Cancer Cytogenetics E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 2071

Veröffentlichungsjahr: 2015

Beschreibung

The first three editions of this acclaimed book presented a much-needed conceptual synthesis of this rapidly moving field. Now, Cancer Cytogenetics, Fourth Edition, offers a comprehensive, expanded, and up-to-date review of recent dramatic advances in this area, incorporating a vast amount of new data from the latest basic and clinical investigations. * New contributors reflecting broader international authorship and even greater expertise * Greater emphasis throughout on the clinical importance and application of information about cytogenetic and molecular aberrations * Includes a complete coverage of chromosome aberrations in cancer based on an assessment of the 60,000 neoplasms cytogenetically investigated to date * Now produced in full color for enhanced clarity * Covers how molecular genetic data (PCR-based and sequencing information) are collated with the cytogenetic data where pertinent * Discusses how molecular cytogenetic data (based on studies using FISH, CGH, SNP, etc) are fused with karyotyping data to enable an as comprehensive understanding of cancer cytogenetics as is currently possible

Leseprobe

CONTENTS

Cover

Title Page

Contributors

Preface to the Fourth Edition

CHAPTER 1: How it all began

References

CHAPTER 2: Cytogenetic methods

Sampling for cytogenetic analysis

Chromosome banding

In situ

hybridization

Genomic arrays

Large-scale sequencing

Interpretation of cytogenetic data

References

CHAPTER 3: Cytogenetic nomenclature

Designation of regions and bands

Karyotypic nomenclature

Nomenclature of tumor cell populations

In situ

hybridization nomenclature

References

CHAPTER 4: Nonrandom chromosome abnormalities in cancer

Primary and secondary neoplasia-associated chromosome abnormalities

Why and how do chromosome aberrations arise?

When do chromosome aberrations arise?

In which cells do chromosome aberrations arise?

Are acquired chromosome aberrations sufficient for neoplastic proliferation?

Do all tumors have chromosome abnormalities, and are such changes present only in neoplastic cells?

General effects of structural and numerical chromosome abnormalities

At what resolution level are neoplasia-associated mutations best studied?

Pathogenetic versus phenotypic tumor classification

References

CHAPTER 5: From chromosomes to genes

Types of fusion genes

Generation of fusion genes

Methods to identify fusion genes

Conclusion

References

CHAPTER 6: Acute myeloid leukemia

Most AML harbor clonal chromosomal abnormalities

Characteristic chromosomal abnormalities in AML

Characteristic karyotypic patterns in AML

Acknowledgments

References

CHAPTER 7: Myelodysplastic syndromes

Diagnosis

Clinical correlations

Cytogenetic analysis

Cytogenetic findings in MDS

Other technologies

Emerging paradigms

Summary

References

CHAPTER 8: Chronic myeloid leukemia

The discovery and characterization of the Philadelphia chromosome

Cytogenetic abnormalities in CML CP

Molecular pathology of the t(9;22)(q34;q11) in CML

Treatment of CML

Disease monitoring of CML during treatment

Cytogenetic evolution in Ph-positive CML

Molecular genetic evolution in Ph-positive CML

Summary

Acknowledgments

References

CHAPTER 9: Chronic myeloproliferative neoplasms

The classic

BCR–ABL1

-negative MPN: PV, ET, and PMF

“Nonclassic”

BCR–ABL1

-negative MPN

Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of

PDGFRA

,

PDGFRB

, and

FGFR1

Concluding remarks

Acknowledgments

References

CHAPTER 10: Acute lymphoblastic leukemia

Morphologic, immunophenotypic, and cytogenetic characteristics

Most patients with ALL have characteristic, acquired karyotypic abnormalities in their leukemic cells

Established ploidy groups in ALL

Structural rearrangements

Submicroscopic abnormalities

Relapsed ALL

BCR–ABL1

-like or Ph-like ALL

Clinical correlations

Classification of abnormalities according to lineage

Age associations

Down syndrome (DS)

Prognosis

Summary

Acknowledgments

References

CHAPTER 11: Mature B- and T-cell neoplasms and Hodgkin lymphoma

Classification of mature lymphoid neoplasms

B- and T-cell development and physiological B- and T-cell receptor rearrangements

Chromosomal translocations involving IG and TCR loci

Cytogenetic evolution in lymphoid neoplasms

Chromosomal aberrations common to multiple subtypes of mature lymphoid neoplasms

Mature B-cell neoplasms

Mature T-cell and NK-cell neoplasms

Hodgkin lymphoma (HL)

Clinical correlations

Acknowledgments

References

CHAPTER 12: Tumors of the upper aerodigestive tract

Squamous cell carcinomas of the head and neck

Other tumors of the nasal cavity, sinuses, and nasopharynx

Salivary glands

Esophageal cancer

Summary

References

CHAPTER 13: Tumors of the lung

Diagnostically relevant genetic biomarkers in lung cancer

Therapeutic importance of acquired genomic aberrations in lung cancer

Pleura

Summary

References

CHAPTER 14: Tumors of the digestive tract

Large intestine

Colorectal tumors are characterized by recurrent chromosome aberrations

Clonal relationship among synchronously growing colorectal tumors

Correlation between karyotypic and phenotypic features

Pancreas

Liver and biliary tract

Stomach

Small intestine

Summary

Acknowledgment

References

CHAPTER 15: Tumors of the urinary tract

Kidney

Bladder

Ureter

Urethra

Clinical correlations

Summary

Acknowledgments

References

CHAPTER 16: Tumors of the breast

Benign breast disorders

Breast carcinoma

Summary

Acknowledgment

References

CHAPTER 17: Tumors of the female genital organs

Ovary

Uterus

Fallopian tube

Vagina and vulva

Summary

Acknowledgment

References

CHAPTER 18: Tumors of the male genital organs

Testis

Prostate

Penis

Summary

Acknowledgment

References

CHAPTER 19: Tumors of endocrine glands

Thyroid

Parathyroid

Pituitary gland

Adrenal gland

Thymus

Endocrine pancreas

References

CHAPTER 20: Tumors of the nervous system

Neuroepithelial tumors

Neuronal and mixed neuronal–glial tumors (GNT)

