Some neoplasms and some hamartomatous syndromes: genetic considerations

Copyright 9 Munksgaard 1998

Int, ,1. Oral Maxillofac. Surg. 1998; 27." 363-369

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Oral& MaxillCacidSurg ISSN 0901-5027

Pathology

Some neoplasmsand some hamartomatoussyndromes:

M. Michael Cohen, Jr Department of Oral & Maxillofacial Sciences, Faculty of Dentistry and Department of Pediatrics, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada

genetic considerations M. M. Cohen, Jr: Some neoplasms and some hamartomatous syndromes: genetic considerations. Int. J. Oral Maxillofac. Surg. 1998; 27: 363-369. 9 Munksgaard, 1998 Abstract. This is the first of three articles on modern genetic concepts of a number of syndromes and disorders. About 1% of cancer mutations arise in the germline and produce a variety of neoplasms and hamartomatous syndromes. However, upward of 10-15% of all cancers have a major inherited component, although many of these are still enigmatic. The genetic basis is presented and following a review of many neoplasms and hamartomatous syndromes, the RET proto-oncogene is discussed as an example.

Modern genetic concepts cast many diseases, disorders, and syndromes in an entirely new light. This is the first of three articles dealing with these topics. All titles in this series are unavoidably long. The subject of the first article appears above. Sometimes conditions that are clinically related are later found to be related at the molecular level. The second article in this series will deal with this concept: Achondroplasia, hypochondroplasia, and thanatophoric dysplasia: clinically related skeletal dysplasias that are also related at the molecular level. Sometimes conditions that are clinically unrelated are later found to be related at the molecular level. The third article in this series will deal with this concept: Holoprosencephaly, SmithLemli-Opitz syndrome, and nevoid basal cell carcinoma syndrome: whoever would have thought they were related at the molecular level? Genetic aspects of neoplasms and hamartomatous syndromes

Cancer is a genetic disease arising from the accumulation,~ of mutations that

promote clonal selection of cells. Most cancer mutations occur at the somatic cell level. About 1% of cancer mutations arise in the germline and produce a variety of hereditary neoplasms and hamartomatous syndromes. However, upward of 10-15% of all cancers have a major inherited component, although many of these are still enigmatic ~1. Table 1 summarizes the genetic aspects of some neoplasms and hamartomatous syndromes 1-I~ Topics tabulated include the names of conditions, inheritance patterns, chromosome localization of genes, type of mutations, and pertinent comments. Linkage analysis is the main method of mapping inherited neoplasms and hamartomatous syndromes to specific chromosome locations. One obstacle that must be overcome in this analysis is genetic heterogeneity - that is, different genes at different chromosome locations may give rise to the same neoplasm or hamartomatous syndrome. For example, two different genes - one on chromosome 9 (TSC1 gene at 9q34), the other on chromosome 16 (TSC2 gene at 1 6p13.3) can result in tuberous sclerosis (Table 1). Breast cancer can be

Key words: cancer; oncogenes; tumor suppressor genes; RET proto-oncogene.

Accepted for publication 20 February 1998

caused by mutations in BRCA1 on chromosome 17 (17q21), BRCA2 on chromosome 13 (13q12), or in PTEN on chromosome 10 (10q23). Cytogenetic abnormalities sometimes provide clues to the chromosome location of a gene responsible for a given disorder. For example, the observation of balanced translocations involving 17ql 1 observed in patients with type 1 neurofibromatosis led to the chromosome localization of the gene and later to the identification of the gene (Table 1). Once a gene for a neoplasm or a hamartomatous syndrome has been mapped chromosomally, the candidate gene can be isolated by positional cloning strategies or by database searches. Sequence-based analysis of the candidate gene is the gold standard for the identification of the mutant allele. Other investigative approaches include: 1) using information from chromosome deletions arising in cancer cells, referred to as allelic loss or loss of heterozygosity (LOH), 2) analyzing specific oncogenes or tumor suppressor genes for possible mutations in the identified chromosomally mapped region, and 3) using the knowledge of genetic and bio-

