scholarly journals Mutational concordance analysis provides supportive information for double cancer diagnosis

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Keiichi Hatakeyama ◽  
Takeshi Nagashima ◽  
Akifumi Notsu ◽  
Keiichi Ohshima ◽  
Sumiko Ohnami ◽  
...  
Keyword(s):  
Poisson Distribution ◽  
Somatic Mutations ◽  
Double Cancer ◽  
Primary Tumors ◽  
Paired Samples ◽  
Multifocal Lesions ◽  
Mutation Profile ◽  
Tumor Origin ◽  
Tumor Mutational Burden ◽  
Somatic Alterations

Abstract Background Mutation analysis using next-generation sequencing highlights the features of tumors with somatic alterations. However, the mutation profile of double cancer remains unclear. Here, we analyzed tumors derived from the same patient using whole exome sequencing (WES) to investigate the coherence of somatic mutations in double cancer. Methods First, the tumor mutational burden (TMB) was investigated using WES of 5521 tumor specimens from a Japanese pan-cancer cohort. The frequencies of mutation concordance were then compared in these cancers. Finally, we calculated the expected value of mutational concordance fitting a Poisson distribution to determine the relationship between double and metastatic cancers. Results In all, 44, 58, and 121 paired samples were diagnosed as double cancer, multifocal lesions (derived from identical tissues), and metastasis, respectively. Our analysis revealed that common somatic mutations were almost entirely absent in double cancer, whereas primary tumors and metastatic foci harbored several identical alterations. Concordance of the mutation profile in the same patient reflects the tumor origin and development, suggesting the potential for identifying double cancer based on common somatic mutations. Furthermore, according to a Poisson distribution, double cancer could be discriminated based on paired samples from the same patient. The probability of double cancer with more than 10 mutations was ≤1 part-per-billion (ppb, 10− 9). In multifocal lesions, 74% of tumor pairs accumulated ≤10 common mutations, implying a difference in tumor origin within identical tissues. Conclusions These findings indicate that counting common somatic mutations can indicate the differences in origin between tumors derived from the same patient. Our mutation coherence analysis can thus provide beneficial information for diagnosing double cancer.

Molecular differences between lymph nodes (LNs) and distant metastases (mets) in colorectal cancer (CRC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3130-3130
Author(s):  
Alberto Puccini ◽  
Joanne Xiu ◽  
Richard M. Goldberg ◽  
Axel Grothey ◽  
Anthony Frank Shields ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Primary Tumor ◽  
Distant Metastases ◽  
Molecular Profile ◽  
Molecular Heterogeneity ◽  
Missense Mutations ◽  
Primary Tumors ◽  
Paired Samples ◽  
Mutational Burden ◽  
Tumor Mutational Burden

3130 Background: LNs mets are thought to occur before distant mets. However, lymphatic and distant mets arise from independent subclones of the primary tumor, suggesting that LNs are not essential intermediaries for distant mets. We aimed to comprehensively characterize the molecular profile of LN mets and to explore the differences between LN vs distant mets and primary tumors. Methods: Tumor samples from primary CRCs, LNs, and distant mets were analyzed using NGS (MiSeq on 47 genes, NextSeq on 592 genes), immunohistochemistry. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. Results: In total, 11871 tumors samples were examined, comprising primaries (N = 5862), distant (N = 5605) and LNs mets (N = 404). The most frequently mutated genes in LNs were TP53 (72%), APC (61%), KRAS (39%), ARID1A (20%), and PIK3CA (12%). LNs showed a higher mean TMB (13 mut/MB) vs distant mets (9, P < .0001). TMB-high (17mut/MB) was more frequent in primaries and LNs vs distant mets (9.5% and 8.8% vs 4.2%, P < .001 and P = .001, respectively), as well as MSI-H (8.8% and 6.9% vs 3.7%, P < .001 and P = .017, respectively). TMB-high is significantly higher in LNs vs distant mets and primaries (P < .0001), independent of MSI-H status. Analyzing distant mets by location, LNs showed higher TMB compared to lung, liver and peritoneum mets (P < .0001). Overall, LNs showed significantly different rates of mutations in APC, KRAS, PI3KCA, KDM6A, and BRIP1 (P < .01 for all comparisons) vs primaries; while presenting a distinct molecular profile compared to distant mets ( TP53 72 vs 67%; KRAS 39 vs 50%; RNF43 7 vs 4%; ATM 5 vs 3%; KDM6A 4 vs 1%; BRCA2 4 vs 2%; MSH6 3 vs 2%; PTCH1 4 vs 1%; BRCA1 2 vs 1%; GNAS 2 vs 5%; P < .05 for all comparisons). Our cohort of 30 paired samples confirmed the molecular heterogeneity between primaries, LNs, and distant mets. Conclusions: This is the largest study to investigate the molecular differences between LNs mets, distant mets and primary tumors in CRC patients. Our data support the hypothesis that lymphatic and distants mets harbor different mutation profiles which suggests that they may arise from distinct subclones.

