TY - JOUR
T1 - Germline-focused analysis of tumour-detected variants in 49,264 cancer patients
T2 - ESMO Precision Medicine Working Group recommendations
AU - Kuzbari, Z.
AU - Bandlamudi, C.
AU - Loveday, C.
AU - Garrett, A.
AU - Mehine, M.
AU - George, A.
AU - Hanson, H.
AU - Snape, K.
AU - Kulkarni, A.
AU - Allen, S.
AU - Jezdic, S.
AU - Ferrandino, R.
AU - Westphalen, C. B.
AU - Castro, E.
AU - Rodon, J.
AU - Mateo, J.
AU - Burghel, G. J.
AU - Berger, M. F.
AU - Mandelker, D.
AU - Turnbull, C.
N1 - Publisher Copyright:
© 2022 The Authors
PY - 2023/3
Y1 - 2023/3
N2 - 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.
AB - 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.
KW - cancer-susceptibility genes
KW - germline
KW - germline conversion rate
KW - tumour-only sequencing
KW - variants
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U2 - 10.1016/j.annonc.2022.12.003
DO - 10.1016/j.annonc.2022.12.003
M3 - Article
C2 - 36529447
AN - SCOPUS:85146581639
SN - 0923-7534
VL - 34
SP - 215
EP - 227
JO - Annals of Oncology
JF - Annals of Oncology
IS - 3
ER -