The HABP2 G534E Variant Is an Unlikely Cause of Familial Nonmedullary Thyroid Cancer

Sahasrabudhe, Ruta; Stultz, Jacob; Williamson, John B.; Lott, Paul; Estrada, Ana; Bohórquez, Mábel; Palles, Claire; Polanco-Echeverry, Guadalupe; Jaeger, Emma; Martin, Lynn; Echeverry, María Magdalena; Tomlinson, Ian; Carvajal‐Carmona, Luis G.

doi:10.1210/jc.2015-3928

Cited by 35 publications

(28 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the contrary, these results are in line with 4 other recent publications opposing this concept [9-12]. …”

Section: Discussionsupporting

confidence: 91%

“…In contrast, later on, 4 other studies on HABP2 [9-12] investigated the G534E variant, and they could not confirm G534E as a HABP2 variant responsible for the susceptibility to FNMTC in their respective cohorts from different ethnical backgrounds.…”

Section: Discussionmentioning

confidence: 94%

“…No mutations were found in familial or sporadic NMTC cases [9]. Sahasrabudhe et al [12] used 2,105 FNMTC patients (including Hurtle-cell variant of TC) and found that the prevalence of the G534E variant in FNMTC (4.2%) equaled the prevalence in the healthy control population (4.6%) from a previous UK population case-control study (TCUKIN).…”

Section: Discussionmentioning

confidence: 99%

“…For example, Tomsic et al [11] found the HABP2 variant G534E to be relatively frequent (6.1% in familial cases, 8.0% in sporadic cases, and 8.7% in healthy controls) in their studied population (American). A study of the population of the British Isles found a relatively high occurrence of the variant (4.2% in familial cases and 4.6% in controls) but no cosegregation with the disease [12]. Furthermore, an Australian study only found the variant to be present in 1/37 probands (2.7%) but did not segregate with the disease in the family [13].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Frequent and Rare HABP2 Variants Are Not Associated with Increased Susceptibility to Familial Nonmedullary Thyroid Carcinoma in the Spanish Population

et al. 2018

View full text Add to dashboard Cite

Background/Aims: A genomic HABP2 variant was proposed to be responsible for familial nonmedullary thyroid carcinoma (FNMTC). However, its involvement has been questioned in subsequent studies. We aimed to identify genetic HABP2 mutations in a series of FNMTC patients and investigate their involvement in the disease. Methods: HABP2 was sequenced from 6 index patients. Presence of the variants was investigated in all members of one family. Somatic BRAF and RAS “hotspot” mutations were investigated by the Idylla^TM BRAF Mutation Test and/or Sanger sequencing. Results: Two HABP2 variants (p.E393Q and p.G534E) were identified in the index patient from one family with papillary thyroid carcinoma (PTC) (follicular variant). The prevalence of p.E393Q in Spanish control alleles was 0.5% and that of p.G534E was 5.1%. However, neither change cosegregated with the phenotype in 3 affected members and 5 healthy members of the kindred. Interestingly, all 3 members affected by PTC harbored the p.V600E somatic mutation in BRAF. Conclusions: The variant G534E is prevalent in the Spanish population (5.1%); however, p.E393Q is rare (< 1%) and none cosegregated with the FNMTC phenotype. The presence of the noninheritable V600E BRAF mutation in this family supports Knudson’s “double-hit” hypothesis for cancer development and suggests the involvement of more than 1 gene in the clinical expression of FNMTC.

show abstract

“…On the contrary, these results are in line with 4 other recent publications opposing this concept [9-12]. …”

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Frequent and Rare HABP2 Variants Are Not Associated with Increased Susceptibility to Familial Nonmedullary Thyroid Carcinoma in the Spanish Population

et al. 2018

View full text Add to dashboard Cite

show abstract

“…The frequency of HABP2 G534E was 4.2% in cases and 4.6% in controls. There was no association between this variant and NMTC risk across all histological sub-types (PTC, FTC and Hurthle cell) (Sahasrabudhe et al 2015).…”