Tumors of cranial and paraspinal nerves

Tumors of the meninges

Summary

References

CHAPTER 21: Tumors of the eye

Retinoblastoma (RB)

Uveal melanoma (UM)

Chromosome 3

Chromosome 8

Chromosome 6

Chromosome 1

Other chromosome changes

Specific genes in UM

Clinical consequences

Iris and conjunctival melanoma

Other eye tumors

Concluding remarks

Acknowledgments

References

CHAPTER 22: Tumors of the skin

Keratinocytic tumors

Melanocytic tumors

Appendageal tumors

Neural tumors

Summary

Acknowledgments

References

CHAPTER 23: Tumors of bone

Cartilage tumors

Osteogenic tumors

Ewing sarcoma

Notochordal tumors

Giant cell tumors

Miscellaneous bone tumors

Summary

Acknowledgment

References

CHAPTER 24: Soft tissue tumors

Adipocytic tumors

Fibroblastic/myofibroblastic tumors

So-called fibrohistiocytic tumors

Smooth muscle tumors

Pericytic (perivascular) tumors

Skeletal muscle tumors

Vascular tumors

Tumors of uncertain differentiation

Undifferentiated sarcomas

Summary

Acknowledgment

References

Index

End User License Agreement

List of Tables

Chapter 01

Table 1.1 Characteristic neoplasia-associated cytogenetic aberrations detected by banding analyses 1970–1979

Table 1.2 Characteristic cytogenetic aberrations detected by banding analyses of solid tumors 1980–1989

Chapter 02

Table 2.1 Comparison of cytogenetic methodologies

Chapter 06

Table 6.1 WHO classification of acute myeloid leukemia and related precursor neoplasms

Table 6.2 Frequencies of abnormal karyotypes in pediatric and adult AML

Table 6.3 Cytogenetic, molecular genetic, and clinical features of AML-associated chromosomal aberrations

Chapter 07

Table 7.1 World Health Organization MDS classification system

Table 7.2 MDS cytogenetic scoring system—Revised International Prognostic Scoring System

Table 7.3 Recurring chromosomal abnormalities in the myelodysplastic syndromes

Table 7.4 Frequency and significance of mutated genes in MDS

Chapter 08

Table 8.1 Definitions of cytogenetic and molecular response

Table 8.2 Definition of response to TKIs as first-line treatment

Table 8.3 Recommendations for cytogenetic and molecular monitoring of CML

Chapter 09

Table 9.1 2008 World Health Organization (WHO) classification scheme for myeloid neoplasms (data from Vardiman et al., 2008)

Table 9.2 Variant translocations leading to

PDGFRA

-related fusion genes

Table 9.3 Variant translocations leading to

PDGFRB

-related fusion genes

Table 9.4

FGFR1

fusions

Chapter 10

Table 10.1 Cytogenetic, molecular genetic, and clinical features of ALL-associated chromosomal aberrations

Chapter 11

Table 11.1 Chromosomal translocations and other structural aberrations affecting the

IGH

locus in 14q32, the

IGK

locus in 2p12, or the

IGL

locus in 22q11 in mature B-cell malignancies other than multiple myeloma

Table 11.2 Chromosomal translocations affecting the

BCL6

locus in 3q27 in mature B-cell neoplasms

Table 11.3 Comparison of the Kiel, REAL, and WHO classifications of B-cell malignancies

Table 11.4 Overview of frequent and diagnostically relevant chromosomal aberrations in the most common mature B-lymphoid neoplasms

Table 11.5 Recurrent

IG

translocations in multiple myeloma

Table 11.6 Comparison of the Kiel, REAL, and WHO classifications of T- and NK-cell malignant neoplasms

Table 11.7 Overview of frequent and diagnostically relevant chromosomal aberrations in mature T/NK-cell neoplasms

Chapter 12

Table 12.1 Meta-analysis of chromosomal gains in HNSCC

Table 12.2 Meta-analysis of chromosomal losses in HNSCC

Table 12.3 Meta-analysis of chromosomal gains in ESCC

Table 12.4 Meta-analysis of chromosomal losses in ESCC

Table 12.5 Chromosomal copy number gains in EAC

Table 12.6 Chromosomal copy number losses in EAC

Chapter 13

Table 13.1 Diagnostically and therapeutically important genomic aberrations in lung cancer

Chapter 18

Table 18.1 Oncogenic gene fusions identified in prostate cancer involving the

ETS

family of transcription factors (

ERG

,

ETV1

,

ETV4

,

ETV5

, and

FLI1

) and various 5′ fusion partners

Chapter 23

Table 23.1 Characteristic balanced structural chromosome aberrations and gene fusions in bone tumors

Chapter 24

Table 24.1 Characteristic structural chromosome aberrations and corresponding gene fusions in soft tissue tumors

List of Illustrations

Chapter 01

Figure 1.1 Camera lucida drawing of tumor cell mitosis from one of the first (early 1950s) human cancerous effusions submitted to detailed chromosome analysis. The modal number was 75. The stemline also contained numerous abnormal chromosome shapes

Figure 1.2 Unbanded metaphase cell from a bone marrow culture established from a patient with chronic myeloid leukemia. The arrow indicates the Ph chromosome (previously called Ph

1

); the superscript indicated that this was the first cancer-specific aberration detected in Philadelphia. This naming practice was later abandoned, but the abbreviation Ph has for sentimental reasons been retained, since it was the first consistent chromosome abnormality detected in a human malignancy.

