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Original Studies |
Unit on Genetics and Endocrinology, Section on Pediatric Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health (C.A.S., L.S.K., S.E.T., D.J.T., C.G.), Bethesda, Maryland 20892; the Cardiology Division, Departments of Medicine and Cell Biology and Anatomy, Cornell University Medical College, The New York Hospital (C.T.B.), New York, New York 10021; Emeritus Staff, Mayo Clinic (J.A.C.), Rochester, Minnesota 55905; Dana-Farber Cancer Institute, Charles A. Dana Human Cancer Genetics Unit, Richard and Susan Smith Laboratories (D.J.M., C.E.), Boston, Massachusetts 02115; the Tumor Genetics Group, Nuffield Department of Clinical Medicine, University of Oxford, Wellcome Trust Center for Human Genetics (I.P.M.T.), Oxford, United Kingdom OX3 7HN; Institute of Cancer Research (R.S.H.), Sutton, Surrey, United Kingdom SM2 5NG; Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge (C.E.), Cambridge, United Kingdom CB2 2QQ; Wessex Clinical Genetics Service, Princess Ann Hospital (D.M.E., J.T.), Southampton, United Kingdom SO16 5YA; and the Division of Medical Genetics, Department of Genetics, Geneva University Medical School (J.-L.B., S.E.A.), 1211 Geneva, Switzerland
Address all correspondence and requests for reprints to: Constantine A. Stratakis, M.D., D.Sc., Unit on Genetics and Endocrinology, Section on Pediatric Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, 10 Center Drive, MSC1862, Bethesda, Maryland 20892-1862. E-mail: stratakc{at}cc1.nichd.nih.gov
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Abstract |
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Introduction |
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CC and PJS share several features, and their differential diagnosis in individual patients with unusual skin pigmentation and multiple tumors is often difficult. The presence of cardiac and other myxomas may help with the diagnosis, but these tumors may not be present in patients with CC (8). CC, as PJS and the other familial lentiginoses, is inherited in an autosomal dominant manner (11). Lentigines in PJS are indistinguishable from those in CC (8); their presence, particularly in the mucosae, serves to identify families affected with any of the lentiginoses. Among the nongastrointestinal neoplasms associated with PJS, tumors, including thyroid, ovarian, and testicular Sertoli cell neoplasms, are relatively frequent, and all are common in CC (8, 12, 13). In both PJS and CC, large cell, often calcifying, Sertoli cell tumors can produce estradiol, which may lead to precocious puberty or gynecomastia (14, 15). At least one patient with CC and intestinal polyposis and another with a pancreatic tumor have been reported (16).
Because of their substantial phenotypic similarities, it has been suggested that PJS, the other lentiginoses, and CC may share a common molecular etiology (1). An example of such clinical and genetic overlap is that of two related familial syndromes associated with skin abnormalities and endocrine tumors: Cowden disease (CD; MIM 158350) (2, 17) and Ruvalcaba-Myhre-Smith or Bannayan-Zonana syndrome (BZS; MIM 153480) (2, 18, 19). Despite certain differences, these syndromes share hamartomatous polyps, endocrine abnormalities, and mucocutaneous lesions, and both are caused by mutations in the same gene on chromosome 10 that codes for the PTEN protein, a dual specificity phosphatase (20, 21, 22).
A genetic locus has been identified for CC (16) on chromosome 2 (2p16), and the PJS gene was recently identified (23, 24, 25). Germline loss of function mutations in the STK11/LKB1 gene, which encodes a serine-threonine kinase, lead to PJS (24, 25). However, not all families with PJS map to the STK11/LKB1 locus; a second locus on 19q13 and possibly other loci appear likely (26, 27). Likewise, genetic heterogeneity has been documented in CC (28, 29). A large family with CC that does not map to chromosome 2 was reported (28), and this finding was confirmed in our laboratory for other families (29).
In the present study, we investigated two families with CC that did not map to the CNC locus on 2p16 (29); both presented with clinical manifestations of PJS. We studied 16 tumors and tumor cell lines from patients with CC for LOH of the PJS and the CD/BZS loci and excluded these loci from harboring the candidate genetic defects responsible for CC in these two families.
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Subjects and Methods |
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The institutional review boards of the NICHD, NIH, and the Mayo
Clinic approved the contact of the families and the participation of
their members in the NICHD protocol 95-CH-059 on CC and related
disorders. Patients with CC were classified as affected according to
the criteria established by Stratakis et al. (16). Blood and
tissue samples were collected from patients belonging to previously
described families and sporadic cases (16). Tissue was collected in
surgery from seven of these patients and immediately processed to
establish cell lines. The clinical profile of the patients, histology
of their tumors, and source of DNA for molecular analysis (frozen
tissue or tumor cell line) are listed in Tables 1
and 2.
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Twenty milliliters of blood were obtained from each subject in a heparinized syringe and tube. The peripheral blood lymphocytes were separated on a Ficoll gradient and immortalized with Epstein-Barr virus or used for direct DNA extraction, as previously described (16).
Genetic analysis
PCR analysis of the tumors was performed with sets of primers
for the PJS loci-flanking polymorphic markers D19S413, D19S886, and
D19S565 located on 19p13 (23, 24, 25), and D19S926, D19S877, and D19S891
located on 19q13.4 (26). The D10S579, D10S1735, and D10S541 markers
flanking the CD/BZS locus (in a centromere to telomere order) were also
used, as previously described (17, 20). The sequences and genomic order
of these primers are available in the genome database on line
(http://gdbwww.gdb.org/ and http://www-genome.wi.mit.edu). For each of
the markers, the reverse primer was end labeled with
-32P, as previously described (16, 30).
