Publications by authors named "Lorenzo Ferrando"

25 Publications

  • Page 1 of 1

Genetic and molecular subtype heterogeneity in newly diagnosed early- and advanced-stage endometrial cancer.

Gynecol Oncol 2021 Feb 20. Epub 2021 Feb 20.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Objective: To characterize and compare the molecular subtypes and profiles of prospectively-accrued newly-diagnosed early- and advanced-stage endometrial cancers (ECs).

Methods: EC patients consented to an IRB-approved protocol of massively parallel sequencing of 410-468 cancer-related genes; 175 ECs of 7 histologic types (n = 135 FIGO stages I/II, n = 40 FIGO stages III/IV) were included. Previously reported sequencing data from 99 additional advanced-stage ECs were retrieved for comparisons.

Results: Irrespective of histologic type, all 175 ECs could be stratified into the molecular subtypes, with 75 (43%) being of p53 wild-type, 49 (28%) MMR-deficient, 39 (22%) p53 abnormal and 12 (7%) of POLE molecular subtypes. Subtype distribution, mutational and copy number profiles varied according to histologic type. In endometrioid ECs, genetic alterations varied according to histologic grade. Potential therapeutic targets, including high tumor mutational burden, ERBB2 amplification and PIK3CA hotspot mutations, were found across histologic types in 63% (n = 110) of all ECs. Compared to their early-stage counterparts, advanced-stage endometrioid ECs had a significantly higher fraction of genome altered (median 0.1% vs 12%, p < 0.001) and ARID1B mutations (0% vs 11%, p = 0.01), and advanced-stage serous ECs harbored more frequent ERBB2 amplification (18% vs 8%, p > 0.05) and PIK3CA mutations (46% vs 27%, p > 0.05). Whole-genome doubling was found in advanced- but not early-stage carcinosarcomas and clear cell carcinomas.

Conclusions: Our findings demonstrate the molecular heterogeneity within and across histologic types of EC and the increased genomic complexity of advanced-stage ECs. Molecular subtypes are present across EC histologic types and may help stratify EC patients for prognostic and therapeutic purposes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ygyno.2021.02.015DOI Listing
February 2021

Genetic characterization of adult primary pleomorphic uterine rhabdomyosarcoma and comparison with uterine carcinosarcoma.

Histopathology 2021 Feb 2. Epub 2021 Feb 2.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Aims: To characterize the genetic alterations in adult primary uterine rhabdomyosarcomas (uRMSs) and to investigate whether these tumors are genetically distinct from uterine carcinosarcomas (UCSs).

Methods: Three tumors originally diagnosed as primary adult pleomorphic uRMS were subjected to massively parallel sequencing targeting 468 cancer-related genes and RNA-sequencing. Mutational profiles were compared to those from UCSs (n=57) obtained from The Cancer Genome Atlas. Sequencing data analyses were performed using validated bioinformatic approaches.

Results: Pathogenic TP53 mutations and high levels of genomic instability were detected in the three cases. uRMS1 harbored a likely pathogenic YTHDF2-FOXR1 fusion gene. uRMS2 displayed a PPP2R1A hotspot mutation and amplification of multiple genes, including WHSC1L1, FGFR1, MDM2 and CCNE1, whereas uRMS3 harbored an FBXW7 hotspot mutation and an ANKRD11 homozygous deletion. Hierarchical clustering of somatic mutations and copy number alterations revealed that these tumors initially diagnosed as pleomorphic uRMSs and UCSs were similar. Subsequent comprehensive pathologic re-review of the three uRMSs revealed previously un-identified minute pan-cytokeratin-positive atypical glands in one case (uRMS3), favoring its reclassification as UCS with extensive rhabdomyosarcomatous overgrowth.

Conclusions: Adult pleomorphic uRMSs harbor TP53 mutations and high levels of copy number alterations. Our findings underscore the challenge in discriminating between uRMS and UCS with rhabdomyosarcomatous differentiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/his.14346DOI Listing
February 2021

Clonal relationship and directionality of progression of synchronous endometrial and ovarian carcinomas in patients with DNA mismatch repair-deficiency associated syndromes.

