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. 2019 Aug 1;30(8):1221-1231.
doi: 10.1093/annonc/mdz136.

Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working Group

D Mandelker  1 , M Donoghue  2 , S Talukdar  3 , C Bandlamudi  2 , P Srinivasan  2 , M Vivek  4 , S Jezdic  5 , H Hanson  3 , K Snape  3 , A Kulkarni  6 , L Hawkes  7 , J-Y Douillard  5 , S E Wallace  8 , E Rial-Sebbag  9 , F Meric-Bersntam  10 , A George  11 , D Chubb  12 , C Loveday  12 , M Ladanyi  13 , M F Berger  14 , B S Taylor  15 , C Turnbull  16
Affiliations

Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working Group

D Mandelker et al. Ann Oncol. .

Erratum in

Abstract

It is increasingly common in oncology practice to perform tumour sequencing using large cancer panels. For pathogenic sequence variants in cancer susceptibility genes identified on tumour-only sequencing, it is often unclear whether they are of somatic or constitutional (germline) origin. There is wide-spread disparity regarding both the extent to which systematic 'germline-focussed analysis' is carried out upon tumour sequencing data and for which variants follow-up analysis of a germline sample is carried out. Here we present analyses of paired sequencing data from 17 152 cancer samples, in which 1494 pathogenic sequence variants were identified across 65 cancer susceptibility genes. From these analyses, the European Society of Medical Oncology Precision Medicine Working Group Germline Subgroup has generated (i) recommendations regarding germline-focussed analyses of tumour-only sequencing data, (ii) indications for germline follow-up testing and (iii) guidance on patient information-giving and consent.

Keywords: gene; germline; panel; predisposition; sequencing; susceptibility.

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Figures

Figure 1.
Figure 1.
Distribution of variant allele frequency observed in the tumour for variants of true germline origin which were (i) small insertion/deletions (ii) SNVs.
Figure 2.
Figure 2.
Distribution of germline and somatic pathogenic variants detected upon tumour analysis. Only variants classified pathogenic/likely pathogenic AND above VAF threshold are included (blue, germline origin; red, somatic origin; numbers, total number of pathogenic variants observed in tumour).
Figure 3.
Figure 3.
Distribution of germline and somatic pathogenic variants detected upon tumour analysis for 30 high-actionability CSGs. (A) Off-tumour and (B) on-tumour.
Figure 4.
Figure 4.
Distribution of germline and somatic pathogenic variants detected upon tumour analysis for non-high actionability CSGs in associated tumours (on-tumour).
See this image and copyright information in PMC

References

    1. Dias-Santagata D, Akhavanfard S, David SS. et al. Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine. EMBO Mol Med 2010; 2(5): 146–158. - PMC - PubMed
    1. Meric-Bernstam F, Brusco L, Shaw K. et al. Feasibility of large-scale genomic testing to facilitate enrollment onto genomically matched clinical trials. JCO 2015; 33(25): 2753–2762. - PMC - PubMed
    1. Garcia EP, Minkovsky A, Jia Y. et al. Validation of OncoPanel: a targeted next-generation sequencing assay for the detection of somatic variants in cancer. Arch Pathol Lab Med 2017; 141(6): 751–758. - PubMed
    1. Cheng DT, Mitchell TN, Zehir A. et al. Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J Mol Diagn 2015; 17(3): 251–264. - PMC - PubMed
    1. Frampton GM, Fichtenholtz A, Otto GA. et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 2013; 31(11): 1023–1031. - PMC - PubMed

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