Distinct genomic landscapes in radiation-associated angiosarcoma compared with other radiation-associated sarcoma histologies

Authors

Dermawan JK

Chi P

Tap WD

Rosenbaum E

D’Angelo S

Alektiar KM

Antonescu CR

Doi

10.1002/path.6137

PMID: 37350195 · DOI: 10.1002/path.6137 · Journal: J Pathol (2023)

TL;DR

This MSK study performed a comprehensive comparative genomic analysis of 82 radiation-associated (RT) sarcomas across four histotypes – angiosarcoma (AS), malignant peripheral nerve sheath tumor (MPNST), undifferentiated pleomorphic sarcoma (UPS), and osteosarcoma (OS) – using MSK-IMPACT. RT-AS showed a distinct genomic landscape dominated by MYC amplification (75%) with co-occurring FLT4, CRKL, HRAS, and KMT2D alterations, while other RT-sarcomas were driven by TP53 and CDKN2A/CDKN2B loss-of-function events. Each RT-sarcoma histotype harbored distinct mutations and copy number alterations, supporting histotype-specific therapeutic approaches rather than treating RT-sarcomas as a homogeneous category.

Cohort & data

Key findings

  • MYC amplification was present in 75% of RT-AS, exclusively in breast/chest wall cases (87% of the 38 breast cases). No RT-AS from other sites were MYC-amplified (PMID:37350195).
  • RT-AS had more frequent FLT4 (16% vs 8%), CRKL (14% vs 9%), HRAS (14% vs 2%), and KMT2D (11% vs 1%) alterations compared to sporadic AS. HRAS mutations were all hotspot mutations at the Ras GTPase domain (e.g., A59T, Q61R/L) (PMID:37350195).
  • Sporadic AS was enriched for TP53 (23% vs 9%), KDR (24% vs 11%), ATM (10% vs 2%), and ATRX (7% vs 2%) alterations relative to RT-AS (PMID:37350195).
  • CDKN2A/CDKN2B deletions were almost non-existent in RT-AS (2%) but present in 92% of RT-MPNST, 29% of RT-UPS, and 33% of RT-OS (PMID:37350195).
  • RT-MPNST had the most frequent CDKN2A/B deletions (92% vs 44% sporadic), NF1 inactivation (67% vs 36%), TEK deletions (42% vs 6%), and SUZ12 inactivation (33% vs 17%) compared to sporadic MPNST (PMID:37350195).
  • RT-AS harbored the lowest fraction of genome altered (FGA): 9% vs 51% in RT-MPNST, 25% in RT-UPS, 32% in RT-OS (ANOVA P < 0.0001). RT-MPNST had significantly higher FGA than sporadic MPNST (51% vs 31%, P = 0.014) (PMID:37350195).
  • RT-AS had the lowest insertion:SNV and deletion:SNV ratios among RT-sarcomas, while RT-UPS had the highest (adjusted P < 0.05) (PMID:37350195).
  • Translocations were more frequent among RT-MPNST and RT-OS but non-existent in RT-AS (mixed linear effect model P = 0.04) (PMID:37350195).
  • Predominant mutational signatures across all four RT-sarcoma histotypes were associated with errors in DNA repair and replication (defective DNA mismatch repair, slippage during DNA replication) (PMID:37350195).
  • Median time from radiation to RT-sarcoma diagnosis: RT-AS 8.0 years, RT-MPNST 12.5 years, RT-UPS 18.5 years, RT-OS 9.0 years (global log-rank P = 0.0047). MYC-amplified RT-AS had significantly shorter latency than non-MYC-amplified cases (P = 0.0083) (PMID:37350195).
  • No statistically significant differences in overall survival or progression-free survival among the four RT-sarcoma categories, though the cohort was small. Median OS: RT-AS 5.1 years, RT-MPNST 2.1 years, RT-UPS 4.8 years, RT-OS 2.8 years (PMID:37350195).

