Oncology

2021

Caveolin-1 expression predicts favourable outcome and correlates with PDGFRA mutations in gastrointestinal stromal tumours (GISTs)

Bertero L, Gambella A, Barreca A, Osella-Abate S, Chiusa L, Francia di Celle P, Lista P, Papotti M, Cassoni P.

J Clin Pathol. 2021 Jun 21;jclinpath-2021-207595. doi: 10.1136/jclinpath-2021-207595. Online ahead of print.

Abstract

Aims: Novel prognostic markers are warranted for gastrointestinal stromal tumours. Caveolin-1 is a multifunctional protein that proved to be associated with outcome in multiple tumour types. Aim of this study was to investigate Caveolin-1 expression and prognostic efficacy in a series of gastrointestinal stromal tumours.

Methods: Caveolin-1 expression was assessed by immunohistochemistry in a retrospective series of 66 gastrointestinal stromal tumours representative of the different molecular subtypes. Correlations with clinical, histopathological and molecular features were investigated. Statistical analyses were performed as appropriate.

Results: Thirty-five cases out of 66 (53.0%) expressed Caveolin-1. Presence of Caveolin-1 expression correlated with favourable histopathologic and clinical traits, including a lower mitotic count (p=0.003) and lower relapse rate (p=0.005). Caveolin-1 expression also resulted associated with the presence of PDGFRA mutations (p=0.010). Outcome analyses showed a favourable prognostic significance of Caveolin-1 expression in terms of relapse-free survival (HR=0.14; 95% CI=0.03 to 0.63) and overall survival (HR=0.29; 95% CI=0.11 to 0.74), even after adjusting for the mutational subgroup (relapse-free survival: HR=0.14, 95% CI=0.04 to 0.44; overall survival: HR=0.29, 95% CI=0.11 to 0.51) and imatinib treatment (relapse-free survival: HR=0.14, 95% CI=0.02 to 0.81; overall survival: HR=0.29, 95% CI=0.17 to 0.48).

Conclusion: Caveolin-1 represents a novel prognostic marker in gastrointestinal stromal tumours. Further studies are warranted to validate these results and to explore the mechanisms linking Caveolin-1 expression with the PDGFRA oncogenic pathway.

Keywords: gastrointestinal neoplasms; immunohistochemistry; molecular; pathology.

 

High BRAF variant allele frequencies are associated with distinct pathological features and responsiveness to target therapy in melanoma patients

Berrino E, Balsamo A, Pisacane A, Gallo S, Becco P, Miglio U, Caravelli D, Poletto S, Paruzzo L, Debernardi C, Piccinelli C, Zaccagna A, Rescigno P, Aglietta M, Sapino A, Carnevale-Schianca F, Venesio T.

ESMO Open. 2021 Jun;6(3):100133. doi: 10.1016/j.esmoop.2021.100133. Epub 2021 May 10.

Abstract

Background: BRAF mutant melanoma patients are commonly treated with anti-BRAF therapeutic strategies. However, many factors, including the percentage of BRAF-mutated cells, may contribute to the great variability in patient outcomes.

Patients and methods: The BRAF variant allele frequency (VAF; defined as the percentage of mutated alleles) of primary and secondary melanoma lesions, obtained from 327 patients with different disease stages, was assessed by pyrosequencing. The BRAF mutation rate and VAF were then correlated with melanoma pathological features and patients' clinical characteristics. Kaplan-Meier curves were used to study the correlations between BRAF VAF, overall survival (OS), and progression-free survival (PFS) in a subset of 62 patients treated by anti-BRAF/anti-MEK therapy after metastatic progression.

Results: A highly heterogeneous BRAF VAF was identified (3%-90%). Besides being correlated with age, a higher BRAF VAF level was related to moderate lymphocytic infiltration (P = 0.017), to melanoma thickness according to Clark levels, (level V versus III, P = 0.004; level V versus IV, P = 0.04), to lymph node metastases rather than cutaneous (P = 0.04) or visceral (P = 0.03) secondary lesions. In particular, a BRAF VAF >25% was significantly associated with a favorable outcome in patients treated with the combination of anti-BRAF/anti-MEK drug (OS P = 0.04; PFS P = 0.019), retaining a significant value as an independent factor for the OS and the PFS in the multivariate analysis (P = 0.014 and P = 0.003, respectively).