Mod Pathol 2020 Dec 16. Epub 2020 Dec 16.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Sporadic synchronous endometrial (ECs) and ovarian cancers (OCs), although clinically considered to be independent primaries, have been shown to be clonally related and likely constitute metastases from each other. We sought to define whether synchronous ECs/OCs in patients with DNA mismatch repair (MMR)-deficiency syndromes would be clonally related. We subjected synchronous ECs/OCs from four patients (LS3-LS6) with clinically confirmed Lynch syndrome (LS) and one patient with constitutional mismatch repair-deficiency syndrome (CMMRD) to massively parallel sequencing targeting 468 cancer-related genes. Somatic mutations, copy number alterations (CNAs), clonal relatedness and clonal decomposition analyses were performed using previously described bioinformatics methods. All synchronous ECs/OCs analyzed were considered independent primaries based on clinicopathologic criteria. Sequencing analysis revealed that the ECs/OCs of three cases (LS2-CMMRD, L3, L4) harbored similar repertoires of somatic mutations and CNAs and were clonally related. In these three cases, a subset of subclonal mutations in the EC became clonal in the OC, suggesting that the EC was likely the substrate from which the OC developed. LS5's EC/OC had distinct mutational profiles but shared specific CNAs. In contrast, LS6's EC/OC harbored distinct somatic mutations and lacked CNAs, consistent with each tumor constituting an independent primary lesion. In LS5 and LS6, PTEN mutations and PTEN loss of protein expression were found to be restricted to the EC. Finally, re-analysis of sequencing data of sporadic synchronous ECs/OCs supported the observations made in the current study that the directionality of progression is likely from the endometrium to the ovary. In conclusion, contrary to sporadic synchronous ECs/OCs, which are almost invariably clonally related, ECs/OCs simultaneously involving the uterus and ovary in LS patients may represent distinct primary tumors. A subset of MMR-deficiency syndrome-related synchronous ECs/OCs, however, may originate from a single primary tumor at variance with their clinical diagnosis, with the endometrium being the likeliest site of origin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-020-00721-6DOI Listing
December 2020

Whole-exome sequencing analysis of juvenile papillomatosis and coexisting breast carcinoma.

J Pathol Clin Res 2021 Mar 2;7(2):113-120. Epub 2020 Dec 2.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Juvenile papillomatosis (JP) of the breast is a rare benign mass-forming lesion occurring in young women, which is histologically characterized by a constellation of proliferative changes and large cysts, giving it the gross appearance of Swiss cheese. A subset of patients with JP report a family history of breast carcinoma and/or coexisting or subsequent breast carcinoma. We performed whole-exome sequencing of the hyperplastic epithelial component of three JPs, including one with coexisting ductal carcinoma in situ (DCIS) and invasive ductal carcinoma of no special type (IDC-NST). JPs harbored clonal somatic PIK3CA hotspot mutations in two cases. In the JP with coexisting DCIS and IDC-NST, these lesions were clonally related to the associated JP, sharing a clonal PIK3CA E542K somatic hotspot mutation. JP showed a paucity of copy number alterations, whereas the associated DCIS and IDC-NST showed concurrent 1q gains/16q losses, hallmarks of estrogen receptor (ER)-positive breast cancers. We observed JP to harbor a dominant aging-related mutational signature, whereas coexisting DCIS and IDC-NST showed greater exposure to an APOBEC signature. Taken together, our findings suggest that, at least in a subset of cases, JP might constitute the substrate from which DCIS and invasive breast carcinomas develop.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cjp2.190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869928PMC
March 2021

The genomic landscape of metastatic histologic special types of invasive breast cancer.

NPJ Breast Cancer 2020 14;6:53. Epub 2020 Oct 14.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA.

Histologic special types of breast cancer (BC) account for ~20% of BCs. Large sequencing studies of metastatic BC have focused on invasive ductal carcinomas of no special type (IDC-NSTs). We sought to define the repertoire of somatic genetic alterations of metastatic histologic special types of BC. We reanalyzed targeted capture sequencing data of 309 special types of BC, including metastatic and primary invasive lobular carcinomas (ILCs;  = 132 and  = 127, respectively), mixed mucinous ( = 5 metastatic and  = 14 primary), micropapillary ( = 12 metastatic and  = 8 primary), and metaplastic BCs ( = 6 metastatic and  = 5 primary), and compared metastatic histologic special types of BC to metastatic IDC-NSTs matched according to clinicopathologic characteristics and to primary special type BCs. The genomic profiles of metastatic and primary special types of BC were similar. Important differences, however, were noted: metastatic ILCs harbored a higher frequency of genetic alterations in , , , , and than primary ILCs, and in , , , , , and than metastatic IDC-NSTs. Metastatic ILCs displayed a higher mutational burden, and more frequently dominant APOBEC mutational signatures than primary ILCs and matched metastatic IDC-NSTs. and mutations were frequently detected in metastatic mixed mucinous BCs, whereas and were the most frequently altered genes in metastatic micropapillary and metaplastic BCs, respectively. Taken together, primary and metastatic BCs histologic special types have remarkably similar repertoires of somatic genetic alterations. Metastatic ILCs more frequently harbor APOBEC mutational signatures than primary ILCs and metastatic IDC-NSTs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41523-020-00195-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560857PMC
October 2020

The genetic landscape of metaplastic breast cancers and uterine carcinosarcomas.

