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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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). 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.
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). 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t(3;8)(p14.2;q24.1) (11) (Eng, C. and R. S. Brown, unpublished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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Received March 15, 2000.
Accepted March 15, 2000.
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