Pulmonary metastasectomy in renal cell carcinoma: Predictive and prognostic elements from paired histopathological analysis of primary tumors and respective metastases

2021 ◽  
pp. 239936932110285
Author(s):  
Melissa Bersanelli ◽  
Sebastiano Buti ◽  
Letizia Gnetti ◽  
Elena Varotti ◽  
Paolo Carbognani ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Prognostic Value ◽  
Positive Impact ◽  
Left Lung ◽  
Pulmonary Metastasectomy ◽  
Histopathological Analysis ◽  
Primary Tumors ◽  
Paired Samples

Objective: To identify histopathological and immunophenotypical features with potential predictive or prognostic value in patients undergoing pulmonary metastasectomy from renal cell carcinoma (RCC). Methods: We retrospectively collected all consecutive patients undergoing pulmonary metastasectomy from RCC after prior nephrectomy. Paired samples of primary tumors and corresponding pulmonary metastases were analyzed, revising histopathological features and testing C-MET, mTOR, and PD-L1 by immunohistochemistry. Results: A total of 25 patients were included. Median overall survival (mOS) from metastasectomy was 5.5 years (95% CI = 1.9–9.1). The laterality of metastases had a significant predictive value, with median relapse-free survival (mRFS) from metastasectomy not reached (NR) at mean follow-up (FU) of 60.8 months for left lung involvement, mRFS of 52.9 months (95% CI = 0–145.5) for the right lung and 6.4 months (95% CI = 1.7–11) for bilateral metastases ( p = 0.028). Primary RCC with positive expression of mTOR had higher mOS after metastasectomy than negative cases ( p < 0.001), NR at mean FU of 4.3 years versus mOS of 2 years (95% CI = 0.7–3.3), respectively. PD-L1 positivity on intra-tumor (TILs) and peri-tumor (RILs) infiltrating lymphocytes of metastases was related to higher OS, NR versus 2 years (95% CI = 1.2–2.7, p = 0.003), and NR versus 1.4 years (95% CI = 0.2–2.6, p = 0.012), respectively. The shorter was the surgical interval, the more probably the metastases had high c-MET expression (>70%) ( p = 0.007) and PD-L1 expression >10% on TILs ( p = 0.024). Conclusions: mTOR positivity on primary RCC could be a favorable prognostic factor to select patients for pulmonary metastasectomy. The positive impact of PD-L1 expression on immune cells is opposite to the well-known negative prognostic value of PD-L1 on tumor cells in RCC.

scholarly journals Mutation Profile of Aggressive Pheochromocytoma and Paraganglioma with Comparison of TCGA Data

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2389
Author(s):  
Yun Mi Choi ◽  
Jinyeong Lim ◽  
Min Ji Jeon ◽  
Yu-Mi Lee ◽  
Tae-Yon Sung ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
The Cancer Genome Atlas ◽  
Sequencing Analysis ◽  
Poor Overall Survival ◽  
Sdhb Mutation ◽  
Targeted Next Generation Sequencing ◽  
Mutation Profile ◽  
Next Generation Sequencing Analysis ◽  
Number Variation ◽  
Frequent Mutations

In pheochromocytoma and paraganglioma (PPGL), germline or somatic mutations in one of the known susceptibility genes are identified in up to 60% patients. However, the peculiar genetic events that drive the aggressive behavior including metastasis in PPGL are poorly understood. We performed targeted next-generation sequencing analysis to characterize the mutation profile in fifteen aggressive PPGL patients and compared accessible data of aggressive PPGLs from The Cancer Genome Atlas (TCGA) with findings of our cohort. A total of 115 germline and 34 somatic variants were identified with a median 0.58 per megabase tumor mutation burden in our cohort. The most frequent mutation was SDHB germline mutation (27%) and the second frequent mutations were somatic mutations for SETD2, NF1, and HRAS (13%, respectively). Patients were subtyped into three categories based on the kind of mutated genes: pseudohypoxia (n = 5), kinase (n = 5), and unknown (n = 5) group. In copy number variation analysis, deletion of chromosome arm 1p harboring SDHB gene was the most frequently observed. In our cohort, SDHB mutation and pseudohypoxia subtype were significantly associated with poor overall survival. In conclusion, subtyping of mutation profile can be helpful in aggressive PPGL patients with heterogeneous prognosis to make relevant follow-up plan and achieve proper treatment.