Mol Oncol 2020 Oct 5. Epub 2020 Oct 5.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Metaplastic breast carcinoma (MBC) and uterine carcinosarcoma (UCS) are rare aggressive cancers, characterized by an admixture of adenocarcinoma and areas displaying mesenchymal/sarcomatoid differentiation. We sought to define whether MBCs and UCSs harbor similar patterns of genetic alterations, and whether the different histologic components of MBCs and UCSs are clonally related. Whole-exome sequencing (WES) data from MBCs (n = 35) and UCSs (n = 57, The Cancer Genome Atlas) were reanalyzed to define somatic genetic alterations, altered signaling pathways, mutational signatures, and genomic features of homologous recombination DNA repair deficiency (HRD). In addition, the carcinomatous and sarcomatous components of an additional cohort of MBCs (n = 11) and UCSs (n = 6) were microdissected separately and subjected to WES, and their clonal relatedness was assessed. MBCs and UCSs harbored recurrent genetic alterations affecting TP53, PIK3CA, and PTEN, similar patterns of gene copy number alterations, and an enrichment in alterations affecting the epithelial-to-mesenchymal transition (EMT)-related Wnt and Notch signaling pathways. Differences were observed, however, including a significantly higher prevalence of FAT3 and FAT1 somatic mutations in MBCs compared to UCSs, and conversely, UCSs significantly more frequently harbored somatic mutations affecting FBXW7 and PPP2R1A as well as HER2 amplification than MBCs. Genomic features of HRD and biallelic alterations affecting bona fide HRD-related genes were found to be more prevalent in MBCs than in UCSs. The distinct histologic components of MBCs and UCSs were clonally related in all cases, with the sarcoma component likely stemming from a minor subclone of the carcinoma component in the samples with interpretable chronology of clonal evolution. Despite the similar histologic features and pathways affected by genetic alterations, UCSs differ from MBCs on the basis of FBXW7 and PPP2R1A mutations, HER2 amplification, and lack of HRD, supporting the notion that these entities are more than mere phenocopies of the same tumor type in different anatomical sites.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/1878-0261.12813DOI Listing
October 2020

Endometrial Cancers in or Germline Mutation Carriers: Assessment of Homologous Recombination DNA Repair Defects.

JCO Precis Oncol 2019 29;3. Epub 2019 Aug 29.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Endometrial cancer (EC) is not considered a component of the hereditary breast and ovarian cancer syndrome but can arise in patients with germline (g) mutations. Biallelic alterations are associated with genomic features of homologous recombination DNA repair deficiency (HRD) in cancer. We sought to determine if ECs in g mutation carriers harbor biallelic alterations and/or features of HRD.

Methods: Of 769 patients with EC who underwent germline panel testing, 10 pathogenic g mutation carriers were identified, and their tumor- and normal-derived DNA was subjected to massively parallel sequencing targeting at least 410 cancer-related genes. Three g-associated ECs were identified in 232 ECs subjected to whole-exome sequencing by The Cancer Genome Atlas. Somatic mutations, copy number alterations, loss of heterozygosity, microsatellite instability (MSI), and genomic HRD features were assessed.

Results: Of the 13 patients included who had EC, eight harbored pathogenic g mutations and five harbored g mutations. Eight (100%) and two (40%) ECs harbored biallelic and alterations through loss of heterozygosity of the wild-type allele. All ECs harbored somatic mutations. One monoallelic/sporadic g-associated EC had promoter methylation and was MSI high. High large-scale state transition scores, a genomic feature of HRD, were found only in ECs with bi- but not monoallelic alterations. The Signature Multivariate Analysis HRD signature Sig3 was enriched in biallelic g ECs, and the three ECs from The Cancer Genome Atlas with biallelic alterations subjected to whole-exome sequencing displayed a dominant HRD-related mutational signature 3.

Conclusion: A subset of g-associated ECs harbor biallelic alterations and genomic features of HRD, which may benefit from homologous recombination-directed treatment regimens. ECs in mutation carriers might be sporadic and even MSI high, and may potentially benefit from immune-checkpoint inhibition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/PO.19.00103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446423PMC
August 2019

FOXA1 Mutations Reveal Distinct Chromatin Profiles and Influence Therapeutic Response in Breast Cancer.

Cancer Cell 2020 10 3;38(4):534-550.e9. Epub 2020 Sep 3.

Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Mutations in the pioneer transcription factor FOXA1 are a hallmark of estrogen receptor-positive (ER) breast cancers. Examining FOXA1 in ∼5,000 breast cancer patients identifies several hotspot mutations in the Wing2 region and a breast cancer-specific mutation SY242CS, located in the third β strand. Using a clinico-genomically curated cohort, together with breast cancer models, we find that FOXA1 mutations associate with a lower response to aromatase inhibitors. Mechanistically, Wing2 mutations display increased chromatin binding at ER loci upon estrogen stimulation, and an enhanced ER-mediated transcription without changes in chromatin accessibility. In contrast, SY242CS shows neomorphic properties that include the ability to open distinct chromatin regions and activate an alternative cistrome and transcriptome. Structural modeling predicts that SY242CS confers a conformational change that mediates stable binding to a non-canonical DNA motif. Taken together, our results provide insights into how FOXA1 mutations perturb its function to dictate cancer progression and therapeutic response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2020.08.003DOI Listing
October 2020

Sterol synthesis pathway inhibition as a target for cancer treatment.

