Genomic characterization of undifferentiated sarcomatoid carcinoma of the pancreas

Anastasios Gkountakos; Andrea Mafficini; Emil Lou; Giuseppe Malleo; Roberto Salvia; Martina Calicchia; Nicola Silvestris; Emilian Racila; Khalid Amin; Nicola Veronese; Oronzo Brunetti; Pietro Antonini; Giuseppe Ingravallo; Paola Mattiolo; Concetta Saponaro; Floriana Nappo; Michele Simbolo; Elena Bariani; Sara Lonardi; Matteo Fassan; Michele Milella; Rita T. Lawlor; Aldo Scarpa; Claudio Luchini

doi:10.1016/j.humpath.2022.07.011

Genomic characterization of undifferentiated sarcomatoid carcinoma of the pancreas

Anastasios Gkountakos, Andrea Mafficini, Emil Lou, Giuseppe Malleo, Roberto Salvia, Martina Calicchia, Nicola Silvestris, Emilian Racila, Khalid Amin, Nicola Veronese, Oronzo Brunetti, Pietro Antonini, Giuseppe Ingravallo, Paola Mattiolo, Concetta Saponaro, Floriana Nappo, Michele Simbolo, Elena Bariani, Sara Lonardi, Matteo FassanMichele Milella, Rita T. Lawlor, Aldo Scarpa, Claudio Luchini

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Undifferentiated sarcomatoid carcinoma (USC) of the pancreas is a rare but especially aggressive variant of pancreatic ductal adenocarcinoma (PDAC), composed of at least 80% of sarcomatoid cells. This study aimed to elucidate its clinicopathological and molecular features. The study cohort included 10 patients with pancreatic USC. Clinicopathological parameters were determined for each patient. The molecular profile was investigated using next-generation sequencing (NGS). Histologically, all tumors were hypercellular neoplasms with spindle-shaped or sarcomatoid cells. All patients showed vascular and perineural invasion. Most patients had a poor prognosis. NGS showed important similarities with conventional PDAC, including frequent alterations in the classic PDAC drivers, KRAS (100% of cases), TP53 (90%), and CDKN2A (60%). There were also some important distinctions from conventional PDAC: 1) SMAD4, a typical PDAC driver gene, was mutated in only one case (10%); 2) Another distinctive molecular feature was the recurrent KRAS amplification (30% of cases), which is very rare in conventional PDAC. It has been previously reported in another subtype of pancreatic undifferentiated carcinoma, the rhabdoid variant, and may be a key event leading to the acquisition of an undifferentiated phenotype in a subgroup of cases; 3) Lastly, in two different cases, we detected two potentially actionable targets, not belonging to the typical PDAC molecular landscape, such as MCL1 amplification and POLQ mutation. Our study sheds light on this rare tumor type, which shows aggressive biological behavior and few druggable alterations. The most distinctive molecular features of pancreatic USC are the paucity of SMAD4 alterations and recurrent KRAS amplification.

Original language	English (US)
Pages (from-to)	124-133
Number of pages	10
Journal	Human pathology
Volume	128
DOIs	https://doi.org/10.1016/j.humpath.2022.07.011 https://doi.org/10.1016/j.humpath.2022.07.011
State	Published - Oct 2022