Chapter 02

Figure 2.1 Examples of how different cytogenetic techniques can be used to delineate chromosome aberrations at different levels of resolution. A supernumerary ring chromosome (arrow) is identified by G-banding (A) in a soft tissue tumor and shown by multicolor FISH paint (B) to contain sequences from chromosomes 9 (arrowhead) and 12 (arrow). Whole-chromosome painting (C) of chromosomes 9 (red) and 12 (green) corroborates these findings, and multicolor chromosome 12 banding with single-copy probes (D) shows that sequences from the

MDM2

(yellow) and

CDK4

(violet) genes in 12q13–15 are amplified in the rings. Further analysis with SNP array (E) defines the boundaries of the 12q-amplified segments, which include

CDK4

and

MDM2

. The

y

-axis of the upper panel corresponds to relative gene copy number (log2 ratio). The

y

-axis of the lower panel shows the mirrored B-allele frequency (mBAF), which is shifted toward homozygosity (mBAF = 1) in the amplified regions. Array images are courtesy of Dr. K. Hansén Nord.

Chapter 03

Figure 3.1 Schematic presentation (idiogram) of the G-banded human male chromosome complement.

Figure 3.2 Translocation, illustrated as t(9;22)(q34;q11).

Figure 3.3 Inversion, illustrated as inv(16)(p13q22).

Figure 3.4 Deletions may be terminal or interstitial. The terminal deletion del(1)(q23) is illustrated to the left, and the interstitial del(1)(q21q31) to the right.

Figure 3.5 Duplication, illustrated as dup(1)(q21q31).

Figure 3.6 Isochromosome formation, illustrated as i(12)(p10).

Chapter 04

Figure 4.1 Overview of the cancer cytogenetics database as it has evolved since the first descriptions of acquired chromosome aberrations identified by banding techniques in the early 1970s.

Figure 4.2 Metaphase from a cancer cell showing extreme karyotypic complexity. Among the massive numerical as well as structural chromosome abnormalities were also many that represented cytogenetic noise, changes that were found in this cell only.

Figure 4.3 The chromosome aberrations of cancer may in principle exert their effect through gain or loss of genetic material or through structural or regulatory changes brought about by relocation of chromosomal segments.

Chapter 05

Figure 5.1 Cytogenetics-based approach for the detection of fusion genes exemplified by the detection of

MEAF6–PHF1

in low-grade endometrial stromal sarcoma. (A) Partial karyotype showing chromosome aberrations der(1)t(1;6)(p34;p21) and der(6)t(1;6)(p34;p21) together with the corresponding normal chromosomes; breakpoint positions are indicated by arrows. (B) FISH using BAC RP11-508 M23 (green signal) from 1p34 containing the

MEAF6

gene and pool of the RP11-600P03 and RP11-436 J22 BACs (red signal) from 6p21 containing the

PHF1

gene. A part of the probe from 6p21 (red signal) has moved to the derivative chromosome 1, while the entire probe containing

MEAF6

has moved to the derivative chromosome 6. The data suggest that the functional fusion gene is generated on the der(6). (C) G-banding of the metaphase spread shown in (B). (D) Amplification of a 1 kb cDNA in the 5′-RACE analysis (R) using reverse

PHF1

primers and the universal forward primers. (E) Partial sequence chromatograms of the 1 kb cDNA fragment showing the junctions (arrow) of the

MEAF6–PHF1

chimeric transcript (upper) and genomic hybrid DNA fragment (lower). (F) RT-PCR and genomic PCR using specific

MEAF6

and

PHF1

primers. Lane 1, amplification of

MEAF6–PHF1

cDNA fragment; lane 2: amplification of

MEAF6

transcript; lane 3, reciprocal

PHF1–MEAF6

cDNA not amplified; lane 4, amplification of

PHF1

transcript; lane 5, amplification of

MEAF6–PHF1

genomic hybrid DNA fragment. M, 1 kb DNA ladder.

Source

: Panagopoulos et al. (2012) Novel fusion of

MYST/Esa1

-associated factor 6 and PHF1 in endometrial stromal sarcoma. Plos ONE 7, e39354.

Figure 5.2 Combination of banding cytogenetics and RNA-Seq for the detection of the

ZC3H7–BCOR

fusion gene in low-grade endometrial stromal sarcoma. (A) H&E stained section of the endometrial stromal sarcoma. (B) Chromosomal aberrations der(22)t(X;22)(p11;q13) and der(X)t(X;22)(p11;q13) together with the corresponding normal chromosome homologs. RNA was extracted and sequenced. The data were analyzed with FusionMap and 1836 potential fusion transcripts were found, among them the

ZC3H7–BCOR

fusion transcript.

ZC3H7–BCOR

was investigated further because

ZC3H7B

and

BCOR

map to chromosome bands 22q13 and Xp11, respectively. (C) Chimeric

ZC3H7–BCOR

cDNA sequences identified with RNA-Seq. The junction “TCCTTCATGGGCGAGTTATAGT” is in yellow. (D) Verification of

ZC3H7–BCOR

(

Z-B

) and the reciprocal

BCOR–ZC3H7

(

B-Z

) using RT-PCR in two endometrial stromal sarcomas carrying a der(22)t(X;22)(p11;q13). A

ZC3H7B–BCOR

cDNA fragment was found in both cases, whereas the reciprocal

BCOR–ZC3H7B

fusion was detected only in case 1 that was used for RNA-Seq. (E) Sanger sequencing confirmed the

ZC3H7B–BCOR

and

BCOR–ZC3H7B

fusion transcripts.

Chapter 06

Figure 6.1 The t(1;3)(p36;q21) is strongly associated with dysmegakaryocytopoiesis. Arrows indicate breakpoints.