Cancer Lett 2020 Nov 22;493:19-30. Epub 2020 Jul 22.

Department of Internal Medicine, Università degli Studi di Genova, Viale Benedetto XV, 6, 16132, Genova, Italy; IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132, Genova, Italy. Electronic address:

Sterol synthesis is a highly complex and integrated pathway in mammals. In the present review, we briefly summarize the main steps of this pathway, especially concerning its main rate-limiting enzymes, HMG-CoA reductase (HMGCR) and squalene epoxidase (SQLE), in relation with cancer. We focus on studies reporting key findings linking cholesterol with cancer. The inhibition of HMGCR and SQLE to prevent and inhibit cancer are reviewed. Finally, a pan-cancer review of publicly available data on genomic aberrations in the main enzymes involved in sterol biosynthesis and their transcription factors is reported, providing hitherto unexplored findings that may be the subject of future research in cancer metabolomics and tumor targeted treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2020.07.010DOI Listing
November 2020

Fasting-mimicking diet and hormone therapy induce breast cancer regression.

Nature 2020 07 15;583(7817):620-624. Epub 2020 Jul 15.

IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2502-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881940PMC
July 2020

Oncogenic properties and signaling basis of the PAX8-GLIS3 fusion gene.

Int J Cancer 2020 Oct 21;147(8):2253-2264. Epub 2020 May 21.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Hyalinizing trabecular tumors of the thyroid are rare and mostly benign epithelial neoplasms of follicular cell origin, which have recently been shown to be underpinned by the PAX8-GLIS3 fusion gene. In our study, we sought to investigate the potential oncogenic mechanisms of the PAX8-GLIS3 fusion gene. Forced expression of PAX8-GLIS3 was found to increase proliferation, clonogenic potential and migration of human nonmalignant thyroid (Nthy-ori 3-1) and embryonic kidney (HEK-293) cells. Moreover, in xenografts, Nthy-ori 3-1 PAX8-GLIS3 expressing cells generated significantly larger and more proliferative tumors compared to controls. These oncogenic effects were found to be mediated through activation of the Sonic Hedgehog (SHH) pathway. Targeting of smoothened (SMO), a key protein in the SHH pathway, using the small molecule inhibitor Cyclopamine partially reversed the increased proliferation, colony formation and migration in PAX8-GLIS3 expressing cells. Our data demonstrate that the oncogenic effects of the PAX8-GLIS3 fusion gene are, at least in part, due to an increased activation of the SHH pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.33040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679121PMC
October 2020

Circulating Tumor DNA Using Tagged Targeted Deep Sequencing to Assess Minimal Residual Disease in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy.

J Oncol 2020 22;2020:8132507. Epub 2020 Jan 22.

Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy.

In breast cancer patients undergoing neoadjuvant chemotherapy before surgery, there is an unmet need for noninvasive predictive biomarkers of response. The analysis of circulating tumor DNA (ctDNA) in particular has been the object of several reports, but few of them have studied the applicability of tagged targeted deep sequencing (tTDS) to clinical practice and its performance compared with droplet digital PCR (ddPCR). Here, we present the first results from an ongoing study involving a prospectively accrued, monocentric cohort of patients affected by invasive breast cancer, undergoing neoadjuvant chemotherapy followed by surgery with curative intent as per clinical practice. A pretreatment tumor biopsy and plasma samples were collected before and during treatment, after surgery, and every six months henceforth or until relapse, whichever came first. Pretreatment biopsies were sequenced with a 409-gene massive parallel sequencing (MPS) panel, allowing the identification of target mutations and their research in plasma by tTDS and ddPCR as a complementary approach. Using tTDS, we demonstrated the presence of at least one deleterious mutation in all the relapsed cases we studied ( = 4), with an average lead time of six months before clinical relapse. The association with ddPCR was suboptimal, and only one relapsed patient could be identified with such method. tTDS shows potential as an early noninvasive method for the detection of MRD in BC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/8132507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196957PMC
January 2020

Whole-Exome Sequencing Analysis of the Progression from Non-Low-Grade Ductal Carcinoma to Invasive Ductal Carcinoma.

Clin Cancer Res 2020 Jul 27;26(14):3682-3693. Epub 2020 Mar 27.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Ductal carcinoma (DCIS) is a nonobligate precursor of invasive breast cancer. Here, we sought to investigate the level of intralesion genetic heterogeneity in DCIS and the patterns of clonal architecture changes in the progression from DCIS to invasive disease.

