MAIN GENETIC ALTERATIONS IN AYA WITH CANCER · AYA cancers The frequency of germline mutations and...
Transcript of MAIN GENETIC ALTERATIONS IN AYA WITH CANCER · AYA cancers The frequency of germline mutations and...
Cancer in Adolescents and Young Adults (AYA)
Working Group
MAIN GENETIC ALTERATIONS IN AYAWITH CANCER
Emmanouil Saloustros MD, DScGeneral Hospital of Heraklion ‘Venizelio’
Heraklion, Crete, Greece
ESMO Preceptorship Program
Adolescents & young adults malignancies
Lugano, Switzerland 11 May 2018
Overview
✓ The landscape of (somatic) genetic alterations across childhood cancers.
✓ How it compares to adult cancers.
✓ The largest study of germline mutation testing in children and AYA with cancer.
✓ The genetic syndrome you have to remember.
✓ An example of the beauty of AYA cancer research.
✓ 961 tumors from 914 individual patients were sequenced.
✓ 24 types of cancer that cover all major childhood cancer entities.
✓ 95% diagnosed during childhood or adolescence (≤ 18 years) and 5% older (up to 25).
✓ 547 WGS (median coverage 37x) and 414 WES (121x).
✓ Biased towards CNS tumors.
Gröbner SN, et al. Nature 2018
Somatic mutations in the paediatric pan-cancer cohort
Gröbner SN, et al. Nature 2018
✓ 14 lower overall mutation frequencies compared to adult cancers (0.13 vs 1.8mutations per MB.
✓ Somatic mutation burden increased with age (R=0.39, p=2,9x10-6).✓ Relapse tumors harboured significantly more mutations than primary tumors
(p=0.0015)
Gröbner SN, et al. Nature 2018
Genomic instability and recurrent copy-number alterations
Gröbner SN, et al. Nature 2018
Potentially druggable events in paediatric cancers
Only 37% of primary tumors retained these PDEs upon progression
✓ 1699 patients: B-ALL, T-ALL, AML, Neuroblastomas (NBL), Wilms tumors and Osteosarcomas.
✓ All specimens at initial diagnosis.
✓ 98.5% of the patients were 20 yo or younger.
✓ WES, WGS and transcriptome analysis.
Xiaotu M, et al. Nature 2018
Xiaotu M, et al. Nature 2018
Mutational signatures identified from WGS and T-ALL WES data
Mutant allele expression
Xiaotu M, et al. Nature 2018
* Chromothripsis in 11% of all samples
Tumors with at least one driver alteration by WES and WGS
The differing genomic landscape of childhood and adult cancers
Feature Childhood Adult
Mutation rate Lower Higher
Cancer-driving mutations Frequently single Multiple
Mutation specificity Disease-specific Shared
Only 30% of significantly mutated genes overlap with adult pan-cancer analysis
Bandopandhayay P & Meyerson M. Nature 2018
Luminal-A like tumors are more aggressive in younger women.
Subtype BCSM: HR (95% CI)
Luminal A** 2.1 (1.4-3.2)
Luminal B 1.4 (1.1-1.9)
HER2-positive 1.2 (0.8-1.9)
Triple-negative 1.4 (1.0-1.9)
✓ Eight NCCN centers: 2000-2007.✓ 17K women with stage I-III disease: 1,916 younger than ≤40 at diagnosis.✓ Median follow up: 6.4 years.**Only significant after controlling for detection method
Partridge AH, et al. J Clin Oncol. 2016
Do not forget the host
Very young premenopausal patients have the largest benefit from OFS
Francis P, et al. New Engl J Med. 2014
350 pts (11.5%) < 35 yrs94% received chemotherapy
Germline mutations in predisposition genes in AYA cancers
✓ The frequency of germline mutations and the implications ofsuch mutations have not been studied well.
✓ Most studies have relied on candidate gene approach andselected families.
✓ Advances in sequencing technologies allow to sequence thewhole exome and whole genome relatively cheaply and fast.
✓ 1120 patients, 565 cancer-associated genes, with focus on 60genes associated with cancer-predisposition syndromes.