Bibliographical note

Funding Information:
The authors thank the patient #10 and his family for donating his remains for the advancement of cancer research, with the hope that this work will be of benefit to future patients. Author contributions: AG, AM, EL, NS, AS, CL: study conception and design; EL, GM, RS, NS, ER, KA, OB, GI, FN, SL, MF, MM, AS, CL: provided original material for the study; EL, GM, RS, NS, ER, KA. OB, GI, FN, SL, MF, MM, AS, CL: clinical analysis; ER, KA, GI, PM, EB, MF, AS, CL: histological analysis; AG, AM, MC, MS, RTL, AS, CL: molecular analysis; all authors: data elaboration, discussion and interpretation; AG, CL: paper writing; all authors: final editing and approval of the present version. Data availability statement: All data of this research are available in the current manuscript, related files and supplementary material. ☆ Competing interest: Emil Lou reports honorarium and travel expenses for a research talk at GlaxoSmithKline (2016); honoraria and travel expenses for lab-based research talks, and equipment for laboratory-based research from Novocure (2018–21); consultant, Nomocan Pharmaceuticals (unpaid); scientific advisory board member, Minnetronix, LLC (2018–present; unpaid); consultant and speaker honorarium, Boston Scientific US (2019); institutional principal investigator for clinical trials sponsored by Celgene, Novocure, LLC, Intima Biosciences, and the National Cancer Institute; and University of Minnesota membership in the Caris Life Sciences Precision Oncology Alliance (unpaid). Sara Lonardi reports research funding from Amgen, Merck Serono, Bayer, Roche, Eli Lilly, AstraZeneca, Bristol Myers Squibb; honoraria from Roche, Eli Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, Amgen; participation in advisory board for Amgen, Merck Serono, Eli Lilly, AstraZeneca, Incyte, Daiichi-Sankyo, Bristol Myers Squibb, Servier, Merck Sharp & Dohme. The other authors have no conflicts of interest. ☆☆ Funding: This study is supported by Personal University Funding for Research (“FUR Prof. Luchini” 2021), Associazione Italiana Ricerca sul Cancro (AIRC IG n. 26343); Fondazione Cariverona: Oncology Biobank Project “Antonio Schiavi” (prot. 203885/2017); Fondazione Italiana Malattie Pancreas (FIMP-Ministero Salute J38D19000690001); Italian Ministry of Health (RF CO-2019-12369662: CUP: B39C21000370001). Furthermore, this research was also supported by contributions from the family of the patient #10, who donated his remains for research autopsy and by fundraising for pancreatic cancer research from friends and family of Gayle Huntington.

Funding Information:
Funding: This study is supported by Personal University Funding for Research (“FUR Prof. Luchini” 2021), Associazione Italiana Ricerca sul Cancro (AIRC IG n. 26343); Fondazione Cariverona: Oncology Biobank Project “Antonio Schiavi” (prot. 203885/2017); Fondazione Italiana Malattie Pancreas (FIMP-Ministero Salute J38D19000690001); Italian Ministry of Health (RF CO-2019-12369662: CUP: B39C21000370001). Furthermore, this research was also supported by contributions from the family of the patient #10, who donated his remains for research autopsy and by fundraising for pancreatic cancer research from friends and family of Gayle Huntington.

Publisher Copyright:
© 2022 Elsevier Inc.

Keywords

KRAS
Pancreatic cancer
Pancreatic ductal adenocarcinoma
Sarcomatoid
Undifferentiated

PubMed: MeSH publication types

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Gkountakos, A., Mafficini, A., Lou, E., Malleo, G., Salvia, R., Calicchia, M., Silvestris, N., Racila, E., Amin, K., Veronese, N., Brunetti, O., Antonini, P., Ingravallo, G., Mattiolo, P., Saponaro, C., Nappo, F., Simbolo, M., Bariani, E., Lonardi, S., ... Luchini, C. (2022). Genomic characterization of undifferentiated sarcomatoid carcinoma of the pancreas. Human pathology, 128, 124-133. https://doi.org/10.1016/j.humpath.2022.07.011, https://doi.org/10.1016/j.humpath.2022.07.011

Gkountakos, A, Mafficini, A, Lou, E, Malleo, G, Salvia, R, Calicchia, M, Silvestris, N, Racila, E , Amin, K, Veronese, N, Brunetti, O, Antonini, P, Ingravallo, G, Mattiolo, P, Saponaro, C, Nappo, F, Simbolo, M, Bariani, E, Lonardi, S, Fassan, M, Milella, M, Lawlor, RT, Scarpa, A & Luchini, C 2022, 'Genomic characterization of undifferentiated sarcomatoid carcinoma of the pancreas', Human pathology, vol. 128, pp. 124-133. https://doi.org/10.1016/j.humpath.2022.07.011, https://doi.org/10.1016/j.humpath.2022.07.011

@article{70914fd363dd4c089c63876e4cf44ba9,

title = "Genomic characterization of undifferentiated sarcomatoid carcinoma of the pancreas",