Experimental Design: Synchronous DCIS ( = 27) and invasive ductal carcinomas of no special type (IDC-NSTs; = 26) from 25 patients, and pure DCIS ( = 7) from 7 patients were microdissected separately and subjected to high-depth whole-exome ( = 56) or massively parallel sequencing targeting ≥410 key cancer-related genes ( = 4). Somatic genetic alterations, mutational signatures, clonal composition, and phylogenetic analyses were defined using validated computational methods.

Results: DCIS revealed genetic alterations similar to those of synchronously diagnosed IDC-NSTs and of non-related IDC-NSTs from The Cancer Genome Atlas (TCGA), whereas pure DCIS lacked mutations. Clonal decomposition and phylogenetic analyses based on somatic mutations and copy number alterations revealed that the mechanisms of progression of DCIS to invasive carcinoma are diverse, and that clonal selection might have constituted the mechanism of progression from DCIS to invasive disease in 28% (7/25) of patients. DCIS displaying a pattern of clonal selection in the progression to invasive cancer harbored higher levels of intralesion genetic heterogeneity than DCIS where no clonal selection was observed.

Conclusions: Intralesion genetic heterogeneity is a common feature in DCIS synchronously diagnosed with IDC-NST. DCIS is a nonobligate precursor of IDC-NST, whose mechanisms of progression to invasive breast cancer are diverse and vary from case to case.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-2563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367727PMC
July 2020

Genomic profiling of primary and recurrent adult granulosa cell tumors of the ovary.

Mod Pathol 2020 08 12;33(8):1606-1617. Epub 2020 Mar 12.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Adult-type granulosa cell tumor (aGCT) is a rare malignant ovarian sex cord-stromal tumor, harboring recurrent FOXL2 c.C402G/p.C134W hotspot mutations in 97% of cases. These tumors are considered to have a favorable prognosis, however aGCTs have a tendency for local spread and late recurrences, which are associated with poor survival rates. We sought to determine the genetic alterations associated with aGCT disease progression. We subjected primary non-recurrent aGCTs (n = 7), primary aGCTs that subsequently recurred (n = 9) and their matched recurrences (n = 9), and aGCT recurrences without matched primary tumors (n = 10) to targeted massively parallel sequencing of ≥410 cancer-related genes. In addition, three primary non-recurrent aGCTs and nine aGCT recurrences were subjected to FOXL2 and TERT promoter Sanger sequencing analysis. All aGCTs harbored the FOXL2 C134W hotspot mutation. TERT promoter mutations were found to be significantly more frequent in recurrent (18/28, 64%) than primary aGCTs (5/19, 26%, p = 0.017). In addition, mutations affecting TP53, MED12, and TET2 were restricted to aGCT recurrences. Pathway annotation of altered genes demonstrated that aGCT recurrences displayed an enrichment for genetic alterations affecting cell cycle pathway-related genes. Analysis of paired primary and recurrent aGCTs revealed that TERT promoter mutations were either present in both primary tumors and matched recurrences or were restricted to the recurrence and absent in the respective primary aGCT. Clonal composition analysis of these paired samples further revealed that aGCTs display intra-tumor genetic heterogeneity and harbor multiple clones at diagnosis and relapse. We observed that in a subset of cases, recurrences acquired additional genetic alterations not present in primary aGCTs, including TERT, MED12, and TP53 mutations and CDKN2A/B homozygous deletions. Albeit harboring relatively simple genomes, our data provide evidence to suggest that aGCTs are genetically heterogeneous tumors and that TERT promoter mutations and/or genetic alterations affecting other cell cycle-related genes may be associated with disease progression and recurrences.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-020-0514-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390666PMC
August 2020

Development of a long non-coding RNA signature for prediction of response to neoadjuvant chemoradiotherapy in locally advanced rectal adenocarcinoma.

PLoS One 2020 5;15(2):e0226595. Epub 2020 Feb 5.

Department of Internal Medicine, Università degli Studi di Genova, Genova, Italy.

Standard treatment for locally advanced rectal adenocarcinoma (LARC) includes a combination of chemotherapy with pyrimidine analogues, such as capecitabine, and radiation therapy, followed by surgery. Currently no clinically useful genomic predictors of benefit from neoadjuvant chemoradiotherapy (nCRT) exist for LARC. In this study we assessed the expression of 8,127 long noncoding RNAs (lncRNAs), poorly studied in LARC, to infer their ability in classifying patients' pathological complete response (pCR). We collected and analyzed, using lncRNA-specific Agilent microarrays a consecutive series of 61 LARC cases undergoing nCRT. Potential lncRNA predictors in responders and non-responders to nCRT were identified with LASSO regression, and a model was optimized using k-fold cross-validation after selection of the three most informative lncRNA. 11 lncRNAs were differentially expressed with false discovery rate < 0.01 between responders and non-responders to NACT. We identified lnc-KLF7-1, lnc-MAB21L2-1, and LINC00324 as the most promising variable subset for classification building. Overall sensitivity and specificity were 0.91 and 0.94 respectively, with an AUC of our ROC curve = 0.93. Our study shows for the first time that lncRNAs can accurately predict response in LARC undergoing nCRT. Our three-lncRNA based signature must be independently validated and further analyses must be conducted to fully understand the biological role of the identified signature, but our results suggest lncRNAs may be an ideal biomarker for response prediction in the studied setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226595PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001901PMC
April 2020