scholarly journals BRAF/NRAS Mutation Frequencies Among Primary Tumors and Metastases in Patients With Melanoma

2012 ◽  
Vol 30 (20) ◽  
pp. 2522-2529 ◽  
Author(s):  
Maria Colombino ◽  
Mariaelena Capone ◽  
Amelia Lissia ◽  
Antonio Cossu ◽  
Corrado Rubino ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Primary Melanoma ◽  
Similar Distribution ◽  
Nras Mutation ◽  
Tissue Samples ◽  
Primary Tumors ◽  
Paired Samples ◽  
Automated Dna Sequencing ◽  
Tumor Tissues ◽  
Visceral Metastases

Purpose The prevalence of BRAF, NRAS, and p16CDKN2A mutations during melanoma progression remains inconclusive. We investigated the prevalence and distribution of mutations in these genes in different melanoma tissues. Patients and Methods In all, 291 tumor tissues from 132 patients with melanoma were screened. Paired samples of primary melanomas (n = 102) and synchronous or asynchronous metastases from the same patients (n = 165) were included. Tissue samples underwent mutation analysis (automated DNA sequencing). Secondary lesions included lymph nodes (n = 84), and skin (n = 36), visceral (n = 25), and brain (n = 44) sites. Results BRAF/NRAS mutations were identified in 58% of primary melanomas (43% BRAF; 15% NRAS); 62% in lymph nodes, 61% subcutaneous, 56% visceral, and 70% in brain sites. Mutations were observed in 63% of metastases (48% BRAF; 15% NRAS), a nonsignificant increase in mutation frequency after progression from primary melanoma. Of the paired samples, lymph nodes (93% consistency) and visceral metastases (96% consistency) presented a highly similar distribution of BRAF/NRAS mutations versus primary melanomas, with a significantly less consistent pattern in brain (80%) and skin metastases (75%). This suggests that independent subclones are generated in some patients. p16CDKN2A mutations were identified in 7% and 14% of primary melanomas and metastases, with a low consistency (31%) between secondary and primary tumor samples. Conclusion In the era of targeted therapies, assessment of the spectrum and distribution of alterations in molecular targets among patients with melanoma is needed. Our findings about the prevalence of BRAF/NRAS/p16CDKN2A mutations in paired tumor lesions from patients with melanoma may be useful in the management of this disease.

Genomic analysis of primary malignant melanoma of the esophagus.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21515-e21515
Author(s):  
Jingjing Li ◽  
Shi Yan ◽  
Wenyan Guan ◽  
Xiao Xiao ◽  
Bing Liu ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Somatic Mutations ◽  
Genome Instability ◽  
Mapk Signaling ◽  
Primary Malignant Melanoma ◽  
Base Substitution ◽  
Pathway Enrichment Analysis ◽  
Driver Genes ◽  
Primary Tumors ◽  
Genetic Characteristics

e21515 Background: Primary malignant melanoma of the esophagus (PMME) is an exceedingly rare disease but behave more aggressively and have a poorer prognosis. No specific histopathological classification and therapy strategies have been established for this type of disease due to lack of both tumor biological and genetics perception to PMME. Methods: We performed whole exome sequencing on 29 dissections including 23 primary tumors and 6 metastatic lymph nodes from 18 PMME patients. The genetic characteristics including somatic mutations and copy number variation (CNV) of PMME were compared to 398 skin cutaneous melanoma (SKCM), 67 mucosal melanoma (MM) and 79 uveal melanoma (UVM). Using multi-region sequencing, we reconstructed the phylogenetic structure and inferred the evolutionary mode. Results: We found that PMME/MM have similar genomic patterns to SKCM but distinct from UVM. Frequently mutated driver genes such as MUC16, BRAF, NRAS, NF1, KMT2C, POLE, PTPRT, RANBP2 appeared in both SKCM and PMME/MM cohorts. Of note, pathway enrichment analysis using identified driver genes revealed that melanoma pathway and MAPK signaling pathway were among the top affected pathways in MM/PMME as well as in SKCM. UVR-associated single base substitution signature 7 (SBS7) was not a dominant signature (median: 0.17, range:0̃0.79) in PMME/MM but 99 percent (89/90) of them do have it. An overall concordant trend in genome instability was found between PMME and SKCM. Significant CNV events at arm level showed the similar changes in PMME and SKCM, including amplification regions of 1q, 6p, 7p, 8q, 15q, 20p and deletion of 10p, 10q, 11p. CDKN2A loss appeared as a shared focal event by PMME and SKCM. To elucidate the evolution trajectory of spatially separated samples, we also performed multi-region sequencing, and the phylogenetic analysis suggested that whole genome doubling (WGD) was an early and clonal event, which preceded the majority of somatic mutations and CNV. Most driver genes such as NF1, RANBP2 and MUC16 mutated after WGD except TP53. Above findings suggested that WGD might be capable of promoting ongoing genome instability and shaping the evolution in PMME. Moreover, parallel evolution of RANBP2 was recurrently observed indicating the existence of constraints and selection. Conclusions: Our data showed that PMME/MM exhibited genetic features very similar to SKCM so it might not be excluded from treatments currently used for common SKCM.

