Umut Arda BAYRAKTAR, Feride İffet ŞAHİN, Mert POLAT, Yunus Kasım TERZİ

Klinik ekzom verilerinin yeniden sınıflandırılması hastaların yaklaşık olarak yarısında klinik değerlendirmede anlamlı değişmelere neden olmaktadır

Amaç: Gen varyantlarının patojenitelerindeki değişmelerin (yeniden sınıflandırma) klinik önemleri genetik/klinik veriler arttıkça giderek daha çok anlaşılmaktadır. Bize göre bu durum hastaların varyantları yeniden sınıflandırıldığında genetik risk değerlendirmesinde kliniksel açıdan önemli tutarsızlıklara yol açabilmektedir. Bu çalışmada, hastalarımızın klinik ekzom sekanslama (CES) verilerini yeniden sınıflandırarak bu verilerin klinik açıdan anlamlılığını değerlendirdik. Gereç ve Yöntem: Kendisinde kanser teşhis edilmiş veya ailesel kanser yatkınlığı olan 23 hastanın CES verileri incelendi. İncelenen varyantlar ACMG veri tabanı kullanılarak 2020 yılında sınıflandırıldıktan sonra ertesi yıl tekrardan sınıflandırıldı. Hastaların klinik hikayelerini ve yapılan müdahaleleri kaydedebilmek için hasta dosyaları incelendi. Bulgular: CES verilerinin ilk incelenmesinde, benign olmayan 80 varyant tespit edilmiştir (26 olası patojenik/patojenik ve 54 önemi bilinmeyen varyant (VUS)). Yeniden sınıflandırma sonrası 10 hastada (%43) 15 varyantın (%19) klinik önemi değişmiştir. Klinik önemi artan tek varyant BRCA2 geninin ekzon 23’ündeki c.9097 dup varyantı olmuştur (olası patojenikten patojeniğe). Yeniden analiz sonrası dokuz hastada 14 varyantın klinik önemi azalmıştır: patojenikten olası patojeniğe (2 varyant), patojenikten VUS’a (2 varyant), olası patojenikten VUS’a (4 varyant) ve VUS’dan benigne (6 varyant). Sonuç: Çalışılan hastaların yaklaşık yarısında CES verilerinin klinik öneminin yeniden analizler sonrası değiştiği düşünüldüğünde, genetik varyantlar ile ilişkili verilerin klinikteki takip durumlarından bağımsız olarak düzenli aralıklarla değerlendirilmesi gerektiğine inanmaktayız.

Anahtar Kelimeler:

Kanser, klinik ekzom sekanslama, olası patojenik/patojenik varyantlar

Reclassification of clinical exome data leads to significant clinical assessment changes in almost half of the patients

Purpose: With the global accumulation of genetic/clinical data, we are understanding the clinical significance of the reclassification of pathogenicity for gene variants. We hypothesized that this evolution in classification(s) may cause clinically-relevant discrepancies in the genetic risk assessment of subjects. In this study, we sought to reclassify the clinical exome sequence (CES) data of our patients to assess whether these changes would have clinical significance. Materials and Methods: The study included CES data of 23 cases diagnosed with cancer or familial cancer predisposition. The variants were first classified in 2020 and then reclassified a year after based on the ACMG database. Chart reviews were performed to record clinical history and interventions. Results: In the first classification of CES data, a total of 80 variants were identified as being not benign (26 likely pathogenic/pathogenic and 54 variants of undetermined significance (VUS)). The clinical significance of fifteen variants (19%) changed after reclassification in 10 patients (43%). The only upgraded variant was the c.9097 dup in exon 23 of BRCA2 gene (likely pathogenic to pathogenic). Fourteen variants were downgraded at reanalysis in 9 patients: from pathogenic to likely pathogenic (2 variants), pathogenic to VUS (2), likely pathogenic to VUS (4), and VUS to benign (6). Conclusion: Considering that the clinical significance of CES data changed due to reclassification in almost half of the studied patients, we believe genetic variant-related data should be assessed at regular intervals, regardless of follow-up status in the clinic.

Keywords:

cancer, clinical exome sequencing, likely pathogenic/pathogenic variants,

PDF

___

Hood L, Galas D. The digital code of DNA . Nature. 2003;421:444-8.
Reddy EP, Reynolds RK, Santos E, Barbacid M. A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene. Nature. 1982;300:149-52.
Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004;10:789-99.
Amendola LM, Jarvik GP, Leo MC, McLaughlin HM, Akkari Y, Amaral MD et al. Performance of ACMG-AMP variant-interpretation guidelines among nine laboratories in the clinical sequencing exploratory research consortium. Am J Hum Genet. 2016;98:1067-76.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24.
Rivera-Muñoz EA, Milko LV, Harrison SM, Azzariti DR, Kurtz CL, Lee K et al. ClinGen variant curation expert panel experiences and standardized processes for disease and gene-level specification of the ACMG/AMP guidelines for sequence variant interpretation. Hum Mutat. 2018;39:1614-22.
Ji J, Leung ML, Baker S, Deignan JL, Santani A. Clinical exome reanalysis: Current practice and beyond. Mol Diagn Ther. 2021;25:529-36.
Al-Nabhani M, Al-Rashdi S, Al-Murshedi F, Al-Kindi A, Al-Thihli K, Al-Saegh A et al. Reanalysis of exome sequencing data of intellectual disability samples: Yields and benefits. Clin Genet. 2018;94:495-501.
Felicio PS, Grasel RS, Campacci N, de Paula AE, Galvao HCR, Torrezan GT et al. Whole-exome sequencing of non-BRCA1/BRCA2 mutation carrier cases at high-risk for hereditary breast/ovarian cancer. Hum Mutat. 2021;42:290-9.
Susswein LR, Marshall ML, Nusbaum R, Postula KJV, Weissman SM, Yackowski L et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet.Med. 2016;18:823-32.
Fernandes GC, Michelli RAD, Galvão HCR, Paula AE, Pereira R, Andrade CE et al. Prevalence of BRCA1/BRCA2 mutations in a Brazilian population sample at-risk for hereditary breast cancer and characterization of its genetic ancestry. Oncotarget. 2016;7:80465-81.
Mehta A, Vasudevan S, Sharma SK, Kumar D, Paniqrahi M, Suryavanshi M et al. Germline BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance associated with breast/ovarian cancer: a report from North India. Cancer Manag Res. 2018;10:6505-16.
Rahman N. Realizing the promise of cancer predisposition genes. Nature. 2014;505:302-8.
Garber KB, Vincent LM, Alexander JJ, Bean LJH, Bale S, Hegde M. Reassessment of genomic sequence variation to harmonize interpretation for personalized medicine. Am. J. Hum. Genet. 2016;99:1140-9.
Esterling L, Wijayatunge R, Brown K, Morris B, Hughes E, Pruss D et al. Impact of a cancer gene variant reclassification program over a 20-year period. JCO Precis Oncol. 2020;4:944-954.
Ndugga-Kabuye MK, Issaka RB. Inequities in multi-gene hereditary cancer testing: lower diagnostic yield and higher VUS rate in individuals who identify as Hispanic, African or Asian and Pacific Islander as compared to European. Fam Cancer. 2019;18:465-69.
Muir SM, Reagle R. Characterization of variant reclassification and patient re-contact in a cancer genetics clinic. J Genet Couns. 2022;31:1261-72.
Macklin S, Durand N, Atwal P, Hines S. Observed frequency and challenges of variant reclassification in a hereditary cancer clinic. Genet Med. 2018;20:346-50.