ARID1A determines luminal identity and therapeutic response in estrogen-receptor-positive breast cancer.

Nat Genet 2020 02 13;52(2):198-207. Epub 2020 Jan 13.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Mutations in ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, are the most common alterations of the SWI/SNF complex in estrogen-receptor-positive (ER) breast cancer. We identify that ARID1A inactivating mutations are present at a high frequency in advanced endocrine-resistant ER breast cancer. An epigenome CRISPR-CAS9 knockout (KO) screen identifies ARID1A as the top candidate whose loss determines resistance to the ER degrader fulvestrant. ARID1A inactivation in cells and in patients leads to resistance to ER degraders by facilitating a switch from ER-dependent luminal cells to ER-independent basal-like cells. Cellular plasticity is mediated by loss of ARID1A-dependent SWI/SNF complex targeting to genomic sites of the luminal lineage-determining transcription factors including ER, forkhead box protein A1 (FOXA1) and GATA-binding factor 3 (GATA3). ARID1A also regulates genome-wide ER-FOXA1 chromatin interactions and ER-dependent transcription. Altogether, we uncover a critical role for ARID1A in maintaining luminal cell identity and endocrine therapeutic response in ER breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0554-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341683PMC
February 2020

Identification of recurrent FHL2-GLI2 oncogenic fusion in sclerosing stromal tumors of the ovary.

Nat Commun 2020 01 2;11(1):44. Epub 2020 Jan 2.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

Sclerosing stromal tumor (SST) of the ovary is a rare type of sex cord-stromal tumor (SCST), whose genetic underpinning is currently unknown. Here, using whole-exome, targeted capture and RNA-sequencing, we report recurrent FHL2-GLI2 fusion genes in 65% (17/26) of SSTs and other GLI2 rearrangements in additional 15% (4/26) SSTs, none of which are detected in other types of SCSTs (n = 48) or common cancer types (n = 9,950). The FHL2-GLI2 fusions result in transcriptomic activation of the Sonic Hedgehog (SHH) pathway in SSTs. Expression of the FHL2-GLI2 fusion in vitro leads to the acquisition of phenotypic characteristics of SSTs, increased proliferation, migration and colony formation, and SHH pathway activation. Targeted inhibition of the SHH pathway results in reversal of these oncogenic properties, indicating its role in the pathogenesis of SSTs. Our results demonstrate that the FHL2-GLI2 fusion is likely the oncogenic driver of SSTs, defining a genotypic-phenotypic correlation in ovarian neoplasms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-13806-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940380PMC
January 2020

Development of a predictor of one-year mortality in older patients with cancer by geriatric and oncologic parameters.

J Geriatr Oncol 2020 05 6;11(4):610-616. Epub 2019 Nov 6.

Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genoa, Italy. Electronic address:

Objectives: More than 60% of the new cancer diagnoses are currently made in older adults, a highly heterogeneous population. Reliable and time-saving tools to define older adults' prognosis are needed to inform the oncologist's decisions in routine clinical practice. We sought to define a multi-domain classification tool for the prediction of all-cause one-year mortality in a cohort of older adults with solid tumors.

Materials And Methods: We conducted a single-centre, prospective study of patients with solid cancer aged 65 or older and with G8 score ≤ 14. All patients underwent a comprehensive geriatric assessment (CGA) before starting their surgical or medical treatment. One-year mortality was recorded. A CGA-based prediction tool of one-year mortality was developed and subsequently validated in two independent training and testing cohorts with a 70/30 split, respectively.

Results: 162 patients were enrolled. Mean patient age was 78 ± 5.5 years. Forty-three percent of the patients were men. Colorectal and breast cancer were the most common diagnoses. The clinical variables selected for the development of the new classifier (MetaGENUA®) were: mini-nutritional assessment (MNA), instrumental day life activities (IADL), Cumulative Illness Rating Scale (CIRS), geriatric depression scale (GDS), age, and cancer stage. In our independent validation cohort, MetaGENUA® showed high specificity (0.86) and AUC = 0.71 (95% CI = 0.55-0.87).

