Dr. Pacini was the recipient of the Merck-Serono Prize at the ETA Meeting 2008.
Reviewing Editor: Luca Persani
The Authors declare no conflict of interest related to this work.
Correspondence:
Furio Pacini
Section of Endocrinology and Metabolism
University of Siena
Viale Bracci,1
53100 Siena
The clinical and genetic features of patients with familial non-medullary thyroid cancer (FNMTC)
are heterogeneous and far from being defined. Familial predisposition in differentiated thyroid
carcinoma is reported in 3-10% of the cases (1,2), in absence of recognized predisposing
syndromes (Cowden syndrome, Werner syndrome, Carney complex, Familial adenomatous
polyposis) and the risk of developing the same tumor in first-degree relatives of subjects with
differentiated thyroid cancer (DTC) is significantly higher than in the general population (3,4). Until
now, no specific genetic alterations have been demonstrated in the blood of FNMTC patients, apart
from susceptibility loci found in a few pedigrees with FNMTC (5-7). Recent studies (8) reported that
patients with FNMTC display the features of “anticipation phenomenon”, that is the tendency for
children to develop clinical disease at an earlier age than the affected parents. In fact, after ruling
out the bias of screening effect, patients in the second generation presented an earlier age at
disease presentation at diagnosis and at disease onset compared to the first generation and their
tumours were more frequently multifocal and bilateral, had higher rate of lymph node metastases
at surgery and worse outcome compared to the first generation. The presence of genetic
anticipation has been reported in several non-thyroidal diseases (Table1). In thyroid diseases the
occurrence of disease anticipation has been reported in a large multigenerational family with
medullary thyroid cancer (9), but in this case the occurrence of anticipation is uncertain because it
was biased by the introduction of genetic analysis as a screening procedure. Preliminary evidence
of genetic anticipation has been also reported in familial cases of Graves' disease (10).
Table 1. Human diseases with demonstrated or suggested anticipation phenomenon.
Several molecular mechanism(s) possibly underlying genetic anticipation have been studied in
familiar disorders, mainly benign, with particular attention to the telomere-telomerase complex.
Telomeres are special structures consisting of a tandem repeats of the sequence TTAGGG at the
ends of chromosomes that are maintained by telomerase, a specialized ribonucleoprotein complex
that includes an RNA template (TERC) and a reverse transcriptase catalytic subunit (TERT).
Telomerase expression is low or absent in most of human somatic tissues, while it is expressed in
germ and stem cell compartments. Telomeric DNA is dynamic, being progressively lost with each
cell division due to incomplete replication of the ends of linear DNA. When telomeres become
critically short, the cells undergo senescence or apoptosis but if the integrity of checkpoints
mechanisms are altered genomic instability is triggered and leads to cycles of chromosome
breakage and fusion, in a period called “crisis” that permit the acquisition of further genetic
alterations. Although most cells die by apoptosis during the “crisis”, rare cells survive and maintain
stable short telomere lengths through the reactivation of telomerase that facilitates cell
immortalization (11). The strong association of telomerase re-activation with cancer provides
evidence that this mechanism plays an important role in cancer development (Figure 1). RTL
segregates in families (12,13) and a decrease in telomere length may play a role in age-related
genetic instability (14). Interestingly, patients who have inherited or acquired genetic defects in
telomere maintenance seem to have an increased risk of developing familial benign disease such
as dyscheratosis congenital syndrome (15) and malignant diseases such as head, neck, lung,
breast, and renal cancers (16).
Figure 1. In cells with intact signalling pathways, short telomeres trigger either senescence or apoptosis. In
cells with disabled checkpoints, short dysfunctional telomeres trigger chromosome instability, perpetuated
through recurrent breakage-fusion-bridge cycles. Few cells, through reactivation of a telomere maintenance
mechanism, usually telomerase, stabilize telomere length and chromosome ends, resulting in cell
immortalization. Upon additional somatic events, the latter may eventually acquire malignant phenotype
(figure adapted from Londono-Vallejo. Biochimie 91:73-82, 2008).
In sporadic thyroid cancer telomerase re-activation is reported in nearly 50% of thyroid cancer
tissues and in the past same authors proposed that the detection of telomerase activity may be
helpful to distinguish between malignant and benign thyroid tumours (16-18), but the large majority
of these studies were conducted on tumor tissues, while blood was not investigated. Recently, first
evidence has been provided that patients with FNMTC have dysfunctional telomeres compared to
patients with sporadic differentiated thyroid cancer, patients with benign thyroid diseases, healthy
subjects and unaffected siblings of FNMTC patients (19). FNMTC patients had significantly shorter
relative telomere length (RTL) in their peripheral blood cells, compared to sporadic cases and
normal controls. hTERT gene was significantly amplified in FNMTC patients respect to control
groups and it was significantly more represented in 2nd generation with respects to 1st generation.
In addition, hTERT mRNA levels and the protein activity were significantly increased in FNMTC
patients compared to control groups.
In conclusion, evidences have been provided for the presence in FNMTC of genetic anticipation at
the clinical level and of short telomere lengths, hTERT gene amplification and increased
telomerase expression in peripheral white blood cells at the molecular level. It is possible that
patients born with short telomeres might reach earlier in life the threshold telomere length sufficient
to trigger cancer development and this observation is consistent with the presence of genetic
anticipation observed in FNMTC patients. If further confirmed in larger series, these results might
propose measurement of RTL, as a marker of predisposition to FNMTC.
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