Germline-focused analysis of tumour-detected variants in 49,264 cancer patients: ESMO Precision Medicine Working Group recommendations.
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ICR Authors
Authors
Kuzbari, Z
Bandlamudi, C
Loveday, C
Garrett, A
Mehine, M
George, A
Hanson, H
Snape, K
Kulkarni, A
Allen, S
Jezdic, S
Ferrandino, R
Westphalen, CB
Castro, E
Rodon, J
Mateo, J
Burghel, GJ
Berger, MF
Mandelker, D
Turnbull, C
Bandlamudi, C
Loveday, C
Garrett, A
Mehine, M
George, A
Hanson, H
Snape, K
Kulkarni, A
Allen, S
Jezdic, S
Ferrandino, R
Westphalen, CB
Castro, E
Rodon, J
Mateo, J
Burghel, GJ
Berger, MF
Mandelker, D
Turnbull, C
Document Type
Journal Article
Date
2023-03-01
Date Accepted
2022-12-11
Abstract
BACKGROUND: The European Society for Medical Oncology Precision Medicine Working Group (ESMO PMWG) was reconvened to update its 2018/19 recommendations on follow-up of putative germline variants detected on tumour-only sequencing, which were based on an analysis of 17 152 cancers. METHODS: We analysed an expanded dataset including 49 264 paired tumour-normal samples. We applied filters to tumour-detected variants based on variant allele frequency, predicted pathogenicity and population variant frequency. For 58 cancer-susceptibility genes, we then examined the proportion of filtered tumour-detected variants of true germline origin [germline conversion rate (GCR)]. We conducted subanalyses based on the age of cancer diagnosis, specific tumour types and 'on-tumour' status (established tumour-gene association). RESULTS: Analysis of 45 472 nonhypermutated solid malignancy tumour samples yielded 21 351 filtered tumour-detected variants of which 3515 were of true germline origin. 3.1% of true germline pathogenic variants were absent from the filtered tumour-detected variants. For genes such as BRCA1, BRCA2 and PALB2, the GCR in filtered tumour-detected variants was >80%; conversely for TP53, APC and STK11 this GCR was <2%. CONCLUSION: Strategic germline-focused analysis can prioritise a subset of tumour-detected variants for which germline follow-up will produce the highest yield of most actionable true germline variants. We present updated recommendations around germline follow-up of tumour-only sequencing including (i) revision to 5% for the minimum per-gene GCR, (ii) inclusion of actionable intermediate penetrance genes ATM and CHEK2, (iii) definition of a set of seven 'most actionable' cancer-susceptibility genes (BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6 and RET) in which germline follow-up is recommended regardless of tumour type.
Citation
Annals of Oncology, 2023, 34 (3), pp. 215 - 227
Source Title
Annals of Oncology
Publisher
ELSEVIER
ISSN
0923-7534
eISSN
1569-8041
1569-8041
1569-8041
Collections
Research Team
Translational Genetics