Conclusions: MetaGENUA® predicts one-year mortality in older patients with cancer with high specificity. As such, MetaGENUA® is predicted to reveal as a useful tool to guide the oncologist's decisions in clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jgo.2019.10.018DOI Listing
May 2020

Whole-exome sequencing and RNA sequencing analyses of acinic cell carcinomas of the breast.

Histopathology 2019 Dec 13;75(6):931-937. Epub 2019 Oct 13.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Aims: Acinic cell carcinoma (ACC) of the breast is a rare histological form of triple-negative breast cancer (TNBC). Despite its unique histology, targeted sequencing analysis has failed to identify recurrent genetic alterations other than those found in common forms of TNBC. Here we subjected three breast ACCs to whole-exome and RNA sequencing to determine whether they would harbour a pathognomonic genetic alteration.

Methods And Results: DNA and RNA samples from three breast ACCs were subjected to whole-exome sequencing and RNA-sequencing, respectively. Somatic mutations, copy number alterations, mutational signatures and fusion genes were determined with state-of-the-art bioinformatics methods. Our analyses revealed TP53 hotspot mutations associated with loss of heterozygosity of the wild-type allele in two cases. Mutations affecting homologous recombination DNA repair-related genes were found in two cases, and an MLH1 pathogenic germline variant was found in one case. In addition, copy number analysis revealed the presence of a somatic BRCA1 homozygous deletion and focal amplification of 12q14.3-12q21.1, encompassing MDM2, HMGA2, FRS2, and PTPRB. No oncogenic in-frame fusion transcript was identified in the three breast ACCs analysed.

Conclusions: No pathognomonic genetic alterations were detected in the breast ACCs analysed. These tumours have somatic genetic alterations similar to those of common forms of TNBC, and may show homologous recombination deficiency or microsatellite instability. These findings provide further insights into why breast ACCs, which are usually clinically indolent, may evolve into or in parallel with high-grade TNBC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/his.13962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878125PMC
December 2019

Correction to: Schlafen-11 expression is associated with immune signatures and basal-like phenotype in breast cancer.

Breast Cancer Res Treat 2019 10;177(3):773

Department of Internal Medicine (DiMI), University of Genoa and Ospedale Policlinico San Martino, Viale Benedetto XV, 6, 16132, Genoa, Italy.

In the original publication of the article, the funding information was incorrectly published. The corrected funding statement is given in this correction article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10549-019-05348-zDOI Listing
October 2019

PAX8-GLIS3 gene fusion is a pathognomonic genetic alteration of hyalinizing trabecular tumors of the thyroid.

Mod Pathol 2019 12 4;32(12):1734-1743. Epub 2019 Jul 4.

Department of Oncology, University of Turin, at Città della Salute Hospital, Torino, Italy.

The hyalinizing trabecular adenoma/tumor is a rare and poorly characterized follicular-derived thyroid neoplasm recently shown to harbor recurrent PAX8-GLIS1 or PAX8-GLIS3 gene fusions. Here we sought to define the repertoire of genetic alterations of hyalinizing trabecular tumors, and whether PAX8-GLIS3 fusions are pathognomonic for hyalinizing trabecular tumors. A discovery series of eight hyalinizing trabecular tumors was subjected to RNA-sequencing (n = 8), whole-exome sequencing (n = 3) or targeted massively parallel sequencing (n = 5). No recurrent somatic mutations or copy number alterations were identified in hyalinizing trabecular tumor, whereas RNA-sequencing revealed the presence of a recurrent genetic rearrangement involving PAX8 (2q14.1) and GLIS3 (9p24.2) genes in all cases. In this in-frame fusion gene, which comprised exons 1-2 of PAX8 and exons 3-11 of GLIS3, GLIS3 is likely placed under the regulation of PAX8. Reverse transcription RT-PCR and/or fluorescence in situ hybridization analyses of a validation series of 26 hyalinizing trabecular tumors revealed that the PAX8-GLIS3 gene fusion was present in all hyalinizing trabecular tumors (100%). No GLIS1 rearrangements were identified. Conversely, no PAX8-GLIS3 gene fusions were detected in a cohort of 237 control thyroid neoplasms, including 15 trabecular thyroid lesions highly resembling hyalinizing trabecular tumor from a morphological standpoint, as well as trabecular/solid follicular adenomas, solid/trabecular variants of papillary carcinoma, and Hurthle cell adenomas or carcinomas. Our data provide evidence to suggest that the PAX8-GLIS3 fusion is pathognomonic for hyalinizing trabecular tumors, and that the presence of the PAX8-GLIS3 fusion in thyroid neoplasms may be used as an ancillary marker for the diagnosis of hyalinizing trabecular tumor, thereby avoiding overtreatment in case of misdiagnoses with apparently similar malignant tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-019-0313-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442035PMC
December 2019

Schlafen-11 expression is associated with immune signatures and basal-like phenotype in breast cancer.

