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Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Identification of PKHD1 mutations in Brain, Breast and Rectal tumors by Next Generation DNA Sequencing
Duaa Mohammed Almehmadi1,2, Abdulrhman Saleh Dairi2, Amal Ali Hassan3,4
1Department of Internal medicine, King Faisal General Hospital Makkah, Makkah, Saudi Arabia.
Introduction:
It is well established that the PKHD1 mutations are associated with autosomal recessive polycystic kidney disease (ARPKD). Although, PKHD1 mutations are also detected in certain cancer types, to our knowledge in rare tumors such as, atypical teratoid rhabdoid tumor (ATRT), primary neuro-ectodermal tumor (PNET), atypicalchoroid plexus papilloma (a-CPP), amelanotic ano-rectal melanoma (AMM), and breast phyllodes tumors PKHD1 mutations profiling is not reported.
Methods:
In order to determine the PKHD1 gene mutation patterns in the brain, rectal, and breast tumors we have analyzed these tumor DNA by Ion Proton Next generation DNA sequencing.
Results:
Next-generation DNA sequencing on Ion Proton identified unique and common missense mutations in the brain, breast and ano-rectal tumors. All mutations were benign, and only one pathogenic mutation in p. (Cys3346Arg) found in AMM tumor. In phyllodes tumor of breast, two unique missense variants were detected (rs113562492) p. (Met2841Val); and (rs137972270) in p. (Arg589Cys) and these variants are not present in other tumors tested. The variant rs137972270 was reported only in two cases sofar in ClinVar database. Missense variants such as rs115045643, rs116809571, rs115338476, and rs76895755 are found only in PNET, and a variant rs62406032 in a-CPP, another one rs35445653 in ATRT cases were unique for these tumors, which are not present in other tumors. Several synonymous and intronic variants of PKHD1 gene were also found in these tumors. A synonymous variant p. (Asp395Asp), rs1896976 and two intronic SNPs viz., rs1326605, and rs1571084 were found in all tumors tested. The SNP rs9395699 in IVS66 was found uniquely in IPC breast tumor only in this study. Allele coverage, allele ratio, p-value, Phred qual score, sequencing coverage, alleles frequencies were also analysed, the p-values and Phred quality score were significantly higher.
Conclusion:
These tumors did not have any insertion/ deletion mutations, nonsense, or truncated mutations in it. The screening of PKHD1 gene revealed signature mutations for the solid tumors studied by NGS method. This investigation may help in understanding these tumor pathology at molecular level.
Insights
PKHD1 gene mutations were profiled in rare brain, breast, and rectal tumors using next-generation sequencing. While most mutations were benign, this study identified unique PKHD1 variants, offering insights into tumor pathology.
Area of Science:
- Genomics
- Oncology
- Molecular Biology
Background:
- PKHD1 gene mutations are linked to autosomal recessive polycystic kidney disease (ARPKD).
- PKHD1 mutations have been observed in various cancers, but their profiling in rare tumors like atypical teratoid rhabdoid tumor (ATRT), primary neuro-ectodermal tumor (PNET), atypical choroid plexus papilloma (a-CPP), amelanotic ano-rectal melanoma (AMM), and breast phyllodes tumors remains largely unreported.
Purpose of the Study:
- To investigate the mutation patterns of the PKHD1 gene in brain, rectal, and breast tumors.
- To identify unique and common PKHD1 variants in these rare solid tumors.
Main Methods:
- DNA from brain, rectal, and breast tumors was analyzed using Ion Proton Next-Generation DNA sequencing.
- Mutation profiling included identification of missense, synonymous, and intronic variants.
Main Results:
- Next-generation sequencing revealed unique and common missense mutations in PKHD1 across the studied tumors.
- A single pathogenic mutation (p.Cys3346Arg) was found in an amelanotic ano-rectal melanoma (AMM) tumor.
- Several unique missense variants were identified in PNET, a-CPP, ATRT, and breast phyllodes tumors, with some variants being rare or previously unreported.
Conclusions:
- The studied solid tumors lacked insertion/deletion, nonsense, or truncated mutations in the PKHD1 gene.
- PKHD1 gene screening identified distinct mutation signatures for these solid tumors using next-generation sequencing.
- This molecular-level investigation may enhance the understanding of these rare tumor pathologies.
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