abstract = "Undifferentiated sarcomatoid carcinoma (USC) of the pancreas is a rare but especially aggressive variant of pancreatic ductal adenocarcinoma (PDAC), composed of at least 80% of sarcomatoid cells. This study aimed to elucidate its clinicopathological and molecular features. The study cohort included 10 patients with pancreatic USC. Clinicopathological parameters were determined for each patient. The molecular profile was investigated using next-generation sequencing (NGS). Histologically, all tumors were hypercellular neoplasms with spindle-shaped or sarcomatoid cells. All patients showed vascular and perineural invasion. Most patients had a poor prognosis. NGS showed important similarities with conventional PDAC, including frequent alterations in the classic PDAC drivers, KRAS (100% of cases), TP53 (90%), and CDKN2A (60%). There were also some important distinctions from conventional PDAC: 1) SMAD4, a typical PDAC driver gene, was mutated in only one case (10%); 2) Another distinctive molecular feature was the recurrent KRAS amplification (30% of cases), which is very rare in conventional PDAC. It has been previously reported in another subtype of pancreatic undifferentiated carcinoma, the rhabdoid variant, and may be a key event leading to the acquisition of an undifferentiated phenotype in a subgroup of cases; 3) Lastly, in two different cases, we detected two potentially actionable targets, not belonging to the typical PDAC molecular landscape, such as MCL1 amplification and POLQ mutation. Our study sheds light on this rare tumor type, which shows aggressive biological behavior and few druggable alterations. The most distinctive molecular features of pancreatic USC are the paucity of SMAD4 alterations and recurrent KRAS amplification.",

keywords = "KRAS, Pancreatic cancer, Pancreatic ductal adenocarcinoma, Sarcomatoid, Undifferentiated",

author = "Anastasios Gkountakos and Andrea Mafficini and Emil Lou and Giuseppe Malleo and Roberto Salvia and Martina Calicchia and Nicola Silvestris and Emilian Racila and Khalid Amin and Nicola Veronese and Oronzo Brunetti and Pietro Antonini and Giuseppe Ingravallo and Paola Mattiolo and Concetta Saponaro and Floriana Nappo and Michele Simbolo and Elena Bariani and Sara Lonardi and Matteo Fassan and Michele Milella and Lawlor, {Rita T.} and Aldo Scarpa and Claudio Luchini",

note = "Funding Information: The authors thank the patient #10 and his family for donating his remains for the advancement of cancer research, with the hope that this work will be of benefit to future patients. Author contributions: AG, AM, EL, NS, AS, CL: study conception and design; EL, GM, RS, NS, ER, KA, OB, GI, FN, SL, MF, MM, AS, CL: provided original material for the study; EL, GM, RS, NS, ER, KA. OB, GI, FN, SL, MF, MM, AS, CL: clinical analysis; ER, KA, GI, PM, EB, MF, AS, CL: histological analysis; AG, AM, MC, MS, RTL, AS, CL: molecular analysis; all authors: data elaboration, discussion and interpretation; AG, CL: paper writing; all authors: final editing and approval of the present version. Data availability statement: All data of this research are available in the current manuscript, related files and supplementary material. ☆ Competing interest: Emil Lou reports honorarium and travel expenses for a research talk at GlaxoSmithKline (2016); honoraria and travel expenses for lab-based research talks, and equipment for laboratory-based research from Novocure (2018–21); consultant, Nomocan Pharmaceuticals (unpaid); scientific advisory board member, Minnetronix, LLC (2018–present; unpaid); consultant and speaker honorarium, Boston Scientific US (2019); institutional principal investigator for clinical trials sponsored by Celgene, Novocure, LLC, Intima Biosciences, and the National Cancer Institute; and University of Minnesota membership in the Caris Life Sciences Precision Oncology Alliance (unpaid). Sara Lonardi reports research funding from Amgen, Merck Serono, Bayer, Roche, Eli Lilly, AstraZeneca, Bristol Myers Squibb; honoraria from Roche, Eli Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, Amgen; participation in advisory board for Amgen, Merck Serono, Eli Lilly, AstraZeneca, Incyte, Daiichi-Sankyo, Bristol Myers Squibb, Servier, Merck Sharp & Dohme. The other authors have no conflicts of interest. ☆☆ Funding: This study is supported by Personal University Funding for Research (“FUR Prof. Luchini” 2021), Associazione Italiana Ricerca sul Cancro (AIRC IG n. 26343); Fondazione Cariverona: Oncology Biobank Project “Antonio Schiavi” (prot. 203885/2017); Fondazione Italiana Malattie Pancreas (FIMP-Ministero Salute J38D19000690001); Italian Ministry of Health (RF CO-2019-12369662: CUP: B39C21000370001). Furthermore, this research was also supported by contributions from the family of the patient #10, who donated his remains for research autopsy and by fundraising for pancreatic cancer research from friends and family of Gayle Huntington. Funding Information: Funding: This study is supported by Personal University Funding for Research (“FUR Prof. Luchini” 2021), Associazione Italiana Ricerca sul Cancro (AIRC IG n. 26343); Fondazione Cariverona: Oncology Biobank Project “Antonio Schiavi” (prot. 203885/2017); Fondazione Italiana Malattie Pancreas (FIMP-Ministero Salute J38D19000690001); Italian Ministry of Health (RF CO-2019-12369662: CUP: B39C21000370001). Furthermore, this research was also supported by contributions from the family of the patient #10, who donated his remains for research autopsy and by fundraising for pancreatic cancer research from friends and family of Gayle Huntington. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2022",

