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


✓ 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

main genetic alterations in aya with cancer · aya cancers the frequency of germline mutations and...

Documents