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The clinical value of genetic analyses of bone and soft tissue tumors

Walther, Charles LU (2016) In Lund University Faculty of Medicine Doctoral Dissertation Series 2016:14.
Abstract (Swedish)
Popular Abstract in Swedish

Tumörer i ben och mjukdelar är vanliga men utgör endast 1 % av alla maligna neoplasier. De elakartade tumörerna är ofta utmanande att diagnostisera pga deras relativt likartade morfologi samt att de är ovanliga. Således är all tilläggsinformation värdefull och genetiska analysmetoder kan bidra med information som är användbar och i vissa fall tom avgörande för diagnostik, behandling och prognos. Vi har använt olika genetiska analysmetoder såsom cytogenetik, fluorescens in-situ hybridisering (FISH), singel nukleotid polymorfism (SNP) array, polymeras kedjereaktion (PCR) och sekvensering (next generation sequencing-NGS) för att utvärdera deras kliniska användbarhet. Olika typer av såväl benigna som... (More)
Popular Abstract in Swedish

Tumörer i ben och mjukdelar är vanliga men utgör endast 1 % av alla maligna neoplasier. De elakartade tumörerna är ofta utmanande att diagnostisera pga deras relativt likartade morfologi samt att de är ovanliga. Således är all tilläggsinformation värdefull och genetiska analysmetoder kan bidra med information som är användbar och i vissa fall tom avgörande för diagnostik, behandling och prognos. Vi har använt olika genetiska analysmetoder såsom cytogenetik, fluorescens in-situ hybridisering (FISH), singel nukleotid polymorfism (SNP) array, polymeras kedjereaktion (PCR) och sekvensering (next generation sequencing-NGS) för att utvärdera deras kliniska användbarhet. Olika typer av såväl benigna som maligna ben och mjukdels tumörer har analyserats i detta syfte. Tumörmaterialet vi använt består av finnålsaspirat, färskfrusen vävnad samt formalinfixerade prover.

I arbete I jämförde vi karyotyper utförda på material från finnålsaspirat, mellannålsbiopsier samt kirurgiska biopsier. Cytogenetisk analys hittade klonala avvikelser i 64 % av de kirurgiska biopsierna, i 48 % av mellannålsbiopsierna samt i 24 % av finnålsaspiraten. Resultaten indikerar att cytogenetisk analys bör utföras på kirurgiska biopsier i första hand.

I arbete II analyserade vi en tumör hos en 10-årig flicka som diagnostiserats med ett jättefibroadenom i bröstet. SNP array visade förlust av heterozygositet och uniparentella disomier för kromosmer 10, 11 och 22 samt en homozygot deletion av en gen kallad PARVA. Dessa resultat visar hur SNP array kan användas för att erhålla information avseende pediatriska brösttumörer.

I arbete III visade vi att en balanserad t(7:19)(q22:q13) translokation resulterar i en ny fusionsigen karakteristisk för en malign kärltumör kallad pseudomyogent hemangiendotheliom. Resultaten baseras på en kombination av cytogenetik, FISH, PCR och RNA sekvensering.

I arbete IV använde vi framgångsrikt RNA sekvensering på formalinfixerad vävnad för att undersöka förekomst av fusionsgener i benigna fibrösa histiocytom (dermatofibrom). En ny fusionsgen involverande proteinkinas C familjen upptäcktes.

I arbete V studerade vi pediatriska rhabdomyosarkom med huvudsakligen SNP array och fann att denna teknik kunde detektera flera diagnostiskt och prognostiskt viktiga genetiska avvikelser. Dock behövs ytterligare undersökningsmetoder för att vidare utreda genfusioner.

Sammanfattningsvis kan således genetiska undersökningsmetoder ge kliniskt relevant och användbar information avseende tumörer i ben och mjukdelar. Vilken typ av metod som ska användas beror på tillgängligt material och frågeställningen. Sekvenseringsteknikerna blir snabbt mer tillgängliga och användbara vilket leder till att deras kliniska betydelse troligtvis kommer att öka framöver. (Less)
Abstract
Tumors of bone and soft tissue are common but only constitute 1 % of all malignant tumors. The malignant tumors are often difficult to diagnose due to their rarity and morphological resemblance between subtypes. This makes the diagnostic process challenging. Thus, there is a need for ancillary techniques, such as genetic analyses, not only for diagnostic purposes, but also for obtaining information that could be useful for treatment and prognosis. Different types of bone and soft tissue tumors, both benign and malignant, were analyzed. The tumor material used included needle aspiration biopsies, fresh and frozen surgical biopsies and formalin-fixed tissue. In paper I we compared karyotypes obtained by fine needle aspiration (FNA),... (More)
Tumors of bone and soft tissue are common but only constitute 1 % of all malignant tumors. The malignant tumors are often difficult to diagnose due to their rarity and morphological resemblance between subtypes. This makes the diagnostic process challenging. Thus, there is a need for ancillary techniques, such as genetic analyses, not only for diagnostic purposes, but also for obtaining information that could be useful for treatment and prognosis. Different types of bone and soft tissue tumors, both benign and malignant, were analyzed. The tumor material used included needle aspiration biopsies, fresh and frozen surgical biopsies and formalin-fixed tissue. In paper I we compared karyotypes obtained by fine needle aspiration (FNA), core-needle (CNB) and surgical biospies. Chromosome banding analysis found clonal aberrations in 64% of surgical biopsies, in 48% of CNB and in 24% of FNA. These results suggest that chromosome banding analysis should be avoided on FNA and CNB. In paper II a pediatric giant fibroadenoma was analyzed with SNP array, revealing trisomies, uniparental isodisomy for chromosomes 10, 11 and 22 and a homozygous deletion of PARVA, indicating that SNP array provides information on pediatric breast tumors. In paper III we showed that the balanced translocation t(7;19)(q22;q13) results in a novel fusion gene SERPINE1-FOSB, which characterizes a malignant vascular tumor called pseudomyogenic hemangioendothelioma. The results were obtained by combining FISH, PCR and NGS-based RNA sequencing. In paper IV we successfully used RNA sequencing on formalin-fixed tissue to search for gene fusions in benign fibrous histiocytoma; a novel member of the protein kinase C family was shown to be involved. In paper V we studied pediatric rhabdomyosarcomas using mainly SNP array. We could show that this technique reveals many diagnostically and prognostically important aberrations, but that additional technologies for gene fusion detection must be employed.