Zhang J, et al. New Engl J Med. 2015
Frequency of pediatric cancer types
Zhang J, et al. New Engl J Med. 2015
Median age 6.9 years; range: 8 days – 19.7 years
Categories of the 565 cancer genes analyzed for germline mutations
Zhang J, et al. New Engl J Med. 2015
Mutations were identified in 8.5% of the patients
Zhang J, et al. New Engl J Med. 2015
*1.1% in the 1000 Genomes Project and 0.6% in autism study.
Mutation rate according to cancer subtype
Zhang J, et al. New Engl J Med. 2015
✓ ACC: 27/39 (69%)✓ Hypodiploid ALL: 9/47 (19%)✓ Choroid plexus carcinoma: 1/4 (25%)
Gröbner SN, et al. Nature 2018
Germline mutations in cancer predisposition genes
Medical and family history
✓ Available for 75/95 mutation carriers.
✓ Genetic testing has been offered ONLY to 12 patients.
✓ Family history data available for 58/75 and 23 (40%) indicatedfamily history of cancer.
✓ Only 13 (22%) had a history that was consistent with an underlyinggenetic syndrome.
Zhang J, et al. New Engl J Med. 2015
Some thoughts
✓ Prevalence may be underestimated: coverage, gene selection, VUS (226) characterization.
✓ ‘Unexpected’ germline mutations: TP53, PMS2 and RET mutations in Ewing sarcomas.
✓ Eight patients with BRCA1/2 and PALB2 mutations.
✓ 4 mosaic mutations (de novo) in TP53 and RB1.
✓ At a minimum, this work highlights the fact that family history alone is an unreliable guide to the likelihood of a cancer-predisposition syndrome in any patient with a newly diagnosed cancer.
Zhang J, et al. New Engl J Med. 2015Maris JM. New Engl J Med. 2015
Li-Fraumeni Syndrome (LFS)OMIM#151623
✓ Cancer predisposition syndrome associated with the development of
various tumors: soft tissue sarcoma, osteosarcoma,, brain tumors,
adrenocortical carcinoma, leukemias pre-menopausal breast cancer
(mostly <35yrs and Her2+) among others.
✓ LFS-related tumors occur in childhood or young adulthood.
✓ Caused by deleterious TP53 germline mutations with autosomal dominant
inheritance pattern.
✓ TP53 carriers face an elevated risk for multiple cancer diagnosis; estimated
at 50% by age 30 years and 90% by age 60 years.
Criteria for TP53 genetic testing
ΕΡΓΑΣΤΗΡΙΟΜΟΡΙΑΚΗΣΔΙΑΓΝΩΣΤΙΚΗΣΕΘΝΙΚΟΚΕΝΤΡΟΕΡΕΥΝΑΣΦΥΣΙΚΩΝΕΠΙΣΤΗΜΩΝ«ΔΗΜΟΚΡΙΤΟΣ»
ΙνστιτούτοΡαδιοϊσοτόπων&ΡαδιοδιαγνωστικώνΠροϊόντων
15310ΑΓΙΑΠΑΡΑΣΚΕΥΗΑΤΤΙΚΗΣ
Ιστολ. τύπος BrCa: πορογενές διηθητικό grade II, Ki67: 30-40%, e-
cadherin+, ker34+ (υβριδικό, προέλευση πόροι που γειτνιάζουν τα λοβία) -
βιοψία µαστεκτοµής: υπολειµµατικό DCIS 3cm, grade ΙΙ, 0/7 nodes+
ER: + (20%) PR: ++ (60%) HER2: 3+
Άλλα στοιχεία ιστορικού: ca επινεφριδίου 18m (5cm)
Καταγωγή: Κύπρος (π+µ)
Εµµηναρχή: 13
Αντισυλληπικά: ΟΧΙ Ορµονοθεραπεία: ΟΧΙ
Ηµεροµηνία: 24/2/2011
A Li-Fraumeni family tree
Courtesy of Florentia Fostira PhD
It is not an AYA cancer syndrome
✓ From 1730 French suggestivepatients, 415 mutation carriers wereidentified.