scholarly journals Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors

2018 ◽  
Vol 116 (2) ◽  
pp. 619-624 ◽  
Author(s):  
Charles Li ◽  
Elena Bonazzoli ◽  
Stefania Bellone ◽  
Jungmin Choi ◽  
Weilai Dong ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Somatic Mutations ◽  
Driver Mutations ◽  
Cancer Evolution ◽  
Metastatic Tumors ◽  
Driver Genes ◽  
Primary Tumors ◽  
Mutational Landscape ◽  
Recurrent Tumors ◽  
Bet Inhibitors

Ovarian cancer remains the most lethal gynecologic malignancy. We analyzed the mutational landscape of 64 primary, 41 metastatic, and 17 recurrent fresh-frozen tumors from 77 patients along with matched normal DNA, by whole-exome sequencing (WES). We also sequenced 13 pairs of synchronous bilateral ovarian cancer (SBOC) to evaluate the evolutionary history. Lastly, to search for therapeutic targets, we evaluated the activity of the Bromodomain and Extra-Terminal motif (BET) inhibitor GS-626510 on primary tumors and xenografts harboring c-MYC amplifications. In line with previous studies, the large majority of germline and somatic mutations were found in BRCA1/2 (21%) and TP53 (86%) genes, respectively. Among mutations in known cancer driver genes, 77% were transmitted from primary tumors to metastatic tumors, and 80% from primary to recurrent tumors, indicating that driver mutations are commonly retained during ovarian cancer evolution. Importantly, the number, mutation spectra, and signatures in matched primary–metastatic tumors were extremely similar, suggesting transcoelomic metastases as an early dissemination process using preexisting metastatic ability rather than an evolution model. Similarly, comparison of SBOC showed extensive sharing of somatic mutations, unequivocally indicating a common ancestry in all cases. Among the 17 patients with matched tumors, four patients gained PIK3CA amplifications and two patients gained c-MYC amplifications in the recurrent tumors, with no loss of amplification or gain of deletions. Primary cell lines and xenografts derived from chemotherapy-resistant tumors demonstrated sensitivity to JQ1 and GS-626510 (P = 0.01), suggesting that oral BET inhibitors represent a class of personalized therapeutics in patients harboring recurrent/chemotherapy-resistant disease.

scholarly journals Analysis of HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinomas and Paired Normal Mucosae Reveals Cyclin D1 Deregulation and Compensatory Effect of Cyclin D2

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 792
Author(s):  
Jiří Novotný ◽  
Veronika Bandúrová ◽  
Hynek Strnad ◽  
Martin Chovanec ◽  
Miluše Hradilová ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Head And Neck ◽  
Squamous Cell ◽  
Normal Mucosa ◽  
Typical Feature ◽  
Cyclin D2 ◽  
Primary Tumors ◽  
Normal Tissues ◽  
Paired Samples ◽  
Hpv Status

Aberrant regulation of the cell cycle is a typical feature of all forms of cancer. In head and neck squamous cell carcinoma (HNSCC), it is often associated with the overexpression of cyclin D1 (CCND1). However, it remains unclear how CCND1 expression changes between tumor and normal tissues and whether human papillomavirus (HPV) affects differential CCND1 expression. Here, we evaluated the expression of D-type cyclins in a cohort of 94 HNSCC patients of which 82 were subjected to whole genome expression profiling of primary tumors and paired normal mucosa. Comparative analysis of paired samples showed that CCND1 was upregulated in 18% of HNSCC tumors. Counterintuitively, CCND1 was downregulated in 23% of carcinomas, more frequently in HPV-positive samples. There was no correlation between the change in D-type cyclin expression and patient survival. Intriguingly, among the tumors with downregulated CCND1, one-third showed an increase in cyclin D2 (CCND2) expression. On the other hand, one-third of tumors with upregulated CCND1 showed a decrease in CCND2. Collectively, we have shown that CCND1 was frequently downregulated in HNSCC tumors. Furthermore, regardless of the HPV status, our data suggested that a change in CCND1 expression was alleviated by a compensatory change in CCND2 expression.