Conclusion: These results definitively support the role of the BRAF VAF as a potential prognostic and predictive biomarker in melanoma patients in the context of BRAF inhibition.

Keywords: BRAF mutations; increased survival; melanoma; variant allele frequency.

 

DNA methylation profiling discriminates between malignant pleural mesothelioma and neoplastic or reactive histological mimics

Bertero L, Righi L, Collemi G, Koelsche C, Hou Y, Stichel D, Schrimpf D,Flucke U, Petersen I, Vokuhl C, Fröhling S, Bironzo P, Scagliotti GV, Cassoni P, Papotti M, von Deimling A

J Mol Diagn. 2021 Jul;23(7):834-846. doi: 10.1016/j.jmoldx.2021.04.002. Epub 2021 Apr 20.

Abstract

The diagnosis of malignant pleural mesothelioma (MPM) is challenging because of its potential overlap with other neoplasms or even with reactive conditions. DNA methylation analysis is effective in diagnosing tumors. In the present study, this approach was tested for use in MPM diagnosis. The DNA methylation patterns of a discovery cohort and an independent-validation cohort of MPMs were compared to those of 202 cases representing malignant and benign diagnostic mimics (angiosarcoma, desmoid-type fibromatosis, epithelioid sarcoma, leiomyosarcoma, lung adenocarcinoma, lung squamous cell carcinoma, melanoma, nodular fasciitis, reactive mesothelial hyperplasia, sclerosing fibrous pleuritis, solitary fibrous tumor, and synovial sarcoma). By both unsupervised hierarchical clustering and t-distributed stochastic neighbor embedding analysis, MPM samples in the discovery cohort exhibited a DNA methylation profile different from those of other neoplastic and reactive mimics. These results were confirmed in the independent validation cohort and by in silico analysis of the MPM-The Cancer Genome Atlas data set. Copy number variation profiles were also inferred to identify molecular hallmarks of MPM, including CDKN2A and NF2 deletions. Methylation profiling was effective in the diagnosis of MPM, although caution is advised in samples with low tumor cell content.

 

Identification of 22 susceptibility loci associated with testicular germ cell tumors

Pluta J, Pyle LC, Nead KT, Wilf R, Li M, Mitra N, Weathers B, D'Andrea K, Almstrup K, Anson-Cartwright L, Benitez J, Brown CD, Chanock S, Chen C, Cortessis VK, Ferlin A, Foresta C, Gamulin M, Gietema JA, Grasso C, Greene MH, Grotmol T, Hamilton RJ, Haugen TB, Hauser R, Hildebrandt MAT, Johnson ME, Karlsson R, Kiemeney LA, Lessel D, Lothe RA, Loud JT, Loveday C, Martin-Gimeno P, Meijer C, Nsengimana J, Quinn DI, Rafnar T, Ramdas S, Richiardi L, Skotheim RI, Stefansson K, Turnbull C, Vaughn DJ, Wiklund F, Wu X, Yang D, Zheng T, Wells AD, Grant SFA, Rajpert-De Meyts E, Schwartz SM, Bishop DT, McGlynn KA, Kanetsky PA, Nathanson KL; Testicular Cancer Consortium

Nature Communications volume 12, Article number: 4487 (2021) Cite this article

Abstract

Testicular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95th percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation.

 

 

Cancers emerging early in adulthood: Analysis of trends and patterns in European cancer registries

 

Scelo G, Maule M, Richiardi L

Eur J Cancer. 2021 Jan;143:33-39. doi: 10.1016/j.ejca.2020.10.026. Epub 2020 Dec 2.

Abstract

Background: Although cancer is typically a disease of the older age groups, some types start emerging early in adulthood. This implies that exposures and stressors occurring before adulthood might play a role in the risk of cancer in adults. Little research has been conducted in this area.

Methods: We used European data from the Cancer in Five Continents Vol. XI to calculate cumulative risks by the end of subsequent adulthood decades of age (20-29, 30-39, 40-49) for 34 cancer sites and classified them as early-age emerging cancers if they reached 0.005% by 29 years old, intermediate-age emerging cancers by 39 years old, and late-age emerging cancers after 40 years old. We used data from Cancer in Five Continents Plus to analyse time trends in incidence rates by age groups over the period 1998-2012.

