrocystic Breast Disease in a 16-Year-Old Female With PTEN Hamartoma Tumor Syndrome J. Clin. Oncol., January 20, 2006; 24(3): 525 - 527. [Full Text] [PDF]

				J. M. Carethers Unwinding the Heterogeneous Nature of Hamartomatous Polyposis Syndromes JAMA, November 16, 2005; 294(19): 2498 - 2500. [Full Text] [PDF]

				D A Lee, M E Grossman, P Schneiderman, and J T Celebi Genetics of skin appendage neoplasms and related syndromes J. Med. Genet., November 1, 2005; 42(11): 811 - 819. [Abstract] [Full Text] [PDF]

				S. Agrawal, R. Pilarski, and C. Eng Different splicing defects lead to differential effects downstream of the lipid and protein phosphatase activities of PTEN Hum. Mol. Genet., August 15, 2005; 14(16): 2459 - 2468. [Abstract] [Full Text] [PDF]

				J. E. Garber and K. Offit Hereditary Cancer Predisposition Syndromes J. Clin. Oncol., January 10, 2005; 23(2): 276 - 292. [Abstract] [Full Text] [PDF]

				R Pilarski and C Eng Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome J. Med. Genet., May 1, 2004; 41(5): 323 - 326. [Full Text]

				C.-H. Kwon, X. Zhu, J. Zhang, and S. J. Baker mTor is required for hypertrophy of Pten-deficient neuronal soma in vivo PNAS, October 28, 2003; 100(22): 12923 - 12928. [Abstract] [Full Text] [PDF]

				D. C.I. Goberdhan and C. Wilson PTEN: tumour suppressor, multifunctional growth regulator and more Hum. Mol. Genet., October 15, 2003; 12(90002): R239 - 248. [Abstract] [Full Text] [PDF]

				J H M Merks, L S de Vries, X-P Zhou, P Nikkels, P G Barth, C Eng, and R C M Hennekam PTEN hamartoma tumour syndrome: variability of an entity J. Med. Genet., October 1, 2003; 40(10): e111 - 111. [Full Text] [PDF]

				M B Delatycki, A Danks, A Churchyard, X-P Zhou, and C Eng De novo germline PTEN mutation in a man with Lhermitte-Duclos disease which arose on the paternal chromosome and was transmitted to his child with polydactyly and Wormian bones J. Med. Genet., August 1, 2003; 40(8): e92 - 92. [Full Text] [PDF]

				T. Kimura, A. Suzuki, Y. Fujita, K. Yomogida, H. Lomeli, N. Asada, M. Ikeuchi, A. Nagy, T. W. Mak, and T. Nakano Conditional loss of PTEN leads to testicular teratoma and enhances embryonic germ cell production Development, April 15, 2003; 130(8): 1691 - 1700. [Abstract] [Full Text] [PDF]

				K. A. Waite and C. Eng BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels Hum. Mol. Genet., March 15, 2003; 12(6): 679 - 684. [Abstract] [Full Text] [PDF]

				S. Marino, P. Krimpenfort, C. Leung, H. A. G. M. van der Korput, J. Trapman, I. Camenisch, A. Berns, and S. Brandner PTEN is essential for cell migration but not for fate determination and tumourigenesis in the cerebellum Development, March 9, 2003; 129(14): 3513 - 3522. [Abstract] [Full Text] [PDF]

				J M Smith, E P E Kirk, G Theodosopoulos, G M Marshall, J Walker, M Rogers, M Field, J J Brereton, and D J Marsh Germline mutation of the tumour suppressor PTEN in Proteus syndrome J. Med. Genet., December 1, 2002; 39(12): 937 - 940. [Full Text] [PDF]

				G. Li, G. W. Robinson, R. Lesche, H. Martinez-Diaz, Z. Jiang, N. Rozengurt, K.-U. Wagner, D.-C. Wu, T. F. Lane, X. Liu, et al. Conditional loss of PTEN leads to precocious development and neoplasia in the mammary gland Development, September 1, 2002; 129(17): 4159 - 4170. [Abstract] [Full Text] [PDF]