Tumor and linkage analysis
The microsatellite alterations seen in the tumors were classified as previously described (30). Loss of heterozygosity (LOH) was present when only one allele was evident in tumor DNA vs. two alleles in the corresponding bands of blood DNA. Microsatellite length instability was present when multiple bands were seen in the amplified tumor DNA vs. one or two in peripheral blood DNA. Specimens that were not successfully amplified were excluded from the analysis. The results are expressed as a percentage of the total number of informative loci in both tumor and blood samples. Linkage analysis was performed with the LINKAGE (version 5.1) package of computer programs, as previously described (16, 31).
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Results |
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The clinical findings in family YC01 are described in Table 1
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This family has been reported previously (32) and was included with the
CAR01 code in the series studied by Stratakis et al. (16).
The propositus was studied at the NIH (indicated by the
arrow, family member II.5, Table 1). Although variable, the
pigmentation in this family with CC was similar to that in patients
with PJS, with the exception of a pigmented lesion, which to date has
been described in only one patient with PJS (3) but was present in all
members of the YC01 family (Fig. 1).
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mother was then found to have multiple breast myxoid fibroadenomas. The
other affected members of this family have spotty skin pigmentation
that is characteristic of both CNC and PJS, but no endocrine or other
tumors (including gastrointestinal hamartomas). Genetic analysis
LOH for each of the 2 investigated polymorphic markers flanking
the PJS locus was present in 1 of the 16 tumors and tumor cell lines
derived from patients with CC from YC01 and other families (Table 2 and
Fig. 2). The overall LOH rate
for 19p in these samples was 6.3%, which is not different from LOH
rates for random loci in the genome in various tumors (Tables 2 and 3) (30, 33). The observed rate is
significantly lower than the 37.5% LOH rate for this genetic locus
shown by comparative genomic hybridization in PJS families (23), a
percentage that was even higher after microscope-guided laser
dissection of abnormal cells from histological slides of tumors from
patients with PJS.
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).
Likewise, there was no significant LOH for the other loci tested in CC
tumors in this study. It is noteworthy that there was no significant
LOH for the PTEN locus on 10q23 (Table 3). Linkage analysis
using markers corresponding to the PJS loci on 19p13 and 19q13 and the
CD/BZS region on 10q23 excluded these loci from harboring the
susceptibility genes for CC in these families (LOD scores of -2 or
less; Table 3). Haplotype inspection (data not shown) showed that
affected individuals within families did not share genotypes,
confirming linkage results and exclusion in those particular families
in which LOD scores were not lower than -2 (Table 3).
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Discussion |
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Because the STK11/LKB1 and PTEN genes appear to function as tumor suppressor genes (17, 20, 21, 22, 23, 24, 25), whereas the function of the CC gene is unknown (30), it is possible that these molecules are members of a family of proteins that regulate the same cellular process. Examples of such clinical and genetic overlap between various familial syndromes sharing defects in a molecular pathway are well known in tumor genetics. They include the Muir-Torre and hereditary, nonpolyposis colorectal cancer syndromes (34) and the multiple endocrine neoplasia type 2 syndromes and Hirschprung disease (35). However, in this study, the two non-2p-linked CC families did not map to the 19p13, 19q13, and 10q23 loci either, and tumors from patients with CC did not show LOH for these loci despite having an overall significant genomic instability, previously documented by our laboratory and others (30, 36).
These findings suggest that the PJS and the PTEN genes may not play a significant role in the molecular pathogenesis of tumors associated with CC despite the clinical and histological similarities between these disorders. It should be remembered, however, that the PJS locus was identified by screening only DNA of colonic polyps excised from patients with this syndrome. No other tumors associated with PJS were included in the study by Hemminki et al. (23), and no polyps or other colonic lesions from patients with CC were available to us. It is possible, therefore, that LOH for the PJS genomic region is necessary for oncogenesis in the colon but not in other organs affected by PJS or CC. According to Knudson’s hypothesis (37), LOH is necessary for oncogenesis in the presence of a recessive mutant allele, whereas a dominant mutant allele is sufficient for tumorigenesis. If tissue-specific conditions were to determine the dominant or recessive function of the mutant PJS allele, a variable pattern of LOH for the PJS locus would be observed in the tissues studied from patients with the syndrome. A similar example has been observed for menin, the gene responsible for multiple endocrine neoplasm type 1; there is LOH at the menin locus in most tumors associated with the syndrome (i.e. carcinoids, and parathyroid and pituitary adenomas), but not in others (38). Thus, the possibility exists that the PJS genes play a role in the expression of the CC phenotype in noncolonic tissues, but do not have a tumor suppression function.
In summary, despite substantial clinical overlap among CC, PJS, CD, and BZS, in at least 2 families with the complex that did not map to the CNC locus the disease did not segregate with markers from the PJS and CD/BZS loci. LOH for these loci appears to be a rare and most likely random event in tumors from patients with CC.
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Acknowledgments |
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Received December 17, 1997.
Revised April 8, 1998.
Accepted May 7, 1998.
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This article has been cited by other articles:
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  A J Bauer and C A Stratakis The lentiginoses: cutaneous markers of systemic disease and a window to new aspects of tumourigenesis J. Med. Genet., November 1, 2005; 42(11): 801 - 810. [Abstract] [Full Text] [PDF]
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 F. Cetta, M. R. Pelizzo, M. C. Curia, and A. Barbarisi Genetics and Clinicopathological Findings in Thyroid Carcinomas Associated with Familial Adenomatous Polyposis Am. J. Pathol., July 1, 1999; 155(1): 7 - 9. [Full Text] [PDF]
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 F. Cetta Comment on Carney Complex and Related Syndromes and their Genetic Loci J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1491 - 1491. [Full Text]
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C. A. Stratakis Carney Complex and Related Syndromes and their Genetic Loci--Author's Response J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1491a - 1492. [Full Text]
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