Pan-Genomic Sequencing Reveals Actionable CDKN2A/2B Deletions and Kataegis in Anaplastic Thyroid Carcinoma
Round 1
Reviewer 1 Report
In this manuscript Stenman, Yang et al. performed a pan-genomic analysis in tumor samples from a cohort of 8 patients with anaplastic thyroid carcinoma based on whole genome sequencing and RNA sequencing. The authors identified variants in established ATC-related genes as well as in 13 additional cancer genes. They also observed a focal hypermutation phenotype related to APOBEC (implied in kataegis) in 50% of the cases. The authors corroborated the importance of CDKN1A and CDKN1B in ATC. Variants were found in the promoter region of TERT, as well as a XPO5-CHST9 genes fusion. The manuscript is well written, the method is appropriated, and the conclusions are reasonable.
General comments:
This is an interesting study that bring new information in the characterization of anaplastic thyroid carcinoma.
Minor comments:
The authors should comply with the journal guidelines on genetic nomenclature, following the Human Genome Variation Society (http://varnomen.hgvs.org) and preferentially including, in the first time the mutation appear, the description at the DNA level and rs number (if available).
Author Response
Please see the attached rebuttal letter.
Author Response File: Author Response.docx
Reviewer 2 Report
The manuscript “Pan-genomic sequencing reveals actionable CDKN1A/2B deletions and kataegis in anaplastic thyroid carcinoma” is well organized and written.
Although the authors have performed NGS and RNA sequencing in only 8 ATC samples, which is a quite small number to represent a good cohort, they have confirmed CDKN2A/CDKN2B gene deletions, coupled with downregulation of the corresponding mRNA when compared to diploid cases. The authors have also shown regions of hypermutability and found a novel fusion gene involving XPO5 oncogene in only one case.
The article is well structured and written. Just few small notes:
- line 36: shouldn´t it be “which” instead of “with”?
- line 44: review “predominantly presents”
- line 57: review “not least”
- line 103: tissue… WAS collected
Results and particularly conclusions, could be more elaborated and explored.
Is there any explanation/alternative for why two cases (103 and 109) and no mutation/alteration whatsoever? Is this a common finding in ATCs?
Do the authors obtain any results on miRNA expression?
Are the authors addressing a potential role for the XPO5-CHST9 fusion gene on ATCs or other thyroid tumors?
As a conclusion the authors state that the majority of ATCs displayed loss of CDKNs. Although the sample size is small (n=8), it would be exactly 50% and not the majority.
Author Response
Please see the attached rebuttal letter.
Author Response File: Author Response.docx