Clinical and Genetic Features of a Large Monocentric Series of Familial Non-Medullary Thyroid Cancers

Abstract

Several low penetration susceptibility risk loci or genes have been proposed in recent years with a possible causative role for familial non-medullary thyroid cancer (FNMTC), though the results are still not conclusive or reliable. Among all the candidates, here fully reviewed, a new extremely rare germline variant c.3607A>G (p.Y1203H) of the DUOX2 gene, has been recently reported to co-segregate with the affected members of one non-syndromic FNMTC family. We aimed to validate this finding in our series of 33 unrelated FNMTC Italian families, previously found to be negative for two susceptibility germline variants in the HABP2 and MAP2K5 genes. Unfortunately, the DUOX2 p.Y1203H variant was not found in either the 74 affected or the 12 not affected family members of our series. We obtained interesting data by comparing the clinico-pathological data of the affected members of our kindreds with a large consecutive series of sporadic cases, followed at our site. We found that familial tumors had a statistically significant more aggressive presentation at diagnosis, though not resulting in a worst outcome. In conclusion, we report genetic and clinical data in a large series of FNMTC kindreds. Our families are negative for variants reported as likely causative, namely those lying in the HABP2, MAP2K5 and DUOX2 genes. The extensive review of the current knowledge on the genetic risk factors for non-syndromic FNMTCs underlies how the management of these tumors remains mainly clinical. Despite the more aggressive presentation of familial cases, an appropriate treatment leads to an outcome similar to that observed for sporadic cases.

Unilateral Surgery for Medullary Thyroid Carcinoma: Seeking for Clinical Practice Guidelines

“…The trend toward more favorable primary MTC stages leads to the need to avoid overtreatment by adapting the resection strategy on a case-by-case basis. Prerequisites for this are the comprehensive clinical and laboratory diagnosis of the individual case as well as the structural availability of qualified pathologists, in order to obtain an intraoperative frozen section analysis though considering the above reported limitations (32)(33)(34)(35). If the preoperative criteria indicate a sporadic, unifocal, and with expected biochemical cured MTC, and the intraoperative frozen section excludes desmoplasia and capsular infiltration or finds them only to a minor extent, the resection could be limited.…”

Identification of NID1 as a novel candidate susceptibility gene for familial non-medullary thyroid carcinoma using whole-exome sequencing

“…As first step, we mined the literature for candidate non-syndromic FNMTC susceptibility genes. In total, we identified 114 candidate genes across 32 independent studies ( 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 30 , 31 , 33 , 34 , 35 , 36 , 37 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ). A list of included genes and studies is provided in Supplementary data (Supplementary Table 1, see section on supplementary materials given at the end of this article).…”

“…The analysis of different kindreds with FNMTC advocates for an autosomal dominant inheritance with incomplete penetrance and variable expressivity ( 1 , 4 , 5 , 6 , 7 , 8 ). In the past years, several studies reported FNMTC-associated chromosomal loci ( 3 , 15 , 16 , 17 , 18 ) and predisposing risk variants in over 100 genes, including SRGAP1 , CHEK2 , SRRM2 , TIFF-1/NKX2 , FOXE1 , NOP53 , HABP2 , ANO7 , CAV2 , KANK1 , PIK3CB , PKD1L1 , PTPRF , BROX , RHBDD2 , ATM , MAP2K5 , EWSR1 , POT1 , TIAM1 and SPRY4 ( 1 , 3 , 7 , 12 , 15 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ). Recently, using whole-genomic sequencing, a group has identified variants in genes that were enriched in tumourigenic signalling pathways such as MAPK/ERK and PI3K/AKT in families with NMTC ( 19 ).…”

Susceptibility Genes and Chromosomal Regions Associated With Non-Syndromic Familial Non-Medullary Thyroid Carcinoma: Some Pathogenetic and Diagnostic Keys

“…In this same family, in addition to the germinal missense variant p.Tyr1203His (c.3607A>G) in DUOX2, the p.Gln61Arg somatic mutation in KRAS was detected in a follicular variant of mPTC and the somatic mutation of BRAF V600E in a classic form of mPTC ( 26 ). Unfortunately, the role of this germline variant could not be confirmed in a recent series of 33 unrelated Italian FNMTC kindreds ( 91 ).…”