month = oct,

doi = "10.1016/j.humpath.2022.07.011",

language = "English (US)",

volume = "128",

pages = "124--133",

journal = "Human pathology",

issn = "0046-8177",

publisher = "W.B. Saunders",

}

TY - JOUR

T1 - Genomic characterization of undifferentiated sarcomatoid carcinoma of the pancreas

AU - Gkountakos, Anastasios

AU - Mafficini, Andrea

AU - Lou, Emil

AU - Malleo, Giuseppe

AU - Salvia, Roberto

AU - Calicchia, Martina

AU - Silvestris, Nicola

AU - Racila, Emilian

AU - Amin, Khalid

AU - Veronese, Nicola

AU - Brunetti, Oronzo

AU - Antonini, Pietro

AU - Ingravallo, Giuseppe

AU - Mattiolo, Paola

AU - Saponaro, Concetta

AU - Nappo, Floriana

AU - Simbolo, Michele

AU - Bariani, Elena

AU - Lonardi, Sara

AU - Fassan, Matteo

AU - Milella, Michele

AU - Lawlor, Rita T.

AU - Scarpa, Aldo

AU - Luchini, Claudio

N1 - Funding Information: The authors thank the patient #10 and his family for donating his remains for the advancement of cancer research, with the hope that this work will be of benefit to future patients. Author contributions: AG, AM, EL, NS, AS, CL: study conception and design; EL, GM, RS, NS, ER, KA, OB, GI, FN, SL, MF, MM, AS, CL: provided original material for the study; EL, GM, RS, NS, ER, KA. OB, GI, FN, SL, MF, MM, AS, CL: clinical analysis; ER, KA, GI, PM, EB, MF, AS, CL: histological analysis; AG, AM, MC, MS, RTL, AS, CL: molecular analysis; all authors: data elaboration, discussion and interpretation; AG, CL: paper writing; all authors: final editing and approval of the present version. Data availability statement: All data of this research are available in the current manuscript, related files and supplementary material. ☆ Competing interest: Emil Lou reports honorarium and travel expenses for a research talk at GlaxoSmithKline (2016); honoraria and travel expenses for lab-based research talks, and equipment for laboratory-based research from Novocure (2018–21); consultant, Nomocan Pharmaceuticals (unpaid); scientific advisory board member, Minnetronix, LLC (2018–present; unpaid); consultant and speaker honorarium, Boston Scientific US (2019); institutional principal investigator for clinical trials sponsored by Celgene, Novocure, LLC, Intima Biosciences, and the National Cancer Institute; and University of Minnesota membership in the Caris Life Sciences Precision Oncology Alliance (unpaid). Sara Lonardi reports research funding from Amgen, Merck Serono, Bayer, Roche, Eli Lilly, AstraZeneca, Bristol Myers Squibb; honoraria from Roche, Eli Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, Amgen; participation in advisory board for Amgen, Merck Serono, Eli Lilly, AstraZeneca, Incyte, Daiichi-Sankyo, Bristol Myers Squibb, Servier, Merck Sharp & Dohme. The other authors have no conflicts of interest. ☆☆ Funding: This study is supported by Personal University Funding for Research (“FUR Prof. Luchini” 2021), Associazione Italiana Ricerca sul Cancro (AIRC IG n. 26343); Fondazione Cariverona: Oncology Biobank Project “Antonio Schiavi” (prot. 203885/2017); Fondazione Italiana Malattie Pancreas (FIMP-Ministero Salute J38D19000690001); Italian Ministry of Health (RF CO-2019-12369662: CUP: B39C21000370001). Furthermore, this research was also supported by contributions from the family of the patient #10, who donated his remains for research autopsy and by fundraising for pancreatic cancer research from friends and family of Gayle Huntington. Funding Information: Funding: This study is supported by Personal University Funding for Research (“FUR Prof. Luchini” 2021), Associazione Italiana Ricerca sul Cancro (AIRC IG n. 26343); Fondazione Cariverona: Oncology Biobank Project “Antonio Schiavi” (prot. 203885/2017); Fondazione Italiana Malattie Pancreas (FIMP-Ministero Salute J38D19000690001); Italian Ministry of Health (RF CO-2019-12369662: CUP: B39C21000370001). Furthermore, this research was also supported by contributions from the family of the patient #10, who donated his remains for research autopsy and by fundraising for pancreatic cancer research from friends and family of Gayle Huntington. Publisher Copyright: © 2022 Elsevier Inc.

