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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


✓ 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)


Genomic instability and recurrent copy-number alterations


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


Mutational signatures identified from WGS and T-ALL WES data

Mutant allele expression


* 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


Median age 6.9 years; range: 8 days – 19.7 years

Categories of the 565 cancer genes analyzed for germline mutations


Mutations were identified in 8.5% of the patients


*1.1% in the 1000 Genomes Project and 0.6% in autism study.

Mutation rate according to cancer subtype


✓ ACC: 27/39 (69%)✓ Hypodiploid ALL: 9/47 (19%)✓ Choroid plexus carcinoma: 1/4 (25%)


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.


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