Thus, different genetic techniques provide different types of information, which must be taken into account when selecting method(s) for clinical, diagnostic purposes. None of the techniques used in the present studies is sufficient for detecting all clinically relevant genetic aberrations in bone and soft tissue tumors. (Less)
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author
supervisor
opponent
  • Associate professor, MD Hansson, Magnus, Chair of Soft Tissue and Bone Pathology, Sahlgrenska University Hospital and Department of Medical Biosciences, Section for Pathology, Umeå University, Sweden
organization
publishing date
type
Thesis
publication status
published
subject
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2016:14
pages
60 pages
publisher
Division of Clinical Genetics, Lund University
defense location
Lecture hall C4, Centralblocket, University Hospital, Lund
defense date
2016-02-05 10:00
ISSN
1652-8220
ISBN
978-91-7619-240-5
language
English
LU publication?
yes
id
7613130c-bb14-41e2-93a8-9d49454fd320 (old id 8230769)
date added to LUP
2015-12-18 12:36:04
date last changed
2016-09-19 08:44:51
@phdthesis{7613130c-bb14-41e2-93a8-9d49454fd320,
  abstract     = {Tumors of bone and soft tissue are common but only constitute 1 % of all malignant tumors. The malignant tumors are often difficult to diagnose due to their rarity and morphological resemblance between subtypes. This makes the diagnostic process challenging. Thus, there is a need for ancillary techniques, such as genetic analyses, not only for diagnostic purposes, but also for obtaining information that could be useful for treatment and prognosis. Different types of bone and soft tissue tumors, both benign and malignant, were analyzed. The tumor material used included needle aspiration biopsies, fresh and frozen surgical biopsies and formalin-fixed tissue. In paper I we compared karyotypes obtained by fine needle aspiration (FNA), core-needle (CNB) and surgical biospies. Chromosome banding analysis found clonal aberrations in 64% of surgical biopsies, in 48% of CNB and in 24% of FNA. These results suggest that chromosome banding analysis should be avoided on FNA and CNB. In paper II a pediatric giant fibroadenoma was analyzed with SNP array, revealing trisomies, uniparental isodisomy for chromosomes 10, 11 and 22 and a homozygous deletion of PARVA, indicating that SNP array provides information on pediatric breast tumors. In paper III we showed that the balanced translocation t(7;19)(q22;q13) results in a novel fusion gene SERPINE1-FOSB, which characterizes a malignant vascular tumor called pseudomyogenic hemangioendothelioma. The results were obtained by combining FISH, PCR and NGS-based RNA sequencing. In paper IV we successfully used RNA sequencing on formalin-fixed tissue to search for gene fusions in benign fibrous histiocytoma; a novel member of the protein kinase C family was shown to be involved. In paper V we studied pediatric rhabdomyosarcomas using mainly SNP array. We could show that this technique reveals many diagnostically and prognostically important aberrations, but that additional technologies for gene fusion detection must be employed. <br/><br>
<br/><br>
Thus, different genetic techniques provide different types of information, which must be taken into account when selecting method(s) for clinical, diagnostic purposes. None of the techniques used in the present studies is sufficient for detecting all clinically relevant genetic aberrations in bone and soft tissue tumors.},
  author       = {Walther, Charles},
  isbn         = {978-91-7619-240-5},
  issn         = {1652-8220},
  language     = {eng},
  pages        = {60},
  publisher    = {Division of Clinical Genetics, Lund University},
  school       = {Lund University},
  series       = {Lund University Faculty of Medicine Doctoral Dissertation Series},
  title        = {The clinical value of genetic analyses of bone and soft tissue tumors},
  volume       = {2016:14},
  year         = {2016},
}