				L.-P. Weng, J. L. Brown, K. M. Baker, M. C. Ostrowski, and C. Eng PTEN blocks insulin-mediated ETS-2 phosphorylation through MAP kinase, independently of the phosphoinositide 3-kinase pathway Hum. Mol. Genet., July 15, 2002; 11(15): 1687 - 1696. [Abstract] [Full Text] [PDF]

				C. B. Knobbe, A. Merlo, and G. Reifenberger Pten signaling in gliomas Neuro-oncol, July 1, 2002; 4(3): 196 - 211. [Abstract] [PDF]

				M. Fernandez and C. Eng The Expanding Role of PTEN in Neoplasia: A Molecule for All Seasons? : Commentary re: M. A. Davies, et al., Adenoviral-mediated Expression of MMAC/PTEN Inhibits Proliferation and Metastasis of Human Prostate Cancer Cells. Clin. Cancer Res., 8: 1904-1914, 2002. Clin. Cancer Res., June 1, 2002; 8(6): 1695 - 1698. [Abstract] [Full Text] [PDF]

				X.-P. Zhou, H. Hampel, J. Roggenbuck, N. Saba, T. W. Prior, and C. Eng A 39-bp Deletion Polymorphism in PTEN in African American Individuals: Implications for Molecular Diagnostic Testing J. Mol. Diagn., May 1, 2002; 4(2): 114 - 117. [Abstract] [Full Text] [PDF]

				M M de Jong, I M Nolte, G J te Meerman, W T A van der Graaf, J C Oosterwijk, J H Kleibeuker, M Schaapveld, and E G E de Vries Genes other than BRCA1 and BRCA2 involved in breast cancer susceptibility J. Med. Genet., April 1, 2002; 39(4): 225 - 242. [Abstract] [Full Text] [PDF]

				S. Olschwang, C. Boisson, and G. Thomas Peutz-Jeghers families unlinked to STK11/LKB1 gene mutations are highly predisposed to primitive biliary adenocarcinoma J. Med. Genet., June 1, 2001; 38(6): 356 - 360. [Abstract] [Full Text]

				K. Kurose, X.-P. Zhou, T. Araki, S. A. Cannistra, E. R. Maher, and C. Eng Frequent Loss of PTEN Expression Is Linked to Elevated Phosphorylated Akt Levels, but Not Associated with p27 and Cyclin D1 Expression, in Primary Epithelial Ovarian Carcinomas Am. J. Pathol., June 1, 2001; 158(6): 2097 - 2106. [Abstract] [Full Text] [PDF]

				O. Gimm, H. Chi, P. L. M. Dahia, A. Perren, R. Hinze, P. Komminoth, H. Dralle, P. R. Reynolds, and C. Eng Somatic Mutation and Germline Variants of MINPP1, a Phosphatase Gene Located in Proximity to PTEN on 10q23.3, in Follicular Thyroid Carcinomas J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1801 - 1805. [Abstract] [Full Text]

				L.-P. Weng, J. L. Brown, and C. Eng PTEN coordinates G1 arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model Hum. Mol. Genet., March 1, 2001; 10(6): 599 - 604. [Abstract] [Full Text] [PDF]

				L.-P. Weng, W. M. Smith, J. L. Brown, and C. Eng PTEN inhibits insulin-stimulated MEK/MAPK activation and cell growth by blocking IRS-1 phosphorylation and IRS-1/Grb-2/Sos complex formation in a breast cancer model Hum. Mol. Genet., March 1, 2001; 10(6): 605 - 616. [Abstract] [Full Text] [PDF]

				J. D Fackenthal, D. J Marsh, A.-L. Richardson, S. A Cummings, C. Eng, B. G Robinson, and O. I Olopade Male breast cancer in Cowden syndrome patients with germline PTEN mutations J. Med. Genet., March 1, 2001; 38(3): 159 - 164. [Abstract] [Full Text]

				L.-P. Weng, J. L. Brown, and C. Eng PTEN induces apoptosis and cell cycle arrest through phosphoinositol-3-kinase/Akt-dependent and -independent pathways Hum. Mol. Genet., February 1, 2001; 10(3): 237 - 242. [Abstract] [Full Text] [PDF]