Figure 6.2 The whole-arm der(1;7)(q10;p10), leading to gain of 1q and loss of 7q, is associated with t-AML. The arrow indicates the centromeric breakpoints.

Figure 6.3 The t(2;3)(p21~23;q26) is associated with dysmegakaryocytopoiesis. Arrows indicate breakpoints.

Figure 6.4 The inv(3)(q21q26) (left) and t(3;3)(q21;q26) (right) are strongly associated with prominent dysmegakaryocytopoiesis. Arrows indicate breakpoints.

Figure 6.5 The t(3;21)(q26;q22) is associated with t-AML. Arrows indicate breakpoints.

Figure 6.6 The t(4;12)(q12;p13) is associated with AML with minimal differentiation or without maturation, trilineage dysplasia, and basophilia. Arrows indicate breakpoints.

Figure 6.7 The t(7;11)(p15;p15) is associated with AML with maturation or myelomonocytic leukemia, trilineage dysplasia, and Auer rods. Arrows indicate breakpoints.

Figure 6.8 The t(8;16)(p11;p13) is strongly associated with acute myelomonocytic or monoblastic/monocytic leukemia and erythrophagocytosis. Arrows indicate breakpoints.

Figure 6.9 The t(8;21)(q22;q22) is strongly associated with AML with maturation, granulocytic dysplasia, and Auer rods. Arrows indicate breakpoints.

Figure 6.10 The t(9;11)(p21;q23) is strongly associated with monoblastic/monocytic leukemia and with t-AML. Arrows indicate breakpoints.

Figure 6.11 The t(11;17)(q23;q12) is associated with acute myelomonocytic and monoblastic/monocytic leukemia. Arrows indicate breakpoints.

Figure 6.12 The t(15;17)(q22;q21) is pathognomonic for APL. Arrows indicate breakpoints.

Figure 6.13 The inv(16)(p13q22) is characteristic for acute myelomonocytic leukemia with BM eosinophilia. Arrows indicate breakpoints.

Chapter 07

Figure 7.1 Type of karyotypic abnormalities in MDS.

Figure 7.2 Recurring chromosomal abnormalities in MDS.

Figure 7.3 Deletions of 5q and 7q in myeloid neoplasms. In this del(5q), breakpoints occur in q14 and q33, resulting in interstitial loss of the intervening chromosomal material. In this del(7q), breakpoints occur in q11.2 and q36. In both cases, the critical commonly deleted segments are lost. Normal chromosome 5 and 7 homologs are shown for comparison.

Figure 7.4 Idiogram of the long arm of chromosome 5 showing candidate genes within the commonly deleted segments (CDSs) as reported by various investigators. The proximal CDS in 5q31.2 was identified in MDS, AML, and t-MDS/t-AML, whereas the distal CDS in 5q33.1 was identified in MDS with an isolated del(5q).

Chapter 08

Figure 8.1 Partial karyotype showing the t(9;22)(q34;q11). Arrows indicate breakpoints on the derivative chromosomes.

Figure 8.2 Schematic depiction of the main

BCR–ABL1

fusion gene variants. (A) To the left, the genomic structure of the

BCR

gene, spanning approximately 138 kb and containing 23 exons, is displayed. The breakpoints in most Philadelphia-positive ALL fall in the minor breakpoint cluster region (m-bcr), located in the 3′ half of the approximately 72 kb first intron. The great majority of the breaks in CML occur in the approximately 4.4 kb major breakpoint cluster region (M-bcr), which consists of

BCR

exons 12–15 (also designated b1–b4) and intervening intronic sequences. In a small fraction of CML patients, the breakpoints are located further downstream between

BCR

exons 19 and 21 (also designated e19–e21), in the 2.1 kb micro (μ)-bcr. To the right, the genomic structure of the

ABL1

gene, spanning about 174 kb and containing two alternative first exons, 1b and 1a, followed by exons 2 through 11, is shown. The breakpoints in

ABL1

are located in the introns between exons 1b and 1a and 1a and 2 or 5′ of 1b. (B) To the left, approximate sizes of

BCR

exons 1–23, with the different breakpoints at the cDNA level indicated by arrows, are depicted. To the right, the

ABL1

cDNA with exon 1a followed by exons 2–11 is shown. The arrow indicates the breakpoint at the cDNA level upstream of

ABL1

exon 2. (C) Representation of the fusion gene variants P190

BCR–ABL1

(

BCR

exon 1 fused to

ABL1

exons 2–11; also designated e1a2), P210

BCR–ABL1

(

BCR

exons 1–13 or 1–14 fused to

ABL1

exons 2–11; also termed b2a2 orb3a2), and P230

BCR–ABL1

(

BCR

exons 1–19 fused to

ABL1

exons 2–11).

Chapter 09

Figure 9.1 Examples of cytogenetic aberrations seen in MPN (R-banding with acridine orange). del(13q) may vary in length: del(13)(q13q21) in a case of ET, del(13)(q13q22) in a case of PMF, and del(13)(q13q33) in a case of ET; del(20)(q11q12-13) in a case of PMF; t(5;12)(q33;p13); t(8;13)(p11;q12); and t(8;22)(p11;q11).

Figure 9.2 FISH detection of the 4q12 deletion associated with the

FIP1L1–PDGFRA

fusion. Genomic map with the FISH probes (A) and examples of three-color FISH analysis performed on a control sample (B) and two patients (C/D–E). A map of the 4q12 region, with relevant genes and selected FISH probes, is drawn to scale. Note loss of the 3H20 (

green

) signal in C–E. (E)

Arrow

indicates a seemingly normal-looking chromosome 4 with the cryptic del(4)(q12) (

Source

: Vandenberghe et al. (2004), reproduced with permission).

Chapter 10

Figure 10.1 Karyogram showing a high-hyperdiploid karyotype from a childhood ALL patient: 55, XY, +X, +4, +5, +6, +10, +14, +17, +21, +21.