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Onoo~mm and tumor suppressor genes Of the gene mutations known to cause certain neoplasms and hamartomatous syndromes, two general types may be identified: oncogene mutations, which are of the gain-of-function or activating type and tumor-suppressor gene mutations, which are of the loss-of-function or inactivating type. Most inherited neoplasms and hamartomatous syndromes have autosomal dominant inheritance, and mutations in tumor-suppressor genes are much more common than mutations in oncogenes. Tumorsuppressor gene mutations act recessively at the somatic cell level, being consistent with the Knudson two-hit hypothesis. According to Knudson, the first is a germline mutation that is dominantly inherited. A second mutation occurs in a somatic cell in which the normal allele is inactivated by allelic loss or loss of heterozygosity (LOH)II; A typical example of a tumor-suppressor gene mutation occurs in the patched gene (PTCH) which causes ne, void basal cell carcinoma syndrome (NBCCS) (Table 1); PTCH mutations and the NBCCS are discussed further in the third article of this series. RET mutational phenotypes (Table 1) are among the very few neoplasms and hamartomatous syndromes known to be caused by gerrnline mutations in oncogenes; these are discussed in detail below (Fig. 1).

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The RET proto-oncogene codes for a receptor tyrosine kinase (RTK) consisting of an extracellular ligand binding domain (1-636 aa [amino acid numbers 1-636]), a transmembrane domain (TM, 636-657 aa), and an intracellular split kinase domain (TK1, TK2, 726979 aa) (Fig. 1). RET is an acronym for "REarranged during Transfection'!, RET being cloned as a chimeric oncogene during a classical NIH3T3 transformation assay where the novel transforming gene originated from an /n vitro occurring artefactual rearrangement 9,~8,19,29,32. Normally RET, like other transmembrane receptors, requires a ligand to become activated. Glial cell line-derived

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Fig. 1. RET proto-oncogene encodes a receptor tyrosine kinase (RTK) shown here. Extracellular portion extends from aa (amino acid) 1 to aa 636. Intracellular portion extends from aa 657 to either of two possible isoforms, aa 1072 or aa 1114. SP=signal peptide. CD=Cadherinlike region. Cys=Cysteine-rich region. TM=Transmembrane domain. TK1 =First kinase domain. TK2=Second kinase domain. COOH=Carboxy terminus. Mutation regions shown inelude 1) Hirschsprung disease (HSCR), 2) Familial medullary thyroid carcinoma (FMTC), 3) Multiple endocrine neoplasia, type 2A (MEN2A), and a single missense mutation in TK2 (Met918Thr) flbrmultiple endocrine neoplasia, type 2B (MEN2B). Note rearrangement at aa 713 where three possible rearrangements of RET (RET-PTC1, RET-PTC2, and RET-PTC3) occur frequently in papillary thyroid carcinoma (PTC); oncogenic activation occurs when the extracellular domain of RET is replaced by the amino terminal protein fragments from three other genes (H4, Rla, and ELEI).

neurotrophic factor (GDNF), a member of the TGF]/superfamily, plays this role32. Binding of ligand to RET initiates signal transduction that results in autophosphorylation, activation of other proteins in the growth stimulatory pathway, and production of small regulatory molecules known as second messengers. Ultimately, these signals are transmitted to the nucleus, resulting in cell division19. Growth inhibiting signals are normally generated to prevent cellular proliferation from continuing indefinitely. Precise control over positive and negative signaling events is essential to maintain normal cellular growth. Abnormal receptor stimulation and activation can result from various mutations that are constitutive in nature, i.e., they are ligand independent~9. Neoplasms and hamartomatous syndromes produced by activating, gain-offunction mutations of RET are shown in Fig. 1. Conditions include familial medullary thyroid carcinoma (FMTC), multiple endocrine neoplasia, type 2A (MEN2A), and multiple endocrine neoplasia, type 2B (MEN2B). In a different region of RET, mutations for Hirschsprung disease (HSCR) are also found.

Finally, somatic rearrangements of RET, replacing the extracellular domain by amino terminal fragments from various genes, are frequently found in papillary thyroid carcinoma (PTC)

9,18,29.

Papillary thyroid carcinoma - the most common type of thyroid cancer involves somatic rearrangement of RET in about 35% of cases. Three genes (H4, R l a , and ELE1) fuse with the intracellular domain of RET at its rearrangement site (713 aa), thus activating RET. In chimeric gene PTC1, the fusion partner (H4) like RET, is on chromosome 10 (10qll
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