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