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Challenges of Providing Concordant Interpretation of Somatic Variants in Non-Small Cell Lung Cancer: A Multicenter Study.

Abstract

Background:

Success of multiple-gene mutation tests by next-generation sequencing (NGS), associated with molecular targeting therapies for cancers, depending on the accuracy and consistency of interpreting variants. Here, we summarized reports from clinical laboratories for cases with non-small cell lung cancer (NSCLC) and discussed conflicting interpretations of somatic variants.

Methods:

Three mimetic DNA samples, containing six somatic mutations, were prepared based on three clinical case reports of NSCLC. Clinical reports and genetic testing questionnaires were collected from 67 laboratories enrolled in this investigation.

Results:

Thirty-four laboratories with correct variant results identified two variants, based on FDA approval of targeted drugs for the same tumor, consistently, with strong clinical significance, whereas the other variants were classified with conflicting interpretations. Discordant interpretations were reported for ERBB2 with three different classifications, including strong clinical significance (53.0%, 18/34), potential clinical significance (38.2%, 13/34), and unknown significance (8.8%, 3/34). In the variant therapeutic drug recommendation section, 32.4% of the laboratories (11/34) did not recommend all the available therapeutic drugs designated by the National Comprehensive Cancer Network (NCCN). In the remaining group of 33 laboratories with incorrect variant results, less correct classifications were acquired for the variants with strong clinical significance.

Conclusions:

Owing to numerous reasons, the interpretation of variants differed greatly, which might in turn lead to the inappropriate clinical care of patients with NSCLC. By analyzing the limitations of different databases used by laboratories, we integrated various types of databases with different levels of evidence to form a comprehensive and detailed variant interpretation pipeline, aiming to standardize the variant classification and provide accurate and sufficient therapeutic drug recommendation to clinicians for minimal-inappropriate therapeutic options.

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  • Authors+Show Affiliations

    ,

    National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China. Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China. Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China.

    ,

    National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China. Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China.

    ,

    National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China. Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China. Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China.

    ,

    National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China. Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China. Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China.

    ,

    National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China. Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China.

    National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China. Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China. Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China.

    Source

    Journal of Cancer 10:8 2019 pg 1814-1824

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    31205538

    Citation

    Gao, Peng, et al. "Challenges of Providing Concordant Interpretation of Somatic Variants in Non-Small Cell Lung Cancer: a Multicenter Study." Journal of Cancer, vol. 10, no. 8, 2019, pp. 1814-1824.
    Gao P, Zhang R, Li Z, et al. Challenges of Providing Concordant Interpretation of Somatic Variants in Non-Small Cell Lung Cancer: A Multicenter Study. J Cancer. 2019;10(8):1814-1824.
    Gao, P., Zhang, R., Li, Z., Ding, J., Xie, J., & Li, J. (2019). Challenges of Providing Concordant Interpretation of Somatic Variants in Non-Small Cell Lung Cancer: A Multicenter Study. Journal of Cancer, 10(8), pp. 1814-1824. doi:10.7150/jca.29535.
    Gao P, et al. Challenges of Providing Concordant Interpretation of Somatic Variants in Non-Small Cell Lung Cancer: a Multicenter Study. J Cancer. 2019;10(8):1814-1824. PubMed PMID: 31205538.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Challenges of Providing Concordant Interpretation of Somatic Variants in Non-Small Cell Lung Cancer: A Multicenter Study. AU - Gao,Peng, AU - Zhang,Rui, AU - Li,Ziyang, AU - Ding,Jiansheng, AU - Xie,Jiehong, AU - Li,Jinming, Y1 - 2019/04/21/ PY - 2018/08/28/received PY - 2019/02/21/accepted PY - 2019/6/18/entrez PY - 2019/6/18/pubmed PY - 2019/6/18/medline KW - clinical significance KW - next-generation sequencing KW - non-small cell lung cancer KW - somatic variant SP - 1814 EP - 1824 JF - Journal of Cancer JO - J Cancer VL - 10 IS - 8 N2 - Background: Success of multiple-gene mutation tests by next-generation sequencing (NGS), associated with molecular targeting therapies for cancers, depending on the accuracy and consistency of interpreting variants. Here, we summarized reports from clinical laboratories for cases with non-small cell lung cancer (NSCLC) and discussed conflicting interpretations of somatic variants. Methods: Three mimetic DNA samples, containing six somatic mutations, were prepared based on three clinical case reports of NSCLC. Clinical reports and genetic testing questionnaires were collected from 67 laboratories enrolled in this investigation. Results: Thirty-four laboratories with correct variant results identified two variants, based on FDA approval of targeted drugs for the same tumor, consistently, with strong clinical significance, whereas the other variants were classified with conflicting interpretations. Discordant interpretations were reported for ERBB2 with three different classifications, including strong clinical significance (53.0%, 18/34), potential clinical significance (38.2%, 13/34), and unknown significance (8.8%, 3/34). In the variant therapeutic drug recommendation section, 32.4% of the laboratories (11/34) did not recommend all the available therapeutic drugs designated by the National Comprehensive Cancer Network (NCCN). In the remaining group of 33 laboratories with incorrect variant results, less correct classifications were acquired for the variants with strong clinical significance. Conclusions: Owing to numerous reasons, the interpretation of variants differed greatly, which might in turn lead to the inappropriate clinical care of patients with NSCLC. By analyzing the limitations of different databases used by laboratories, we integrated various types of databases with different levels of evidence to form a comprehensive and detailed variant interpretation pipeline, aiming to standardize the variant classification and provide accurate and sufficient therapeutic drug recommendation to clinicians for minimal-inappropriate therapeutic options. SN - 1837-9664 UR - https://www.unboundmedicine.com/medline/citation/31205538/Challenges_of_Providing_Concordant_Interpretation_of_Somatic_Variants_in_Non-Small_Cell_Lung_Cancer:_A_Multicenter_Study L2 - http://www.jcancer.org/v10p1814.htm DB - PRIME DP - Unbound Medicine ER -