✓ Mean age of first tumor onset was24.9 years.
✓ 43% had multiple tumors.
✓ In children ACC, CNS tumors andsarcomas.
✓ In adults breast cancer and sarcomas.
Bougeard G, et al. J Clin Oncol. 2015
Diagnosis matters (not only for the family)
✓ 107 participants (78 females and 29 males).
✓ Median age at inclusion: 32.9 years (range: 5-67).
✓ November 2011-September 2016.
✓ Standard screening ± diffuse whole body MRI.
✓ 226.4 person-year (1-5 years of screening).
✓ 23 new primary cancers.
✓ 5 (22%) lung adenocarcinomas (4 never smokers).
Caron O, et al. JAMA Oncol. 2017
Half of the mutation carriers do not fulfill testing criteria
Attenuated? Atypical Li-Fraumeni subtype - breast cancer associated -
Courtesy of Florentia Fostira PhD
Patient selection solely based on their age at diagnosis (<35years) AND Her2 positive status
BrCa N=107
Her2+3 (IHC) N=81 Her2+2 (FISH) N=26
TP5340%
BRCA133%
BRCA2…
50% of TP53 carriers do not fulfill the genetic criteria for
genetic testing
TP53 mutations areas prevalent as BRCA1 mutations
All TP53 carriers were Her2+3 by IHC
15 (14%) carry pathogenic mutations in: TP53 (6), BRCA1 (5) & BRCA2 (4)
Fostira F, et al. manuscript under preparation
Small-cell carcinoma of the ovary hypercalcemic type (SCCOHT)
✓ Rare and highly malignant tumor.
✓ Mean age at presentation 23 years. The youngest 14 months!!!
✓ Most common undifferentiated ovarian ca in women younger than 40.
✓ The differential diagnosis is broad.
✓ Large cells in about half the tumors, usually represents a minor to moderate component of the tumor.
✓ 80% of SCCOHT overexpress p53 protein, suggesting that a TP53 mutation may be an underlying cause.
✓ Further investigator is needed.
Rovithi M et al. Case Rep Med. 2011
Witkowski L, et al. Nat Genet. 2014
Familial SCCOHT cases
Family 1:
Unaffected father
Affected daughter
178
Family 3:
Unaffected father
Affected daughter
335
Family 2:
Affected mother
Affected daughter
168
4 1
5
1SMARCA4
EVS1000 Genomes – MAF < 0.0005ExACIn-house exomes
Novel mutations found in SCCOHT familiesMissense, splicing, stop, coding indels, UTRs
Witkowski L, et al. Nat Genet. 2014
SOC1c.1224_1226delGCTinsAG; p.L409Gfs*2
Wild Type
SOC1 Blood DNA Sample 1
SOC1 Blood DNA Sample 2
YIIKDKHILAKACKRLRCVAPTR*
Exon 18 Mid Intron 18
…
Exon 19
*
→ Premature stop → NMD
Germline
Mutation:
c.2617-3 C>G
*
Somatic LOH
(FA3D)
*
Somatic Mutation (FA1M)
c.1027_1027delG; p.V343Cfs*68
Germline Mutation
c.4170+1G>A
*
Germline
Mutation
c.643C>T,
p.Q215*
*
cD
NA
*
Somatic Mutation (FA2D)
c.1687_1700delAACCTCACGGA
GCT; p.N563Gfs*82
Somatic LOH (FA4M)
*
Somatic Mutation (FA4D)
c.1326_1326delC; p.Ser442Argfs*59
*
Germline Mutation
c.3239G>A; p. Gly1080Asp
III-447
SCCO 42
+/-
IV-114
II-461
SCLC 61
II-577
+/+
I-2
PSU
I-3
Distended abdomen 32
I-1100
II-1 II-275
II-365
Lung ca (smoker)
III-141
III-237
III-335
II-872
II-778
II-665
III-1258
III-1356
III-965
III-1062
III-1158
III-755
III-563
III-660
III-853
I-495
I-595
Genetic testing is the big challenge