Familial Papillary Thyroid CancerMany Syndromes, Too Many Genes?1
Charis Eng
Clinical Cancer Genetics and Human Cancer Genetics
Programs
Ohio State University Comprehensive Cancer Center
Columbus, Ohio 43210
and
Cancer Research Campaign Human Cancer Genetics
Research Group
University of Cambridge
Cambridge CB2 2QQ, United Kingdom
Address correspondence and requests for reprints to: Charis Eng, M.D., Ph.D., Ohio State University Human Cancer Genetics, 420 West 12th Avenue, Suite 690 MRF, Columbus, Ohio 43210. medctr.osu.edu or ceng{at}hgmp.mrc.ac.uk
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Introduction
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Not so long ago, claiming that nonmedullary
thyroid cancer could be anything but sporadic was heresy. Clinical and
genetic investigations have come a long way, even in the last few
years, and now it is almost dogma to state that approximately 510%
of all thyroid carcinoma cases will be hereditary. A higher proportion
(25%) of all medullary thyroid carcinoma (MTC) presentations are
hereditary. Whereas the susceptibility gene for hereditary MTC, namely
multiple endocrine neoplasia type 2 (MEN 2), is well defined, finding
the genetic etiology for the familial nonmedullary thyroid carcinoma
syndromes is proving arduous. Germline mutations of the RET
proto-oncogene, on 10q11.2, are associated with more than 92% of all
MEN 2 probands (1), and RET testing is the clinical standard
of care for all MEN 2 and MTC patients (2). The search for the genes
that cause familial nonmedullary thyroid cancer syndromes is proving to
be less straightforward. Part of the reason is that familial
nonmedullary thyroid cancer is not a homogeneous entity, unlike MEN 2.
One gene for a familial nonmedullary thyroid cancer syndrome has been
identified, PTEN, which encodes a tumor suppressor: germline
mutations in PTEN have been found in 80% of individuals
with classic Cowden syndrome, which is characterized by multiple
hamartomas and a high risk of benign and malignant breast and
follicular and papillary thyroid tumors (3) (Table 1
). However, PTEN only
accounts for 5% or less of families with breast and papillary thyroid
carcinomas (PTCs) without other features of Cowden syndrome (4).
Familial adenomatous polyposis, which predisposes to colorectal
carcinoma, is caused by mutations in the APC gene, and PTC
is acknowledged as a minor component tumor in this syndrome (Table 1
).
However, APC seems to have been excluded as a susceptibility
locus in at least some familial PTC families (5). Thus, other
susceptibility genes for PTC exist.
The first "PTC gene" was localized to 19p13.2 in a single
French family with papillary thyroid tumors with cell oxyphilia, which
are an unusual type of oncocytic PTC (6) (Table 1
). A putative locus
for multinodular goiter was mapped to 14q31 in a Canadian kindred (7).
In this family, two PTCs were noted. Indeed, the majority of other
familial PTC families are not linked to either of these two loci
(6, 7, 8). In this issue of the journal, Malchoff et al. (9)
have found another locus for familial PTC, but with a twist. These
investigators have mapped this gene to 1q21 using a multigenerational
family segregating PTC and papillary renal cell carcinoma (RCC). Unlike
the 19p-linked family, the PTCs found in this family are classic
"garden variety" PTC. This is rather significant because we can
consider this 1q21 locus the first classic PTC susceptibility locus to
be mapped. The association with papillary RCC is also worthy of note.
Previously, investigators interested in families with RCC identified
the MET proto-oncogene, encoding a receptor tyrosine kinase,
as the susceptibility gene for familial papillary RCC (10).
MET was excluded as a participant in the 1q-linked
PTC-papillary RCC family (9). Another unusual family segregating clear
cell RCC and PTC was found to harbor a constitutional translocation,
t(3;8)(p14.2;q24.1) (11) (Eng, C. and R. S. Brown, unpublished
observations). Thus, perhaps a gene on 3p14 or 8q24 might be considered
yet another familial PTC susceptibility gene.
Malchoff et al. (9) have shown that the region that
should contain the putative familial PTC susceptibility gene is about
20 cM in length. This would have been a daunting
distance "in the old days," but given the technology and
informatics fallout from the human genome project, these investigators
should be able to identify their gene within a realistic time interval.