Genomic characterization of brain metastases (BM) in high-grade serous ovarian cancer (HGSOC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13580-e13580
Author(s):  
Renata Duchnowska ◽  
Anna Maria Supernat ◽  
Rafał Pęksa ◽  
Marta Łukasiewicz ◽  
Tomasz Stokowy ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Somatic Mutations ◽  
Dna Damage Repair ◽  
Genetic Alterations ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Primary Tumors ◽  
Tp53 Mutations ◽  
Damage Repair

e13580 Background: BM are a rare occurrence in ovarian cancer (OC) and their molecular characteristics is virtually unknown. DNA damage repair (DDR) deficiency is prevalent in OC, and co-mutated TP53 and any DDR denotes high tumor mutation burden (TMB). We genetically characterized a unique series of high-grade serous ovarian cancer (HGSOC) patients who developed BM to identify alterations of potential clinical relevance. Methods: Whole-exome sequencing (2x150bp, SureSelectXT Library Prep Kit, Illumina’s NovaSeq platform) was performed in matched BM, primary tumors (PT) and normal tissue. DNA was extracted from FFPE samples using QIAamp DNA FFPE Tissue Kit (Qiagen, Germany). All mutations were checked with Catalogue of Somatic Mutations in Cancer (COSMIC) and Integrative Genomics Viewer (IGV). Results: Study group included 10 HGSOC patients (International Federation of Gynecology and Obstetrics classification (FIGO) II-IV, mean age at diagnosis 48 years, range 35-59). Median time from primary HGSOC diagnosis to BM was 38 months (range, 18 to 149). TP53 somatic mutations were found in both primary tumor (PT) and BM in 8 patients. The other 2 cases harbored TP53 mutations not reported in COSMIC catalogue: p.S60L and intronic TP53 mutation preceding p.I322 (IGV). In 9 cases TP53 mutations coexisted with germline or somatic DNA damage repair deficiency. Four cases contained BRCA1 mutations (all germline), and none harbored germline BRCA2 mutation. Other mutated genes included MLH1 (2 somatic, 2 germline), ATR (4 germline, 1 somatic), AMT (1 somatic), RAD50 (1 somatic), ERCC4 (1 somatic), FANCD2 (1 somatic) and RPA1 (1 germline). Three mutation signatures defined in the COSMIC database were indentified in BM: 6, 20 and 30. In 6 cases these mutations were shared in PT, and in another 4 their presence in PT could not be determined due to technical reasons. Median survival from BM was 31 months (range, 5 to 184). Conclusions: Genomic analysis of BM provides an opportunity to identify potentially clinically informative alterations. Mutational profiles in PT are generally reflected in BM. Detected genetic alterations suggest their potential sensitivity to PARP inhibitors and immunotherapy.

Gene-specific features (MLH1, MSH2, MSH6, PMS2) of mismatch repair (MMR) protein expression and somatic mutations (muts), microsatellite instability (MSI) and tumor mutational burden (TMB) in MSI-H and MMR-mutated tumor genomic profiles (TGPs).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 505-505 ◽  
Author(s):  
Michael J. Hall ◽  
Joseph Nicholas Bodor ◽  
Joanne Xiu ◽  
Rebecca Feldman ◽  
Axel Grothey ◽  
...  
Keyword(s):  
Protein Expression ◽  
Somatic Mutations ◽  
Germ Line ◽  
Tumor Biomarker ◽  
Dna Repair Genes ◽  
Mmr Genes ◽  
Mutational Burden ◽  
Response Table ◽  
Tumor Mutational Burden ◽  
Repair Genes