Figure 10.2 Karyogram showing a near-haploid karyotype from a childhood ALL patient: 25 < 1n>, X, +Y, +21.

Figure 10.3 Partial karyogram from a BCP-ALL with t(1;19)(q23;p13).

Figure 10.4 Partial karyogram from a BCP-ALL with t(4;11)(q21;q23).

Figure 10.5 (A) Partial karyogram indicating the del(5)(q32q33) (

red star

) and the related idiogram that gives rise to the

EBF1–PDGFRB

fusion. (B) SNP profile from the 5q3 region of chromosome 5 indicating the relevant breakpoints within

PDGFRB

and

EBF1

and the extent of the deletion. The

red bar

indicates the extent of the

EBF1

gene and shows that the deletion results in loss of exon 16.

Figure 10.6 A metaphase hybridized with a dual-color break-apart probe specific for

TLX3

. The normal red/green signal is located on the normal chromosome 5. As a result of the t(5;14)(q35;q32), the red signal remains on the derivative chromosome 5, and the green signal is located on the derivative chromosome 14.

Figure 10.7 Interphase cell hybridized with probes specific for 3′

ABL1

(

red

) and

NUP214

(

green

) showing episomal amplification of

NUP214–ABL1

.

Figure 10.8 (A) Partial karyograms from six patients with iAMP21. The normal chromosome 21 is on the left and the iAMP21 is on the right. The variable morphology and G-banding pattern among individual cells are shown. (B) A metaphase and interphase cells hybridized with probes specific for

ETV6

(

green

) and

RUNX1

(

red

). Multiple copies of

RUNX1

signals are seen clustered in interphase and in tandem duplication on a single abnormal chromosome 21 in metaphase. (C) SNP profiles of chromosome 21 from 11 patients with iAMP21 showing the diversity of copy number abnormalities seen between patients as also reflected in the chromosome morphology.

Figure 10.9 This circus plot indicates the distribution of copy number abnormalities in BCP-ALL. The individual colored ribbons represent the proportion of cases showing each abnormality among the total with copy number changes. They are not mutually exclusive.

Figure 10.10 Pie chart indicating the distribution of the most common mutations within genes/key signaling pathways in BCP-ALL: RAS signaling (

purple

), B-cell development and differentiation (

blue

), cell cycle control (

red

), JAK (

green

), and others (

black

). These mutations are not mutually exclusive.

Figure 10.11 Pie chart illustrating the relative incidences of the significant chromosomal abnormalities in childhood BCP-ALL, listed according to their risk group.

Figure 10.12 Bar chart showing the relative incidences of the significant chromosomal abnormalities (color coded as indicated in the key) according to age. Data taken from UK ALL treatment trials. Provided by Professor Anthony Moorman. Hap/hypo, near haploid, and hypodiploid cases; HeH, high-hyperdiploid cases.

Chapter 11

Figure 11.1 Schematic representation of the mechanisms leading to

IGH

translocations in B-cell malignancies (based on Willis and Dyer, 2000; Küppers and Dalla-Favera, 2001). (A)

IGH

locus germline configuration displaying variable (

V

H

), joining (

J

H

), diversity (

D

H

), and constant (

C

) regions. Switch regions (black and white rectangles) lie upstream of each constant region with the exception of

C

δ.

E

μ and

E

α enhancers are shown in red. (B) Schematic representation of the

VDJ

recombination, class switch recombination, and somatic hypermutation mechanisms. (C) Formation of

IGH

translocations. Depending on the breakpoint location at 14q32, the

IGH

locus may deregulate proto-oncogenes in both partner chromosomes through the translocation (elbowed arrows).

Figure 11.2 Recurrent chromosomal aberrations in CLL and related lymphoid neoplasms. Fluorescence R-banding. (A) Metaphase with trisomy 12. (B) Ideogram and partial karyotype showing del(11)(q14q23). (C) Ideogram and partial karyotype showing del(13)(q13q33).

Figure 11.3 Recurrent chromosomal aberrations in CLL and related lymphoid neoplasms. Fluorescence R-banding. (A) Ideogram and partial karyotype with interstitial deletion in 14q cytogenetically assigned to 14q21q32. (B) Ideogram and partial karyotype showing t(14;19)(q32;q13) involving

IGH

and

BCL3.

Figure 11.4 Translocations t(14;18)(q32;q21) and t(11;14)(q13;q32). Fluorescence R-banding. (A) Ideogram and partial karyotype with t(14;18)(q32;q21) involving

IGH

and

BCL2.

(B) Ideogram and partial karyotype with t(11;14)(q13;q32) involving

IGH

and

CCND1.

Figure 11.5 Translocation t(2;7)(p12;q21) in splenic marginal zone lymphoma. Fluorescence R-banding.

Figure 11.6 Recurrent chromosomal aberrations in marginal zone lymphomas of MALT type and related lymphoid neoplasms. Fluorescence R-banding. (A) Ideogram and partial karyotype with t(11;18)(q21;q21) involving

API2

and

MALT1

. (B) Ideogram and partial karyotype with t(1;14)(p22;q32) involving

BCL10

and

IGH

. (C) Metaphase with trisomy 3 and trisomy 18.

Figure 11.7 Burkitt translocation t(8;14) and variants. (A) Ideogram and partial karyotype with t(8;14)(q24;q32) involving

MYC

and

IGH

. (B) Ideogram and partial karyotype with t(2;8)(p12;q24) involving

IGK

and

MYC

. (C) Ideogram and partial karyotype with t(8;22)(q24;q11) involving

MYC

and

IGL

. Fluorescence R-banding.