				L.-P. Weng, O. Gimm, J. B. Kum, W. M. Smith, X.-P. Zhou, D. Wynford-Thomas, G. Leone, and C. Eng Transient ectopic expression of PTEN in thyroid cancer cell lines induces cell cycle arrest and cell type-dependent cell death Hum. Mol. Genet., February 1, 2001; 10(3): 251 - 258. [Abstract] [Full Text] [PDF]

				M. A PARISI, M. B. DINULOS, K. A LEPPIG, V. P SYBERT, C. ENG, and L. HUDGINS The spectrum and evolution of phenotypic findings in PTEN mutation positive cases of Bannayan-Riley-Ruvalcaba syndrome J. Med. Genet., January 1, 2001; 38(1): 52 - 58. [Full Text]

				C. Eng Will the real Cowden syndrome please stand up: revised diagnostic criteria J. Med. Genet., November 1, 2000; 37(11): 828 - 830. [Full Text]

				A. Perren, P. Komminoth, P. Saremaslani, C. Matter, S. Feurer, J. A. Lees, P. U. Heitz, and C. Eng Mutation and Expression Analyses Reveal Differential Subcellular Compartmentalization of PTEN in Endocrine Pancreatic Tumors Compared to Normal Islet Cells Am. J. Pathol., October 1, 2000; 157(4): 1097 - 1103. [Abstract] [Full Text] [PDF]

				X.-P. Zhou, O. Gimm, H. Hampel, T. Niemann, M. J. Walker, and C. Eng Epigenetic PTEN Silencing in Malignant Melanomas without PTEN Mutation Am. J. Pathol., October 1, 2000; 157(4): 1123 - 1128. [Abstract] [Full Text] [PDF]

				P. M DAHIA, O. GIMM, H. CHI, D. J MARSH, P. R REYNOLDS, and C. ENG Absence of germline mutations in MINPP1, a phosphatase encoding gene centromeric of PTEN, in patients with Cowden and Bannayan-Riley- Ruvalcaba syndrome without germline PTEN mutations J. Med. Genet., September 1, 2000; 37(9): 715 - 717. [Full Text]

				F. Vazquez, S. Ramaswamy, N. Nakamura, and W. R. Sellers Phosphorylation of the PTEN Tail Regulates Protein Stability and Function Mol. Cell. Biol., July 15, 2000; 20(14): 5010 - 5018. [Abstract] [Full Text]

				O. Gimm, T. Attie-Bitach, J. A. Lees, M. Vekemans, and C. Eng Expression of the PTEN tumour suppressor protein during human development Hum. Mol. Genet., July 1, 2000; 9(11): 1633 - 1639. [Abstract] [Full Text] [PDF]

				V. Stambolic, M.-S. Tsao, D. Macpherson, A. Suzuki, W. B. Chapman, and T. W. Mak High Incidence of Breast and Endometrial Neoplasia Resembling Human Cowden Syndrome in pten+/- Mice Cancer Res., July 1, 2000; 60(13): 3605 - 3611. [Abstract] [Full Text]

				X.-P. Zhou, D. J. Marsh, H. Hampel, J. B. Mulliken, O. Gimm, and C. Eng Germline and germline mosaic PTEN mutations associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and lipomatosis Hum. Mol. Genet., March 22, 2000; 9(5): 765 - 768. [Abstract] [Full Text] [PDF]

				G. Guanti, N. Resta, C. Simone, F. Cariola, I. Demma, P. Fiorente, and M. Gentile Involvement of PTEN mutations in the genetic pathways of colorectal cancerogenesis Hum. Mol. Genet., January 22, 2000; 9(2): 283 - 287. [Abstract] [Full Text] [PDF]

				Balanced Translocation of 10q and 13q, Including the PTENGene, in a Boy with a Human Chorionic Gonadotropin-Secreting Tumor and the Bannayan-Riley-Ruvalcaba Syndrome J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4665 - 4670. [Full Text]

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