Section: Habp2mentioning

confidence: 85%

Familial non-medullary thyroid cancer: unraveling the genetic maze

Yang¹,

Ngeow²

2016

Endocrine-Related Cancer

103

View full text Add to dashboard Cite

Familial non-medullary thyroid cancer (FNMTC) constitutes 3-9% of all thyroid cancers. Out of all FNMTC cases, only 5% in the syndromic form has well-studied driver germline mutations. These associated syndromes include Cowden syndrome, familial adenomatous polyposis, Gardner syndrome, Carney complex type 1, Werner syndrome and DICER1 syndrome. It is important for the clinician to recognize these phenotypes so that genetic counseling and testing can be initiated to enable surveillance for associated malignancies and genetic testing of family members. The susceptibility chromosomal loci and genes of 95% of FNMTC cases remain to be characterized. To date, 4 susceptibility genes have been identified (SRGAP1 gene (12q14), TITF-1/NKX2.1 gene (14q13), FOXE1 gene (9q22.33) and HABP2 gene (10q25.3)), out of which only the FOXE1 and the HABP2 genes have been validated by separate study groups. The causal genes located at the other 7 FNMTCassociated chromosomal loci (TCO (19q13.2), fPTC/ PRN (1q21), FTEN (8p23.1-p22), NMTC1 (2q21), MNG1 (14q32), 6q22, 8q24) have yet to be identified. Increasingly, gene regulatory mechanisms (miRNA and enhancer elements) are recognized to affect gene expression and FNMTC tumorigenesis. With newer sequencing technique, along with functional studies, there has been progress in the understanding of the genetic basis of FNMTC. In our review, we summarize the FNMTC studies to date and provide an update on the recently reported susceptibility genes including novel germline SEC23B variant in Cowden syndrome, SRGAP1 gene, FOXE1 gene and HABP2 genes in non-syndromic FNMTC.

show abstract

Whole exome and target sequencing identifies MAP2K5 as novel susceptibility gene for familial non‐medullary thyroid carcinoma

Yan

Gao

Lin

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

Although the genotype-phenotype for familial medullary thyroid carcinoma (FMTC) is well studied, only few low susceptibility risk loci were identified for familial non-medullary thyroid carcinoma (FNMTC). The aim of this study is to screen and identify high-penetrate genes for FNMTC. A total of 34 families with more than two first-degree relatives diagnosed as papillary thyroid cancer without other familial syndrome were recruited. Whole exome and target gene sequencing were performed for candidate variants. These variants were screened and analyzed with ESP6500, ExAC, 1000 genomes project, and the Cancer Genome Atlas (TCGA) with SIFT score and Polyphen2 prediction. Finally, we identified recurrent genetic mutation of MAP2K5 variants c.G961A and c.T1100C (p. A321T and p.M367 T) as susceptibility loci for FNMTC. The frequencies of MAP2K5 c.G961A and c.T1100C were found, 0.0385 and 0.0259 in FNMTC and 0 and 0.00022523 in healthy Chinese controls (n = 2200, P < 0.001), respectively. Both variants were located in the protein kinase domain. The functional study showed that MAP2K5 A321T or M367 T could consistently phosphorylate downstream protein ERK5 on site Ser731 + Thr733 or Ser496, promoting nuclear translocation and subsequently altering target gene expressions. Our data revealed that MAP2K5 variants A321T or M367 T can activate MAP2K5-ERK5 pathway, alter downstream gene expression, and subsequently induce thyroid epithelial cell malignant transformation. While classic MAP2K1/2(MEK1/2)-ERK1/2 signaling is well known for driving sporadic NMTC, our research indicated that MAP2K5 (MEK5) is a susceptibility gene for FNMTC. These findings highlight the potential application of MAP2K5 for molecular diagnosis as well as early prevention.

show abstract

The HABP2 G534E Variant Is an Unlikely Cause of Familial Nonmedullary Thyroid Cancer

Cited by 35 publications

References 31 publications

Frequent and Rare HABP2 Variants Are Not Associated with Increased Susceptibility to Familial Nonmedullary Thyroid Carcinoma in the Spanish Population

Frequent and Rare HABP2 Variants Are Not Associated with Increased Susceptibility to Familial Nonmedullary Thyroid Carcinoma in the Spanish Population

Familial non-medullary thyroid cancer: unraveling the genetic maze

Whole exome and target sequencing identifies MAP2K5 as novel susceptibility gene for familial non‐medullary thyroid carcinoma

Contact Info

Product

Resources

About