PY - 2022/10

Y1 - 2022/10

N2 - Undifferentiated sarcomatoid carcinoma (USC) of the pancreas is a rare but especially aggressive variant of pancreatic ductal adenocarcinoma (PDAC), composed of at least 80% of sarcomatoid cells. This study aimed to elucidate its clinicopathological and molecular features. The study cohort included 10 patients with pancreatic USC. Clinicopathological parameters were determined for each patient. The molecular profile was investigated using next-generation sequencing (NGS). Histologically, all tumors were hypercellular neoplasms with spindle-shaped or sarcomatoid cells. All patients showed vascular and perineural invasion. Most patients had a poor prognosis. NGS showed important similarities with conventional PDAC, including frequent alterations in the classic PDAC drivers, KRAS (100% of cases), TP53 (90%), and CDKN2A (60%). There were also some important distinctions from conventional PDAC: 1) SMAD4, a typical PDAC driver gene, was mutated in only one case (10%); 2) Another distinctive molecular feature was the recurrent KRAS amplification (30% of cases), which is very rare in conventional PDAC. It has been previously reported in another subtype of pancreatic undifferentiated carcinoma, the rhabdoid variant, and may be a key event leading to the acquisition of an undifferentiated phenotype in a subgroup of cases; 3) Lastly, in two different cases, we detected two potentially actionable targets, not belonging to the typical PDAC molecular landscape, such as MCL1 amplification and POLQ mutation. Our study sheds light on this rare tumor type, which shows aggressive biological behavior and few druggable alterations. The most distinctive molecular features of pancreatic USC are the paucity of SMAD4 alterations and recurrent KRAS amplification.

AB - Undifferentiated sarcomatoid carcinoma (USC) of the pancreas is a rare but especially aggressive variant of pancreatic ductal adenocarcinoma (PDAC), composed of at least 80% of sarcomatoid cells. This study aimed to elucidate its clinicopathological and molecular features. The study cohort included 10 patients with pancreatic USC. Clinicopathological parameters were determined for each patient. The molecular profile was investigated using next-generation sequencing (NGS). Histologically, all tumors were hypercellular neoplasms with spindle-shaped or sarcomatoid cells. All patients showed vascular and perineural invasion. Most patients had a poor prognosis. NGS showed important similarities with conventional PDAC, including frequent alterations in the classic PDAC drivers, KRAS (100% of cases), TP53 (90%), and CDKN2A (60%). There were also some important distinctions from conventional PDAC: 1) SMAD4, a typical PDAC driver gene, was mutated in only one case (10%); 2) Another distinctive molecular feature was the recurrent KRAS amplification (30% of cases), which is very rare in conventional PDAC. It has been previously reported in another subtype of pancreatic undifferentiated carcinoma, the rhabdoid variant, and may be a key event leading to the acquisition of an undifferentiated phenotype in a subgroup of cases; 3) Lastly, in two different cases, we detected two potentially actionable targets, not belonging to the typical PDAC molecular landscape, such as MCL1 amplification and POLQ mutation. Our study sheds light on this rare tumor type, which shows aggressive biological behavior and few druggable alterations. The most distinctive molecular features of pancreatic USC are the paucity of SMAD4 alterations and recurrent KRAS amplification.

KW - KRAS

KW - Pancreatic cancer

KW - Pancreatic ductal adenocarcinoma

KW - Sarcomatoid

KW - Undifferentiated

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U2 - 10.1016/j.humpath.2022.07.011

DO - 10.1016/j.humpath.2022.07.011

M3 - Article

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SN - 0046-8177

VL - 128

SP - 124

EP - 133

JO - Human pathology

JF - Human pathology

ER -

Genomic characterization of undifferentiated sarcomatoid carcinoma of the pancreas

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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