Findings: We identified 14 early-age emerging cancers. Nine of them showed significant increasing trends over calendar time in the early decades of adulthood, often more pronouncedly so in 20-29-year-olds than in 30-39 or 40-49-year-olds. The increase of colon cancer rates in the 20-29-year-olds was particularly high with an average annual percent change of 7.9% (95% confidence interval: 5.9%-10%). Decreases in incidence rates were only observed for cancer types classified as intermediate- or late-age emerging cancers.

Interpretation: Cancer prevention efforts seem to have favourably impacted intermediate- and late-age emerging cancer incidence rates. For early-age emerging cancers, aetiological research is needed to identify exposures and stressors occurring early in life, especially for those cancers that have been increasing in young adults. This knowledge will be essential to develop preventive strategies.

Keywords: Cancer risk; Early-life exposures; Time trends; Young adult cancers.

Microenvironment in cutaneous melanomas: a gene expression profile study may explain the role of histological regression

Osella-Abate S, Vignale C, Annaratone L, Nocifora A, Bertero L, Castellano I, Avallone G, Conti L, Quaglino P, Picciotto F, Senetta R, Papotti MG, Cassoni P, Ribero S.

J Eur Acad Dermatol Venereol. 2021 Jan;35(1):e35-e38. doi: 10.1111/jdv.16784. Epub 2020 Aug 4.

2021

The Multifaceted Nature of Tumor Microenvironment in Breast Carcinomas

Annaratone L, Cascardi E, Vissio E, Sarotto I, Chmielik E, Sapino A, Berrino E, Marchiò C.

Pathobiology. 2020;87(2):125-142. doi: 10.1159/000507055. Epub 2020 Apr 23.

2020

Abstract

Heterogeneity in breast carcinomas can be appreciated at various levels, from morphology to molecular alterations, and there are well-known genotypic-phenotypic correlations. Clinical decision-making is strictly focused on the evaluation of tumor cells and is based on the assessment of hormone receptors and of the HER2 status, by means of a combination of immunohistochemical and in situ hybridization techniques. The tumor microenvironment (TME) also shows a multifaceted nature stemming from the different actors populating the intratumoral and the peritumoral stroma of breast carcinomas. Of note, we have now evidence that tumor-infiltrating lymphocytes (TILs) are clinically meaningful as their quantification in the intratumoral stroma strongly correlates with good prognosis, in particular in triple-negative and HER2-positive breast cancer patients. Nevertheless, TILs are just one of the many actors orchestrating the complexity of the TME, which is populated by immune and non-immune cells (cancer-associated fibroblasts, cancer-associated adipocytes), as well as non-cellular components such as chemical inflammation mediators. In this review article we will overview the main features of the distinct cell compartments by discussing (i) the potential impact the TME may have on the prognostic stratification of breast cancers and (ii) the possible predictive value of some markers in the context of immunotherapy in light of the recent results of phase III studies in advanced and early triple-negative breast cancer patients.

 

Evolving concepts in HER2 evaluation in breast cancer: Heterogeneity, HER2-low carcinomas and beyond

Marchiò C, Annaratone L, Marques A, Casorzo L, Berrino E, Sapino A.

Semin Cancer Biol . 2020 Feb 26;S1044-579X(20)30049-3. doi: 10.1016/j.semcancer.2020.02.016. Online ahead of print.

2020

Abstract

The human epidermal growth factor receptor 2 (HER2) is a well-known negative prognostic factor in breast cancer and a target of the monoclonal antibody trastuzumab as well as of other anti-HER2 compounds. Pioneering works on HER2-positive breast cancer in the 90s' launched a new era in clinical research and oncology practice that has reshaped the natural history of this disease. In diagnostic pathology the HER2 status is routinely assessed by using a combination of immunohistochemistry (IHC, to evaluate HER2 protein expression levels) and in situ hybridization (ISH, to assess HER2 gene status). For this purpose, international recommendations have been developed by a consensus of experts in the field, which have changed over the years according to new experimental and clinical data. In this review article we will document the changes that have contributed to a better evaluation of the HER2 status in clinical practice, furthermore we will discuss HER2 heterogeneity defined by IHC and ISH as well as by transcriptomic analysis and we will critically describe the complexity of HER2 equivocal results. Finally, we will introduce the clinical impact of HER2 mutations and we will define the upcoming category of HER2-low breast cancer with respect to emerging clinical data on the efficacy of specific anti-HER2 agents in subgroups of breast carcinomas lacking the classical oncogene addition dictated by HER2 amplification.

