Endocrine Abstracts

Background: Human cancer is characterized by the accumulation of somatic alterations including base substitutions, indels, structural rearrangements and somatic copy number alteration (CNA), either gain or loss, of chromosomes that can be responsible either for initiation and/or cancer progression. About 80% of Sporadic Medullary Thyroid Carcinoma (sMTC) harbor RET or RAS somatic alterations with a negative prognostic role for the presence of the RET mutation; a few studies about the role of chromosomal CNA in MTC have been published so far showing a variable frequency ranging from 50%-77%.

Objective: Aim of this study was to evaluate the global genomic profile of a series of 41 sMTC obtained by Comparative Genomic Hybridization array (array-CGH). The presence of CNAs was compared to the presence of a RET mutation and clinical and pathological features of MTC patients in order to investigate their role in tumor behaviour.

Methods and Results: Twenty-five cases (25/41, 61%) showed at least one CNA with a range of CNA per sample: [1 to 27] while 16 cases (16/41, 39%) did not show any CNA. In general, losses in chromosomal regions were more frequent than gains (91 vs 50 events). Chromosomes most frequently involved in CNA were chromosome 22 (31.7% of cases), chromosome 1 (29.3% of cases), chromosomes 3 (19.5% of cases), chromosomes 10 (17.1% of cases), chromosome 21 (14.6% of cases), while the remaining chromosomes were affected only by few CNAs. When we compared the presence of CNA with the presence of somatic RET mutations, we found that 18/23 RET+ cases (78.3%), showed the presence of at least one CNA, present in only 7/18 (38.9%) RET- cases (P = 0.02). The CNAs in RET+ MTC patients were significantly associated with chromosomes 3 (P = 0.0035) and 10 (P = 0.007). We finally correlated the cases harboring at least one CNA with the outcome of sMTC patients (disease free, persistent disease at biochemical level and metastatic disease) and we found that patients present in a metastatic disease showed a higher rate of CNAs (P = 0.005) and the chromosomes mainly affected by these CNAs were chromosomes 3 (P = 0.002), 9 (P = 0.02), 10 (P = 0.2) and 16 (P = 0.02).

Conclusions: In conclusion, MTC cases showing CNAs were mainly the ones harboring a RET mutation, suggesting that a higher level of chromosomal instability could be responsible for a higher rate of chromosomal alterations. Interestingly, the regions involved with loss and gain show the presence of important tumor suppressor genes and oncogenes, respectively, that could justify a role of these CNAs in the progression of the disease.