Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Poster display session

2362 - Preliminary results on germline and somatic molecular investigations in Romanian Lynch syndrome patients

Date

09 Sep 2017

Session

Poster display session

Topics

Genetic and Genomic Testing, Counseling;  Gastrointestinal Cancers

Presenters

Lucian Negura

Citation

Annals of Oncology (2017) 28 (suppl_5): v158-v208. 10.1093/annonc/mdx393

Authors

L. Negura1, A. Chicos1, R. Avadanei1, A.M. NEGURA2

Author affiliations

  • 1 Oncogenetics, G.T.Popa University of Medicine and Pharmacy, 700115 - Iasi/RO
  • 2 Biology, Alexandru Ioan Cuza University of Iasi, 700506 - Iasi/RO
More

Resources

Abstract 2362

Background

Up to 30% of colorectal cancers (CRCs) have evidence of a familial component, and about 5% are thought to be due to inherited mutations in MMR (MisMatch Repair) genes. Lynch syndrome (LS) is characterized by a very early onset and lifetime risk estimated to 80%. The gold standard for LS diagnostic is complete Sanger sequencing, a very complex and expensive analysis. MMR mutations are detected in only 60% of criteria fulfilling families, while they are present in up to 20% of families not fulfilling these criteria and which are implicitly excluded from genetic counselling. Therefore, we propose an adapted algorithm, based on germline and tumor analysis, intended to increase molecular diagnostic efficiency and CRC casuistry coverage.

Methods

20 LS families were selected according to Amsterdam criteria, and one index case per family agreed to participate by signing informed consent. All coding regions and exon-intron boundaries of MSH2, MLH1 and MSH6 were screened by double strand Sanger sequencing. Sequence variants were interpreted by in-silico analysis. MLPA was performed for large genomic rearrangements. MMR protein expression in tumors was investigated by immunohistochemistry. Somatic tumor DNA was checked for Microsatellite instability (MSI), MLH1 promoter hypermethylation (PHM), as well as for BRAF V600E mutation.

Results

Over 50% of our samples presented germline variants, the majority being benign. Four unclassified variants are altering splicing enhancers. One deleterious variant, but no recurrent MMR mutations were detected. No large genomic rearrangements were identified. IHC showed loss of MSH2 and MLH1 in several samples also presenting high MSI. No PHM was observed, but somatic BRAF V500E showed to be present in several samples. Data from germline analysis correctly correlated with somatic investigations.

Conclusions

This is the first complete molecular approach of LS in Romania. Our work has an important impact on reducing the cost and time of molecular diagnostic, include for diagnostic more patients than usually selected, perform a more efficient diagnostic with >80% mutation finding probability, provide evidence-based recommendations for oncogenetic diagnostic. Acknowledgement: PN-II-RU-TE-2014-4-2257.

Clinical trial identification

Legal entity responsible for the study

G. T. Popa University of Medicine and Pharmacy, Iasi, Romania

Funding

Executive Agency for Higher Education, Research, Development and Innovation Funding (UEFISCDI), Romania

Disclosure

All authors have declared no conflicts of interest.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.