Chapter 12

Figure 12.1 Representative trypsin–Giemsa-banded karyotype from a squamous cell carcinoma cell line (UPCI:SCC131, passage 18). In this cell, there are two relatively normal-appearing chromosomes 11 on the left and two very long derivative chromosomes 11, each with a homogeneously staining region (hsr) at 11q13 and nonchromosome 11-derived chromatin distal to the hsr, with a deletion of 11q14 to 11qter.

Figure 12.2 A t(11;19)(q21;p13.1) resulting in a

MAML2/CRTC1

gene fusion characterizes mucoepidermoid carcinomas. Arrows indicate derivative chromosomes.

Chapter 13

Figure 13.1 Recurrent DNA copy number aberrations in (A) 1780 lung carcinomas and (B) 205 malignant mesotheliomas. Losses are shown in blue and gains in yellow

Chapter 14

Figure 14.1 Distribution of numerical chromosome aberrations in 338 colorectal adenocarcinomas with clonal chromosome aberrations.

Figure 14.2 Distribution of chromosomal breakpoints involved in structural rearrangements in 338 colorectal adenocarcinomas with clonal chromosome aberrations.

Figure 14.3 i(8)(q10) and i(17)(q10) are the most frequent (10%) structural chromosome aberrations in colorectal adenocarcinomas.

Figure 14.4 Distribution of numerical chromosome aberrations in 139 adenomas of the large intestine with clonal chromosome aberrations.

Figure 14.5 Partial karyotypes of chromosome 1 from six benign colon lesions with 1p deletions of various sizes. In the ideogram of chromosome 1 (right), the size of the deleted segment is illustrated for each case. The minimum common deleted region is band 1p36.

Figure 14.6 Ideograms and partial karyotypes illustrating three structural chromosome aberrations, each detected in two macroscopically distinct colorectal tumors from the same patient: del(1)(p13) was found in a carcinoma (T1) and a hyperplastic polyp (T2) from the same patient (Case I); del(1)(p36) was found in two of several tubulovillous adenomas (T2 and T4) from the same patient (Case II); and i(17)(q10) was found in a carcinoma (T1) and a tubular adenoma (T2) from the same patient (Case III).

Figure 14.7 Distribution of numerical chromosome aberrations in 127 pancreatic adenocarcinomas with clonal chromosome aberrations.

Figure 14.8 Distribution of numerical chromosome aberrations in 22 hepatocellular carcinomas with clonal chromosome aberrations.

Figure 14.9 Distribution of numerical chromosome aberrations in 110 hepatoblastomas with clonal chromosome aberrations.

Figure 14.10 Distribution of chromosomal breakpoints involved in structural rearrangements in 129 adenocarcinomas of the stomach with clonal chromosome aberrations.

Figure 14.11 Distribution of numerical chromosome aberrations in 31 GIST of the stomach with clonal chromosome aberrations.

Chapter 15

Figure 15.1 A t(9;11)(p23;q13) (A) and a t(5;11)(q35;q13) (B) are among the most frequent translocations involving 11q13 in oncocytomas.

Figure 15.2 A combination of numerical changes (here tetrasomy 7, trisomy 17, and loss of the Y chromosome; arrows indicate gained or missing chromosomes) characterizes papillary adenoma as well as a subgroup of papillary renal cell carcinoma.

Figure 15.3 Trisomy for chromosomes 3, 7, 12, 16, 17, and 20 and loss of the Y chromosome (arrows indicate gained or lost chromosomes) are observed in clinically aggressive papillary renal cell carcinomas.

Figure 15.4 Partial karyotypes illustrating three different mechanisms leading to loss of or from 3p in clear cell renal cell carcinoma: (A) terminal or interstitial deletions of 3p (the deleted chromosome 3 is to the right in all four examples); (B) unbalanced translocations involving different 3p regions with 8q (left), 14q (middle), and 9q (right); and (C) loss of 3pter–3q11–12 and 3pter–3q21 through unbalanced translocations between 3q and chromosome 11 (left) or chromosome 6 (right).

Figure 15.5 Partial karyotypes (A and B) of a der(3)t(3;5)(p11–22;q13–31), the most frequent structural aberration in clear cell RCC, leading to partial monosomy 3p and partial trisomy 5q.

Figure 15.6 A combination of monosomies for chromosomes 1, 2, 3, 6, 8, 13, 14, and 17 and loss of the Y chromosome (arrows indicate missing chromosomes) characterize chromophobe RCC.

Figure 15.7 FISH evaluation using centromeric probes for chromosomes 1, 7, and 17 performed on interphase nuclei, showing (A) monosomy for chromosomes 1 and 17 and disomy for chromosome 7, consistent with chromophobe type RCC, and (B) trisomy for chromosomes 7 and 17 and disomy for chromosome 1, consistent with papillary type RCC.

Figure 15.8 t(X;1)(p11.2;q21) is a characteristic translocation in a subgroup of renal carcinomas mostly occurring in children and young adults.

Figure 15.9 t(X;17)(p11.2;q25) is a characteristic translocation in a subgroup of renal carcinoma mostly occurring in children and young adults

Figure 15.10 t(6;11)(p12;q12) is a characteristic translocation in a subgroup of renal carcinomas mostly occurring in children and young adults

Figure 15.11 This t(12;15)(p13;q26) is a characteristic translocation in congenital mesoblastic nephroma. (A) This is a cryptic translocation; therefore, FISH analysis using the

ETV6

probe at 12p13 is necessary to confirm the translocation either in (B) metaphase chromosomes or in (C) interphase nuclei

Figure 15.12 t(10;17)(q22;p13) is a characteristic translocation in clear cell sarcoma of the kidney

Figure 15.13 Interphase FISH analysis of cells from the urinary tract: (A) normal hybridization pattern showing disomy for each probe tested; (B) abnormal hybridization pattern consistent with tetrasomy for chromosomes 3 and 7, trisomy 17, and nullisomy for the 9p21 probe (i.e., homozygous deletion of the corresponding region)

Chapter 16

Figure 16.1 Chromosomal rearrangements leading to gain of 1q material are common in breast carcinomas. (A) A whole-arm translocation between chromosomes 1 and 16 is found repeatedly both as the sole anomaly and in complex karyotypes, typically leading to 1q gain and 16q loss. (B) Isochromosome 1q is also identified recurrently both as the sole anomaly and together with other chromosome changes in breast carcinomas.