 

Cold formalin fixation guarantees DNA integrity in formalin fixed paraffin embedded tissues: premises for a better quality of diagnostic and experimental pathology with a specific impact on breast cancer

 

Berrino E, Miglio U, Annaratone L, Maldi E, Piccinelli C, Peano E, Balmativola D, Cassoni P, Pisacane A, Sarotto I, Venesio T, Sapino A, Marchiò C.

Front Oncol. 2020; 10: 173. Published online 2020 Feb 19. doi: 10.3389/fonc.2020.00173

Abstract

Formalin fixation and paraffin embedding (FFPE) represent the standard method to preserve tissue specimens for diagnostic pathology, however formalin fixation induces severe fragmentation of nucleic acids. We investigated whether formalin fixation at 4°C could preserve DNA integrity in FFPE specimens. Paired samples from 38 specimens were formalin fixed at room temperature (stdFFPE) and at 4°C (coldFFPE), respectively. Two independent cohorts were prospectively collected, cohort A (collected 6 years prior to the study, n = 21), cohort B (collected at time of the study, n = 17). DNA was extracted and its integrity evaluated with a qPCR-based assay that produces a normalized integrity index, the QC score (ratio between the quantity of a long and a short amplicon of the same gene). We observed higher QC scores in coldFFPE compared to stdFFPE samples (mean values: 0.69 vs. 0.36, p < 0.0001) and stdFFPE breast cancer specimens showed the most detrimental effect overall. Comparable QC scores were obtained between coldFFPE tissues of both cohorts; conversely, DNA integrity of stdFFPE was significantly lower in cohort A compared to cohort B (p < 0.0001). Of note, QC scores of stdFFPE (but not of coldFFPE) samples were significantly reduced following 6 months of storage (p = 0.0001). Monitored formalin fixation at 4°C outperforms standard fixation in ensuring high-quality DNA, which is key to feasibility of downstream high-throughput molecular analyses. An important effect was observed over storage time, thus suggesting a likely better preservation of archival samples when this cold fixation protocol is used.

 

Prognostic role of PD-L1 and immune-related gene expression profiles in giant cell tumors of bone

 

Metovic J, Annaratone L, Linari A, Osella-Abate S, Musuraca C, Veneziano F, Vignale C, Bertero L, Cassoni P, Ratto N, Comandone A, Grignani G, Piana R, Papotti M.

Cancer Immunol Immunother . 2020 Sep;69(9):1905-1916. doi: 10.1007/s00262-020-02594-9. Epub 2020 May 6.

2020

Abstract

Giant cell tumor of bone (GCTB) is a locally aggressive and rarely metastatic tumor, with a relatively unpredictable clinical course. A retrospective series of 46 GCTB and a control group of 24 aneurysmal bone cysts (ABC) were selected with the aim of investigating the PD-L1 expression levels and immune-related gene expression profile, in correlation with clinicopathological features. PD-L1 and Ki67 were immunohistochemically tested in each case. Furthermore, comprehensive molecular analyses were carried out using NanoString technology and nCounter PanCancer Immune Profiling Panel, and the gene expression results were correlated with clinicopathological characteristics. PD-L1 expression was observed in 13/46 (28.3%) GCTB (and in 1/24, 4.2%, control ABC, only) and associated with a shorter disease free interval according to univariate analysis. Moreover, in PD-L1-positive lesions, three genes (CD27, CD6 and IL10) were significantly upregulated (p < 0.01), while two were downregulated (LCK and TLR8, showing borderline significance, p = 0.06). Interestingly, these genes can be related to maturation and immune tolerance of bone tissue microenvironment, suggesting a more immature/anergic phenotype of giant cell tumors. Our findings suggest that PD-L1 immunoreactivity may help to select GCTB patients with a higher risk of recurrence who could potentially benefit from immune checkpoint blockade.

 

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