Cancer in Adolescents and Young Adults (AYA) Working Group MAIN GENETIC ALTERATIONS IN AYA WITH CANCER Emmanouil Saloustros MD, DSc General Hospital of Heraklion ‘Venizelio’ Heraklion, Crete, Greece ESMO Preceptorship Program Adolescents & young adults malignancies Lugano, Switzerland 11 May 2018
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MAIN GENETIC ALTERATIONS IN AYA WITH CANCER · AYA cancers The frequency of germline mutations and the implications of such mutations have not been studied well. ... New Engl J Med.
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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
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
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.
✓ 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