esmo.org INDICATIONS FOR GERMLINE TESTING FROM TUMOUR-ONLY SEQUENCING Consensus Recommendations from ESMO Working Group ACGS Birmingham 10 th June 2019 Clare Turnbull Professor in Genomic Medicine, Queen Mary University of London and Institute of Cancer Research Clinical Lead for Cancer Genomics, 100,000 Genomes Project, Genomics England Consultant in Cancer Genetics (Honorary), Guys and St Thomas and Barts NHS Trusts Consultant in Public Health Medicine (Honorary), Public Health England
42
Embed
INDICATIONS FOR GERMLINE TESTING FROM TUMOUR-ONLY … · Neuroendocrine Tumor 90 Retinoblastoma 12 Cancer of Unknown Primary 428 Cervical Cancer 87 Wilms Tumor 11 Ovarian Cancer 398
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
esmo.org
INDICATIONS FOR GERMLINE TESTING FROM TUMOUR-ONLY SEQUENCING
Consensus Recommendations from ESMO Working Group
ACGS Birmingham 10th
June 2019
Clare Turnbull Professor in Genomic Medicine, Queen Mary University of London and Institute of Cancer Research
Clinical Lead for Cancer Genomics, 100,000 Genomes Project, Genomics England
Consultant in Cancer Genetics (Honorary), Guys and St Thomas and Barts NHS Trusts
Consultant in Public Health Medicine (Honorary), Public Health England
Clare Turnbull, Institute of Cancer Research, Queen Mary University London (Chair),
Diana Mandelker, Memorial Sloan Kettering
Angela George, Institute of Cancer Research/Royal Marsden
Funda Meric-Bersntam, MD Anderson
Emmanuele Rial-Sebbag, University of Tolouse
Susan Wallace, University of Leicester
Meetings: 6
Data analyses: Mandelker+team, Turnbull
WORKING GROUP
Early tumour testing:
Single mutation/hot-spots testing (genotyping)
Oncogenes
NGSrecent expansion in tumour testing:
Larger panels: more genes
More patients (umbrella/drug-matching trials)
Sequencing entire gene
Tumour suppressor genes (overlap with cancer susceptibility genes)
Approach
Tumour-normal paired sequencing (WGS, research)
Tumour-only (majority including commercial providers)
WHEN SHOULD A FINDING IN THE TUMOUR-ONLY SEQUENCNG
TRIGGER A GERMLINE TEST?
BACKGROUND Somatic==acquired==tumour only
Germline==constitutional
Association with tumour
On-tumour association: “pertinent” but mainly for aetiological reasons -utility==future risk
Standard Actionability : other dominant high penetrance CSGs in clinical usage
Questionable Actionability :
– intermediate penetrance,
– uncertainty of association of monoallelic variants with disease
(BARD1)
Threshold for triggering germline test
UK: 10% rate for detection of pathogenic mutation (NICE 2013;Familial Breast Cancer).
Only single fragment test…but also ‘additional aspects on process’
– ?just molecular test (ie ‘consent’+blood draw upfront)
– ?full genetics consultation+blood draw+molecular test
ALK
APC
ATM
BAP1
BARD1
BMPR1A
BRCA1
BRCA2
BRIP1
CDH1
CDK4
CDKN2A
CHEK2
DICER1
EPCAM
ERCC3
FH FLCN
HOXB13
HRAS
KIT
KRAS
MEN
1
MET
MITF
MLH1
MSH
2
MSH
6
MUTYH
NBN
NF1
NF2
NRAS
PALB2
PDGFRA
PMS2
POLE
PTCH1
PTEN
RAD50
RAD51B
RAD51C
RAD51D
RB1
RET
RUNX1
SDHA
SDHAF2
SDHB
SDHC
SDHD
SMAD3
SMAD4
SMARCA4
SMARCB1
STK11
SUFU
TERT
TGFBR1
TGFBR2
TMEM
127
TP53
TSC1
TSC2
VHL
HA-CSG N Y N N N Y Y Y Y N N N N N N N N N N N N N Y N N Y Y Y Y N N Y N Y N Y N N Y N N Y Y Y Y N Y Y Y Y Y N Y N N Y N N N N N Y Y Y Y
Penetrance H H I H H H H H H H H H I H H H H H I H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H
Robust for clinical implementation Y Y Y Y N Y Y Y Y Y Y Y Y Y N Y Y Y Y Y Y Y Y Y N Y Y Y Y N Y Y Y Y Y Y Y Y Y N Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
Adenocarcinoma In Situ
Adrenocortical Carcinoma
Ampullary Carcinoma
Anal Cancer
Appendiceal Cancer
Bladder Cancer
Bone Cancer
Breast Cancer
Breast Sarcoma
CNS Cancer
Cancer of Unknown Primary
Cervical Cancer
Colorectal Cancer
Embryonal Tumour
Endometrial Cancer
Oesophagogastric Cancer
GIST
Gastrointestinal NET
Germ Cell Tumour
Glioma
Head and Neck Cancer
Hepatobiliary Cancer
Histiocytosis
Melanoma
Mesothelioma
Miscellaneous Brain Tumour
NHL
NSCLC
Nerve Sheath Tumour
Ovarian Cancer
Pancreatic Cancer
Penile Cancer
Phaeochromocytoma
Pineal Tumour
Prostate Cancer
Renal Cell Carcinoma
Retinoblastoma
Salivary Gland Cancer
Sellar Tumour
Sex Cord Stromal Tumour
Skin Cancer
Small Bowel Cancer
Small Cell Lung Cancer
Soft Tissue Sarcoma
Thymic Tumour
Thyroid Cancer
Uterine Sarcoma
Vaginal Cancer
Wilms Tumour
neuro misc
Trophoblast
METHODS III Assignation of tumour-gene combination as ‘associated’, ‘non-associated’ (germline)
Independently reviewed by 4 cancer clinical geneticists (≥2 support ‘associated’)
1. Ahead of confirmatory analysis in germline sample, patients should be provided with
information and offered option to opt-in or opt-out of analysis of germline sample
SUMMARY: RECOMMENDATIONS (SPECIFIC)
MuTYH only taken forwards if biallelic mutations present *VHL analysis not recommended in renal cancers, *** TP53 analysis not recommended in brain cancers