Genes & alterations

Gene Histotype Alteration type Frequency (RT) Frequency (sporadic) Context
MYC ANGS Amplification 75% 13% Breast/chest wall RT-AS; co-occurs with FLT4, CRKL, HRAS, KMT2D
FLT4 ANGS Mostly amplification 16% 8% Stress-activated MAPK cascade; VEGF/VEGFR signaling
CRKL ANGS Amplification 14% 9% Stress-activated MAPK cascade
HRAS ANGS Missense, in-frame insdel 14% 2% Hotspot Ras GTPase domain mutations (A59T, Q61R/L)
KMT2D ANGS, MFH Truncating, missense 11% (AS), 21% (UPS) 1% (AS), 4% (UPS) More frequent in both RT-AS and RT-UPS vs sporadic
TP53 MPNST, MFH, OS LOF mutations, deletions 25-50% 14-57% Infrequent in RT-AS (9%) vs other RT-sarcomas (42-50%)
CDKN2A MPNST, MFH, OS Deletions 29-92% 20-44% Nearly universal in RT-MPNST (92%); rare in RT-AS (2%)
CDKN2B MPNST, MFH, OS Deletions co-deleted with CDKN2A — Co-deleted with CDKN2A
NF1 MPNST Inactivating mutations/deletions 67% 36% Enriched in RT-MPNST
SUZ12 MPNST Inactivating mutations/deletions 33% 17% PRC2 complex component
TEK MPNST Deletions 42% 6% Enriched in RT-MPNST
KDR ANGS Amplification, GOF point mutations 11% 24% Depleted in RT-AS vs sporadic; VEGFR signaling
ATM ANGS Inactivating mutations 2% 10% Depleted in RT-AS vs sporadic
ATRX ANGS Inactivating mutations 2% 7% Depleted in RT-AS vs sporadic
PTPRD MPNST Mutations/deletions 25% 5% Enriched in RT-MPNST
RB1 MFH Truncating/deletions 14% 19% Similar frequencies in RT vs sporadic UPS
PTEN OS Truncating/deletions 17% 14% Similar frequencies in RT vs sporadic OS
FGFR1 OS Amplification 17% 7% Enriched in RT-OS
PTPRT OS Missense 17% 7% Enriched in RT-OS
NOTCH3 MFH Missense 14% 4% Enriched in RT-UPS

Clinical implications

  • RT-sarcomas demonstrate histology-specific genomic profiles, supporting the current approach of treating RT-sarcomas based on histology rather than as a homogeneous category (PMID:37350195).
  • Both primary and RT-AS are treated with taxane-based chemotherapeutic regimens (PMID:37350195).
  • Investigations on small molecular inhibitors of DNA methyltransferase (DNMT1) in sporadic/NF1-related and RT-MPNSTs harboring PRC2-inactivating mutations (e.g., SUZ12) are ongoing (PMID:37350195).
  • Potential molecular targets for precision medicine may be histotype-dependent; the stress-activated MAPK cascade (CRKL, FLT4, HRAS, MYC) and VEGF/VEGFR signaling (FLT4, HRAS, KDR) pathways are activated in RT-AS (PMID:37350195).

Limitations & open questions

  • Survival analysis did not reach statistical significance across RT-sarcoma histotypes, likely due to the small cohort size (n = 82 total, n = 12-44 per histotype) (PMID:37350195).
  • Survival analysis did not account for stage at diagnosis or treatment (e.g., chemotherapy) (PMID:37350195).
  • Allele-specific inactivation status of TP53 was not addressed (PMID:37350195).
  • Targeted NGS panel (MSK-IMPACT) cannot capture all genomic alterations, particularly those involving noncoding regions; whole-genome sequencing would be needed to fully examine the spectrum of genomic alterations (PMID:37350195).
  • The mechanism underlying the exclusive association of MYC amplification with breast/chest wall RT-AS remains unclear (PMID:37350195).
  • Whether the distinct mutational profiles of RT-AS vs sporadic AS translate to different treatment responses is not established (PMID:37350195).

Citations from this paper used in the wiki

  • “RT-AS had more frequent MYC, FLT4, CRKL, HRAS, and KMT2D alterations than sporadic AS (enriched in TP53, KDR, ATM, ATRX), whereas the mutational landscapes of MPNST, UPS, and OS were similar in both RT and non-RT settings.” (Abstract)
  • “CDKN2A/B deletions and TP53 alterations were infrequent in RT-AS compared to other RT-sarcomas.” (Abstract)
  • “Among RT-sarcomas, RT-AS harbored the lowest fraction of genome altered (FGA), while RT-MPNST showed the highest FGA.” (Abstract)
  • “RT-AS has distinct genomic landscape compared to other RT-sarcomas and sporadic AS. Potential molecular targets for precision medicine may be histotype-dependent.” (Abstract/Conclusion)
  • “All 33 RT-AS cases that were MYC amplified were from the breast/chest wall with a history of breast carcinoma (87% of 38 cases). Of the RT-AS from other sites, none were MYC amplified.” (Results)
  • “The RT-AS cases with MYC amplifications had a significantly shorter time interval since radiation to development of RT-sarcoma compared to RT-AS cases without MYC amplifications (log-rank P = 0.0083).” (Results)
  • “RT-MPNST was highly enriched for genome-wide arm level copy number changes, even more so than sporadic MPNST.” (Discussion)

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