Breast Cancer Res Treat 2019 Sep 20;177(2):335-343. Epub 2019 Jun 20.

Department of Internal Medicine (DiMI), University of Genoa and Ospedale Policlinico San Martino, Viale Benedetto XV, 6, 16132, Genoa, Italy.

Purpose: Breast cancer (BC) is a heterogeneous disorder, with variable response to systemic chemotherapy. Likewise, BC shows highly complex immune activation patterns, only in part reflecting classical histopathological subtyping. Schlafen-11 (SLFN11) is a nuclear protein we independently described as causal factor of sensitivity to DNA damaging agents (DDA) in cancer cell line models. SLFN11 has been reported as a predictive biomarker for DDA and PARP inhibitors in human neoplasms. SLFN11 has been implicated in several immune processes such as thymocyte maturation and antiviral response through the activation of interferon signaling pathway, suggesting its potential relevance as a link between immunity and cancer. In the present work, we investigated the transcriptional landscape of SLFN11, its potential prognostic value, and the clinico-pathological associations with its variability in BC.

Methods: We assessed SLFN11 determinants in a gene expression meta-set of 5061 breast cancer patients annotated with clinical data and multigene signatures.

Results: We found that 537 transcripts are highly correlated with SLFN11, identifying "immune response", "lymphocyte activation", and "T cell activation" as top Gene Ontology processes. We established a strong association of SLFN11 with stromal signatures of basal-like phenotype and response to chemotherapy in estrogen receptor negative (ER-) BC. We identified a distinct subgroup of patients, characterized by high SLFN11 levels, ER- status, basal-like phenotype, immune activation, and younger age. Finally, we observed an independent positive predictive role for SLFN11 in BC.

Conclusions: Our findings are suggestive of a relevant role for SLFN11 in BC and its immune and molecular variability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10549-019-05313-wDOI Listing
September 2019

Clinico-pathological associations and concomitant mutations of the RAS/RAF pathway in metastatic colorectal cancer.

J Transl Med 2019 04 29;17(1):137. Epub 2019 Apr 29.

Department of Internal Medicine (Di.M.I.), University of Genoa, Viale Benedetto XV, 6, 16132, Genoa, Italy.

Background: Over the past few years, next-generation sequencing (NGS) has become reliable and cost-effective, and its use in clinical practice has become a reality. A relevant role for NGS is the prediction of response to anti-EGFR agents in metastatic colorectal cancer (mCRC), where multiple exons from KRAS, NRAS, and BRAF must be sequenced simultaneously.

Methods: We optimized a 14-amplicon NGS panel to assess, in a consecutive cohort of 219 patients affected by mCRC, the presence and clinico-pathological associations of mutations in the KRAS, NRAS, BRAF, and PIK3CA genes from formalin-fixed, paraffin-embedded specimens collected for diagnostics and research at the time of diagnosis.

Results: We observed a statistically significant association of RAS mutations with sex, young age, and tumor site. We demonstrated that concomitant mutations in the RAS/RAF pathway are not infrequent in mCRC, and as anticipated by whole-genome studies, RAS and PIK3CA tend to be concurrently mutated. We corroborated the association of BRAF mutations in right mCRC tumors with microsatellite instability. We established tumor side as prognostic parameter independently of mutational status.

Conclusions: To our knowledge, this is the first monocentric, consecutively accrued clinical mCRC cancer cohort tested by NGS in a real-world context for KRAS, NRAS, BRAF, and PIK3CA. Our study has highlighted in clinical practice findings such as the concomitance of mutations in the RAS/RAF pathway, the presence of multiple mutations in single gene, the co-occurrence of RAS and PIK3CA mutations, the prognostic value of tumor side and possible associations of sex with specific mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12967-019-1879-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489172PMC
April 2019

Squalene epoxidase as a promising metabolic target in cancer treatment.

Cancer Lett 2018 07 27;425:13-20. Epub 2018 Mar 27.

Department of Internal Medicine, University of Genoa, Italy; Ospedale Policlinico San Martino, Genoa, Italy. Electronic address:

Oncogenic alteration of the cholesterol synthesis pathway is a recognized mechanism of metabolic adaptation. In the present review, we focus on squalene epoxidase (SE), one of the two rate-limiting enzymes in cholesterol synthesis, retracing its history since its discovery as an antimycotic target to its description as an emerging metabolic oncogene by amplification with clinical relevance in cancer. We review the published literature assessing the association between SE over-expression and poor prognosis in this disease. We assess the works demonstrating how SE promotes tumor cell proliferation and migration, and displaying evidence of cancer cell demise in presence of human SE inhibitors in in vitro and in vivo models. Taken together, robust scientific evidence has by now accumulated pointing out SE as a promising novel therapeutic target in cancer treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2018.03.034DOI Listing
July 2018