TP53 mutational profile in CLL : A retrospective study of the FILO group.

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1 TP53 mutational profile in CLL : A retrospective study of the FILO group. Fanny Baran-Marszak Hopital Avicenne Bobigny France 2nd ERIC workshop on TP53 analysis in CLL, Stresa 2017

2 TP53 abnormalities : Clinical impact Prognostic marker Predictive marker Del17p (+ muttp53?) Del17p (+ muttp53?) Döhner et al, NEJM, 2000 Hallek M, Lancet, 2010 Adverse prognosis Fludarabine resistance

3 TP53 mutations and (del17p) : Clinical impact Similar unfavorable prognostic influence. Do all TP53 mutations have the same clinical impact?

4 Subclones of TP53 : Clinical impact Similar unfavorable prognostic influence. Does the clinical impact of single or multiple clones is the same? Rossi et al, Blood 2014

5

6 Spectrum of TP53 mutations : Clinical impact Does the clinical impact of missense and other mutations is the same? Collado R et al Cancer Letter 2017 Patients carrying missense mutations in DBMs seem to have shorter time to first treatment and OS compared with other missense mutations and non-missense alterations but larger studies are needed to be significant

7 Aims Harmonization of the analysis: Sanger / NGS Guidelines for genetic testing : When to search for the mutations of TP53? Alone or associated with other genes? Create a database of TP53 mutations associated with clinical data Identify CLL mutational TP53 profile Identify the functional effect and the clinical impact of the various alterations

8 1st Quality control p53 French laboratories of the GBMHM NGS Sanger and Working on technical harmonization

9 Clinician prescription In a routine setting Prognostic and theranostic marker Before treatment FISH 17p, 11q, karyotype 1 st line TP53 mutation (NGS) IGHV status? Other mutations? SF3B1, NOTCH1, FBXW7, BIRC3, ATM? At relapse Subsequent lines After 2-3 years of ibrutinib FISH 17p, 11q, karyotype? TP53 mutation (NGS) BTK, PLCG2, TP53 mutations (NGS)

10 Materiel Results depend on % of clonal B lymphocytes in the sample 1 EDTA PBMC 1 blood skin lymph nodes pleura Purified B cells 1 Before treatment: >50% of B lymphocytes in PBMC of CLL patients is usual At relapse: if lymphocytosis <10G/L use purified B cells Pellets frozen DNA extraction Cytogenetics fixed pellets can be analysed as well

11 Sequencing PGM Methods Chip samples 2M reads PGM targeted Panel ampliseqtp53: 24 amplicons (exons 2-11) 2 pools 1,28kb 100% coverage PGM targeted Panel ampliseq 32 amplicons (TP53 exons 2-11)(BTK exon15)(plcg2 exons 19, 20, 24, 27, 30) 2 pools 4,86kb 100% coverage

12 Alignment Variant caller: TMAP software Methods SNP indel List of variants Polymorphism or mutation?

13 Analysis Methods Ion reporter # locus type ref genotype pvalue coverage allele_coverage maf transcript location function codon exon protein coding 5000Exomes clinvar cosmic dbsnp chr17: SNV G G/A ,739 NM_ exonic missense TGG 7 p.arg248trp c.742c>t pathogenic 6546:6545:449rs chr17: SNV T C/C , NM_ intronic rs chr17: SNV T T/C , NM_ exonic synonymous CGG 6 p.(=) c.639a>g AMAF=0.0027:EMAF=0.0193:GMAF= :249885:rs chr17: SNV C T/T , NM_ intronic rs chr17: SNV G G/C , NM_ exonic missense CGC 4 p.pro72arg c.215c>g AMAF=0.4051:EMAF=0.2548:GMAF=0.37 non-pathogenic 45985: rs P value <0.05 Allele variant > 10 reads Exon, 5 UTR Clinician report VAF>1%

14 Analysis Thierry Soussi Data Base and Variant Caller

15 Confirmation Methods

16 Data base 511 TP53 variants were retrospectively collected from centers of the FILO group (French Innovative Leukemia Organization) and laboratories of the GBMHM (Groupe des biologistes moleculaires des hémopathies malignes) Variants were identified in 370 patients mostly with relapse/refractory disease. 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 212 variants were evidenced in 183 patients by Sanger sequencing (exons 4 to 9) with a sensitivity around 15% 299 variants were evidenced in 187 patients by Next Generation Sequencing (exons 2 to 11) with a VAF (variant allelic frequency) >1%. Sanger NGS 59% 41% variants 51% 49% patients NGS sanger multiclonal 14% single clone 86% P<0,0001 patients multiclonal 32% single clone 68%

17 74% of the variants were misense mutations 112/256 patients (44%) had no del(17p) by FISH and TP53 alteration would have been missed before patients (36%) had only a single TP53 mutation - among them 80 (86%) had a TP53 missense mutation The dominant negative effect alleviates the need of a second event such as loss of 17p. Multiple clones are often associated with presence of del(17p)(64%) Only 11 patients (4%) (6 NGS, 5 Sanger) harboured only a partial loss of p53 expression (null mutation with no del(17p)) 6% Results of the FILO study: P53 functional impact 11% 9% 74% missense nonsense indel splice patients single mutation misense P= 0,03 21 Dominant negative effect multiclonal mutations single mutation null Loss of p53 Expression or truncated p53 TP53 mutation without del(17p) TP53 mutation +del(17p)

18 TP53 variants distribution All the variants were found in exons 4 to 9 except 2 in exon 10 One third of the missense variants occurred in known hot spot codons. 21 patients had a mutation at codon 234 (p.y234c) (6%) significantly higher than in: solid tumors (389/76738=0.5%, p<10-9) myeloid (6/1300=0.4%, p<10-9) lymphoid malignancies (17/1358= 1.2 %, p<10-6) low grade lymphomas (5/361=1,3%, p=0,01) This mutation might represent a CLL specific hotspot FILO base (511)

19 CLL mutational profile 84 patients (22%) harbored multiclonal TP53 mutations 70% were detected by NGS 10 patients had between 4 and 8 clones. 42 patients analyzed by NGS (23% ) harbored only small clones (VAF<12%), among them 18/27 (67%) had no del(17p) detectable by FISH neither and would have been missed before NGS. IGHV status was mutated in 45/ 179 (25%) patients Hotspot mutations were more often associated with unmutated IGHV Presence of several clones appeared independent of IGHV status 160 patients % 51% 23% 77% sanger NGS NGS VAF<12% NGS VAF>12% Misense mutations % 68% unmutated IGHV Mutated IGHV 0 hotspot others

20 Conclusion Clinical data are currently being collected to analyse the impact of the various mutations TP53 variants collection is still ongoing for identification of a CLL mutational profile Guidelines for genetic testing are warranted

21 FILO study : patients-clinicians-biologists-scientists We would like to thank all the network collaborators for sharing their experience and data. Tours Caen Rouen Rennes Lille Avicenne St Louis Henri Mondor Pitié Salpétrière Nancy Reims Bordeaux Clermont Ferrand Lyon Service d hématologie biologique Hopital Avicenne Bobigny Toulouse Montpellier Nice

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