Dataset Information

A clinico-genomic analysis of soft tissue sarcoma patients reveals CDKN2A deletion as a biomarker for poor prognosis.

ABSTRACT:

Background

Sarcomas are a rare, heterogeneous group of tumors with variable tendencies for aggressive behavior. Molecular markers for prognosis are needed to risk stratify patients and identify those who might benefit from more intensive therapeutic strategies.

Patients and methods

We analyzed somatic tumor genomic profiles and clinical outcomes of 152 soft tissue (STS) and bone sarcoma (BS) patients sequenced at Stanford Cancer Institute as well as 206 STS patients from The Cancer Genome Atlas. Genomic profiles of 7733 STS from the Foundation Medicine database were used to assess the frequency of CDKN2A alterations in histological subtypes of sarcoma.

Results

Compared to all other tumor types, sarcomas were found to carry the highest relative percentage of gene amplifications/deletions/fusions and the lowest average mutation count. The most commonly altered genes in STS were TP53 (47%), CDKN2A (22%), RB1 (22%), NF1 (11%), and ATRX (11%). When all genomic alterations were tested for prognostic significance in the specific Stanford cohort of localized STS, only CDKN2A alterations correlated significantly with prognosis, with a hazard ratio (HR) of 2.83 for overall survival (p = 0.017). These findings were validated in the TCGA dataset where CDKN2A altered patients had significantly worse overall survival with a HR of 2.7 (p = 0.002). Analysis of 7733 STS patients from Foundation One showed high prevalence of CDKN2A alterations in malignant peripheral nerve sheath tumors, myxofibrosarcomas, and undifferentiated pleomorphic sarcomas.

Conclusion

Our clinico-genomic profiling of STS shows that CDKN2A deletion was the most prevalent DNA copy number aberration and was associated with poor prognosis.

SUBMITTER: Bui NQ

PROVIDER: S-EPMC6739971 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Dysfunction of the circadian clock and polymorphisms of some circadian genes have been linked to cancer development and progression. We investigated the relationship between circadian genes germline variation and susceptibility or prognosis of patients with soft tissue sarcoma. PATIENTS AND METHODS:We considered the 14 single nucleotide polymorphisms (SNPs) of 6 core circadian genes that have a minor allele frequency >?5% and that are known to be associated with cancer risk or prognosis. Genotyping was performed by q-PCR. Peripheral blood and clinic-pathological data were available for 162 patients with liposarcoma or leiomyosarcoma and 610 healthy donors. Associations between the selected clock genes polymorphisms and sarcoma susceptibility or prognosis were tested assuming 3 models of inheritance: additive, recessive and dominant. Subgroup analysis based on sarcoma histotype was performed under the additive genetic model. Multivariate logistic regression and multivariate Cox proportional hazard regression analyses were utilized to assess the association between SNPs with patient susceptibility and survival, respectively. Pathway variation analysis was conducted employing the Adaptive Rank Truncated Product method. RESULTS:Six out of the 14 analyzed SNPs were statistically significantly associated with susceptibility or prognosis of soft tissue sarcoma (P <?0.05). The present analysis suggested that carriers of the minor allele of the CLOCK polymorphism rs1801260 (C) or of PER2 rs934945 (T) had a reduced predisposition to sarcoma (26% and 35% respectively with the additive model) and liposarcoma (33% and 41% respectively). The minor allele (A) of NPAS2 rs895520 was associated with an increased predisposition to sarcoma of 33% and leiomyosarcoma of 44%. RORA rs339972 C allele was associated with a decreased predisposition to develop sarcoma assuming an additive model (29%) and leiomyosarcoma (36%). PER1 rs3027178 was associated with a reduced predisposition only in liposarcoma subgroup (32%). rs7602358 located upstream PER2 was significantly associated with liposarcoma survival (HR: 1.98; 95% CI 1.02-3.85; P?=?0.04). Germline genetic variation in the circadian pathway was associated with the risk of developing soft tissue sarcoma (P?=?0.035). CONCLUSIONS:Genetic variation of circadian genes appears to play a role in the determinism of patient susceptibility and prognosis. These findings prompt further studies to fully dissect the molecular mechanisms.