In traditional positional cloning, the next step for this group would
have been to acquire more PTC families in the hope that there would be
no or not much genetic heterogeneity and that there would be a new
critical recombinant that would help narrow the region further. Once
the region was narrowed to, say, 5 cM these
investigators would perform physical mapping: the assembly of a contig
of cloned fragments that would span the interval of interest, after
which each plausible candidate gene within the interval would be
examined for germline mutations in the families. Unfortunately, we
already know that familial nonmedullary thyroid cancer, indeed even
familial PTC, is not a single syndrome but several syndromes (Table 1
).
Furthermore, assigning affected status might not be straightforward,
especially in smaller families; benign thyroid nodules are relatively
common, occurring in 10% of females. In mapping the 19p familial PTC
locus, Canzian et al. (6) assigned individuals with nodules
and multinodular goiters as affected. It is unclear whether non-PTC
nodules should be considered part of the phenotype or whether this
would be more misleading than helpful. After all, there has never been
solid evidence that demonstrates that such nodules represent
premalignant lesions. Given the early mapping efforts (5, 6, 8, 9), we
already know that there will be at least four susceptibility genes for
familial PTC. There likely will be more. Given these inherent problems
of syndromic heterogeneity, genetic heterogeneity, and a paucity of
large families, how should these investigators proceed, barring
serendipity? One way is to collect a series of PTC and paired
normal thyroid sets and subject their messenger RNA transcripts to
comparative expression array analysis. Transcripts that clearly show
consistently decreased expression between normal thyroid and PTC
(if looking for a tumor suppressor) or consistently increased between
normal tissue and cancer (if an oncogene) would be of interest. Such
classes of transcripts that map to the 1q21 20-cM
interval would be the most promising candidate genes. In this manner,
the investigators would be able to perform targeted mutation analysis.
Another useful adjunctive maneuver would be for these investigators to
use their contig of BACs (bacterial artificial
chromosomes) to examine either for loss of heterozygosity or
amplification in component tumors.
What type of gene should these investigators be looking for? If
we may take any clues from the sporadic setting, then they should be
looking for proto-oncogenes, which encode kinases. RET and
NTRK1, both encoding tyrosine kinases that are not normally
expressed in thyroid follicular epithelium, are activated by being
translocated and juxtaposed against the 5' ends of genes that drive
increased expression in the thyroid follicular cells, leading to PTC
formation. The MET proto-oncogene belongs to the same family
of receptor tyrosine kinase genes as RET, and it is the
susceptibility gene for another papillary cancer. Furthermore, somatic
MET mutations have been found in both sporadic papillary RCC
and PTC (10). In addition, the putative PRCC gene,
scissioned at 1q21.2 in a sporadic papillary RCC (12), seems a
promising PTC candidate gene, and, indeed, this sort of mechanism is
not inconsistent with activation of a proto-oncogene. In considering
the putative PTC susceptibility genes, we must also ponder the etiology
of sporadic PTC. For example, it has been well established that
radiation exposure causes PTC by promoting the formation of the
RET translocation. In Japan, there seems to be an increased
incidence of Hashimoto thyroiditis-associated PTC, a proportion of
which occurs in small familial clusters. Thus, we may postulate that
one of the familial PTC susceptibility genes might not be a traditional
oncogene or tumor suppressor gene but one that increases susceptibility
to radiation exposure. Alternatively, there might be a gene or genes
that promote autoimmune thyroiditis.
In summary, it would seem that familial PTC is a "catch-all"
term that encompasses different syndromes with genetic susceptibility
to PTC. Malchoff et al. (9) might be correct in
suggesting that familial PTC-papillary RCC is one such
syndromic entity and that a particular putative susceptibility gene
will be on chromosome arm 1q. Because the histology of PTCs in
this kindred is "standard," it might not be unreasonable to suggest
that the putative 1q susceptibility gene could account for more
families with PTC than the 19p locus. However, given the multiple
syndromes represented by "familial PTC" and the likelihood of
multiple susceptibility genes, likely comprised of those with variable
penetrances and expressivity, researchers dedicated to sorting out the
genetic etiology of familial PTC will be kept busy for years to
come.\.
Acknowledgments
I thank Oliver Gimm and Albert de la Chapelle for critical
review of the manuscript and acknowledge all the investigators who have
contributed to the study of familial PTC but who could not be cited
here because of space limitations.
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Footnotes
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1 Supported by the American Cancer Society (Grant
RPG-98-211-01-CCE), the U.S. Army Research Medical and Material Command
(Grant DAMD17-98-1-8058), the Mary Kay Ash Charitable Foundation, the
Susan G. Komen Breast Cancer Research Foundation, and the National
Cancer Institute (Grant P30CA16058; to the Comprehensive Cancer
Center). 
Received March 15, 2000.
Accepted March 15, 2000.
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