505 Background: MSI is a tumor biomarker for immunotherapy efficacy that is closely associated w/deficient MMR, and is also variably associated w/somatic muts of the MMR genes, loss of MMR protein expression by immunohistochemistry (IHC), and high TMB. Germ-line muts (Lynch syndrome/LS) in the 4 MMR genes are recognized to have distinct cancer spectrums/penetrance in LS, yet across all tumors, gene-specific variability in MMR IHC, MMR muts, and TMB is understudied. Methods: Results of TGPs performed by Caris Lifesciences (2015-17) were analyzed in colorectal (CRC), endometrial (EC) and all other cancers/tumors (OT) as: 1) all MSI-H tumors (n = 1057) and 2) all tumors w/ ≥1 mut in an MMR gene (n = 470). A subset of cases had IHC for MMR protein and PD-L1 expression. MSI and TMB were determined by NGS. Results: Characteristics of MSI-H tumors and tumors w/ ≥1 MMR mut are seen in the Table. A single MSH6 mut [F1088fs] in a coding microsatellite represented 31% of all MMR muts detected. F1088fs was found in 58% tumors w/MLH1/PMS2 loss (IHC) but only 25% w/MSH2/MSH6 loss (p < 0.001), was more commonly seen in EC vs CRC/OT (p < 0.001), and was negatively associated w/somatic POLE mut (p = 0.002). Distinct mut signatures in the MMR genes (e.g. GLUàSTOP) were seen in tumors w/POLE muts and DNA repair genes. Conclusions: MSI-H and MMR mutated tumors demonstrate marked gene-specific heterogeneity in IHC patterns, TMBs, and somatic muts that may be relevant to treatment selection, resistance, and response. [Table: see text]

CD3 and CD20 immune cell densities in primary tumors, lymph node metastasis, and recurrent disease samples of head and neck squamous cell carcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6551-6551
Author(s):  
Simon Laban ◽  
Romain Remark ◽  
Christian Idel ◽  
Julika Ribbat-Idel ◽  
Andreas Schröck ◽  
...  
Keyword(s):  
Overall Survival ◽  
Immune Cell ◽  
Recurrent Disease ◽  
Primary Site ◽  
Prognostic Impact ◽  
Sample Type ◽  
Primary Tumors ◽  
Node Metastasis ◽  
Paired Samples ◽  
Cell Densities

6551 Background: Immune cell (IC) infiltrates in primary tumors (PT) have been identified as prognostic markers in head and neck squamous cell carcinoma (HNSCC). IC densities may differ among PT, lymph node metastasis (LNM) and recurrent disease (RD) and by primary disease site (oral cavity- OC, oropharynx- OP, hypopharynx- HP, larynx- L). Here, we compare CD3 and CD20 IC densities in PT, LNM and RD in paired samples from different disease sites and determine the prognostic impact of IC infiltrates. Methods: Tissue microarrays with 425 PT, 198 LNM and 46 RD samples--each in triplicate--were stained immunohistochemically for CD3 and CD20 in the same slide. Immune cell densities per mm2 were determined using a digital image analysis software (QuPath). Individual means were calculated from triplicates of each sample. IC infiltrates from different sample types (PT, LNM, RD) and primary tumor sites were compared using Kruskal-Wallis and Mann-Whitney-U tests. Paired samples were compared using Wilcoxon signed rank test. IC densities were classified as CD3 high/low and CD20 high/low for each primary tumor site using the individual median as a cut-off. Overall survival (OS) was calculated using the Kaplan-Meier method. P-values for each hypothesis were corrected using a false discovery rate of 5%. Results: CD3 and CD20 IC densities differed significantly by sample type (both p<0.0001) and primary site (CD3: p=0.012, CD20: p=0.0017). CD3 and CD20 densities were significantly lower in PT compared to LNM or in RD compared to PT and LNM. Paired samples (n=172) revealed a significantly higher CD3 and CD20 density (both p<0.0005) in LNM compared to PT, but no significant differences between PT and RD (n=28, p>0.05). CD3 densities were significantly higher than CD20 densities in all sample types. CD3high patients had the best prognosis in all sites except for OC (q<0.05) independent of CD20 status. In OC, CD3 density was not prognostic, but CD3low/CD20high patients had the worst OS compared to CD3low/CD20low and CD3high/CD20high or even CD3high/CD20low patients (p=0.018) who had the best prognosis. Conclusions: IC densities of CD3 and CD20 vary by sample type and primary site. Except for OC, in all sites the prognostic impact is determined by CD3high, whereas in OSCC only the combination of CD3 and CD20 IC densities achieves a good prognostic value. Interestingly, CD3low/CD20high patients have the worst overall survival in OC patients. Further work is needed to understand the interaction of B- and T cell infiltrates in the tumor, especially in OC.

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