Figure 16.2 Karyogram of a breast carcinoma showing an interstitial 3p deletion (del(3)(p12p14); right homolog) as the sole chromosome abnormality.

Figure 16.3 Examples of chromosomes 8 and 17 copy number changes identified by chromosome comparative genomic hybridization in breast carcinomas. (A) Breast carcinoma showing loss of 8p21–23 and gains of 8p11–12, 8q, and 17q11–21. (B) Breast carcinoma showing loss of 8p21–23, gain of 8q12–24, and two 17q amplicons centered around 17q12–21 and 17q22–24.

Chapter 17

Figure 17.1 Metaphase plate from an ovarian carcinoma with complex chromosomal abnormalities. The arrows point to examples of 19q+, one of the most common rearrangements in this tumor type.

Figure 17.2 A balanced translocation t(12;14)(q14–15;q23–24) is the most characteristic chromosomal rearrangement in uterine leiomyomas.

Figure 17.3 A deletion of the long arm of chromosome 7, typically del(7)(q21.2q31.2), is common in uterine leiomyomas. It may occur secondarily during clonal evolution and is also seen as the sole anomaly.

Figure 17.4 Partial karyotypes of different rearrangements found in endometrial stromal sarcomas. Normal chromosomes are presented for comparison. Arrows indicate breakpoints of rearranged chromosomes: (A) t(7;17)(p15;q21), (B) der(7)t(6;7)(p21;p15)del(6)(q21), (C) t(6;10;10)(p21;q22;p11), (D) t(1;6)(p34;p21), (E) t(X;22)(p11;q13), (F) t(X;17)(p11;q23), and (G) t(10;17)(q22;p13).

Chapter 18

Figure 18.1 G-banding illustration of an isochromosome 12p occurring together with two normal chromosomes 12. This aberration is typical of testicular germ cell tumors of adolescents and young adults

Figure 18.2 Deletions of 10q detected by chromosome comparative genomic hybridization (cCGH) (left) and array CGH (right) in the same prostatic carcinoma. cCGH detected two deletions (in 10q11–21 and 10q22–24), whereas array CGH also identified an additional genomic loss from 10p and a homozygous deletion at 10q23.31

Chapter 19

Figure 19.1 Partial G-banded karyotype of a thyroid adenoma showing the translocation t(5;19)(q13;q13.4). A subset of thyroid adenomas is cytogenetically defined by 19q13 rearrangements.

Figure 19.2 Genomic organization of the 19q13.4 breakpoint region. The breakpoint cluster region has a size of approximately 150 kb. Protein-coding genes are represented by light gray and miRNA clusters by dark gray boxes.

Figure 19.3 Representative G-banded karyotype of a thyroid adenoma with a complex translocation involving 2p21 leading to a

THADA

rearrangement. A subset of thyroid adenomas is cytogenetically defined by 2p21 rearrangements.

Figure 19.4 Partial G-banded karyotype showing the translocation t(2;3)(q13;p25) that can be found in thyroid adenomas as well as in follicular carcinomas.

Figure 19.5 Detection of double minutes (dmin) and homogeneously staining regions (hsr) in neuroblastoma by fluorescence

in situ

hybridization, using probes for

MYCN

(red in a, green in b–d). In metaphase spreads, dmin are observed as single or double dots, reflecting their episomal structure (a). The dmin are typically acentric and segregate at anaphase by tethering to centric chromosomes (b). At interphase, dmin occasionally form clusters in nuclear protrusions or micronuclei (arrows), shown here by a three-dimensional reconstruction from a confocal image sequence (c). In contrast, hsr (arrows) contain linear gene amplifications, with a much larger area of

MYCN

signal than the

MYCN

loci in normal homologs of chromosome 2 (arrowheads); red signals correspond to the chromosome 2 centromere (d).

Chapter 20

Figure 20.1 (A) Karyogram of a glioblastoma with the commonly occurring changes +7 and –10 together with several other aberrations. (B) CGH profile from the same tumor confirming the relative gain of chromosome 7 and relative loss of chromosome 10 material. Green bars to the right of the chromosome ideograms correspond to areas of gained genomic material; red bars to the left correspond to lost chromosomal areas.

Figure 20.2 An ependymal tumor genetically examined at different resolution levels. (A) G-banded chromosomes and corresponding CGH profile. The interstitial 2p deletion from the one aberrant chromosome 2 is marked with an arrow, whereas the normal chromosome 2 is seen to the right. The deletion was confirmed by CGH, which showed breakpoints at 2p16 and 2p23 (marked by arrow and a red bar). (B) FISH analysis using an

ALK

split-apart probe. Three yellow signals (marked with white arrows) indicate nonrearranged

ALK

. Four copies of chromosome 2 are present because this cell was tetraploid. Three normal

ALK

signals are marked by white arrows. The red arrow indicates persisting red signal but loss of green signal (i.e., loss of exons 1–19 of the

ALK

gene) due to the interstitial 2p deletion. (C) The genomic breakpoints of the interstitial 2p deletion leading to the fusion gene

CCDC88A–ALK

.

Chapter 21

Figure 21.1 A large constitutional deletion of chromosome 13 affecting band 13q14. Courtesy of Dr D.M. Lillington, St Bartholomew’s Hospital.

Figure 21.2 Karyotype of a ciliary body uveal melanoma, with characteristic monosomy 3 and i(8q).

Figure 21.3 Examples of 8q gain from two cases of uveal melanoma. Gain of 8q in the form of an isochromosome, or otherwise, is progressively acquired, and individual karyotypes from the same tumor often show a trend for increasing the copy numbers of the abnormal chromosome 8. Here, in the first example, an i(8q) is duplicated, but in the second case, the abnormal chromosome arises through translocation der(8)t(8;8)(p21;q13), which is subsequently duplicated.

Figure 21.4 Two pathways of sequential chromosome changes are found in uveal melanoma, which correlate essentially with tumor location. There are some shared regions of chromosome involvement, but there are mechanistic differences in how these changes arise. The dashed lines indicate where the sequence is not well established, often where there is possible intersection between the pathways. Tumors with both ciliary body and choroid involvement as a group have features of both pathways, presumably because these melanomas when initially developing would favor the pathway related to their location but are subsequently grouped together.

Figure 21.5 Kaplan–Meier survival curve for uveal melanoma patients with a relative genetic imbalance (RGI) for chromosomes 3 and 8. Patients with an RGI have a significantly poorer prognosis (black).

Chapter 22

Figure 22.1 Complex karyotype from a cutaneous malignant melanoma illustrating some of the chromosomal rearrangements frequently seen in this tumor type, such as i(1)(q10), loss of chromosome 9, and deletion of distal 10q.

Figure 22.2 Partial karyotype showing the t(6;22)(p21;q12) in a hidradenoma. The translocation results in fusion of the

EWSR1

gene in band 22q12 with the

POU5F1

gene in 6p21. Arrows indicate breakpoints.

Chapter 23

Figure 23.1 Partial karyotype showing a heterozygous del(8)(q24) (arrowhead) in an osteochondroma.

Figure 23.2 Partial karyotype illustrating the characteristic t(X;6)(q24–26;q15–25) in a subungual exostosis.

Figure 23.3 Chondromyxoid fibroma with complex rearrangements of both chromosomes 6: der(6)t(6;6)(q15;q27)inv(6)(p25q13) (left) and del(6)(q15) (right).

Figure 23.4 Chondrosarcoma with hyperhaploid karyotype. Note retention of two copies of chromosomes 5, 7, and 20.

Figure 23.5 High-grade malignant osteosarcoma with complex karyotype.

Figure 23.6 Parosteal osteosarcoma with a supernumerary ring chromosome as the sole aberration.

Figure 23.7 Karyotype from a Ewing sarcoma displaying the characteristic t(11;22)(q24;q12) as the sole change. Arrows indicate breakpoints. The translocation results in the creation of an

EWSR1–FLI1

fusion gene.

Figure 23.8 Array CGH results in a chordoma, illustrating the frequent loss of several large chromosomal segments and the absence of amplicons in this tumor. The lower part highlights the frequent occurrence of deletions of the 9p21–22 segment harboring the

CDKN2A

tumor suppressor gene.

Figure 23.9 Four different rearrangements affecting distal 11p in a giant cell tumor of bone. From left to right: two telomeric associations, one add(11)(p15), and one r(11).

Figure 23.10 Aneurysmal bone cyst with a three-way t(3;16;17)(p2?4;q22;p13) as the sole change. Arrows indicate breakpoints.

Chapter 24

Figure 24.1 t(3;12)(q28;q14) in a lipoma.

Figure 24.2 t(11;16)(q13;p13) in a chondroid lipoma.

Figure 24.3 Supernumerary ring chromosome in an atypical lipomatous tumor. The arrowhead indicates a telomeric association.

Figure 24.4 t(12;16)(q13;p11) in a myxoid liposarcoma.

Figure 24.5 der(22)t(17;22)(q21;q13) together with two normal copies of chromosome 17 in a dermatofibrosarcoma protuberans.

Figure 24.6 Multiple numerical aberrations (+8, +11, +17, and +20) in an infantile fibrosarcoma. Note that the t(12;15) is cytogenetically cryptic.

Figure 24.7 t(1;10)(p22;q24) in a myxoinflammatory fibroblastic sarcoma.

Figure 24.8 t(7;16)(q33–34;p11) in a low-grade fibromyxoid sarcoma.

Figure 24.9 t(1;2)(p13;q37) in a diffuse-type giant cell tumor.

Figure 24.10 Hyperhaploid karyotype in an inflammatory leiomyosarcoma, showing the typical disomies for chromosomes 5, 20, and 21.

Figure 24.11 t(12;22)(q13;q12) in an angiomatoid fibrous histiocytoma. Cytogenetically identical translocations are found in clear cell sarcoma of soft tissue and a minor subset of myxoid liposarcomas. In the former two tumor types, an

EWSR1–ATF1

fusion gene is formed, whereas the result in liposarcomas is an

EWSR1–DDIT3

chimera.

Figure 24.12 t(X;18)(p11;q11) in a synovial sarcoma from a man.

Figure 24.13 t(11;22)(p13;q12) in a desmoplastic small round cell tumor.

Figure 24.14 t(9;22)(q22;q12) in an extraskeletal myxoid chondrosarcoma. The normal chromosome 9 (left) is a constitutional variant with heterochromatin in the short arm.

Figure 24.15 der(17)t(X;17)(p11;q25) together with two normal copies of the X chromosome in an alveolar soft part sarcoma.

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Cancer Cytogenetics

Chromosomal and Molecular Genetic Aberrations of Tumor Cells

Fourth Edition

EDITION BY

Sverre Heim

Section for Cancer CytogeneticsInstitute for Cancer Genetics and InformaticsOslo University HospitalOslo, Norway

Felix Mitelman

Department of Clinical GeneticsUniversity of LundLund, Sweden

This edition first published 2015 © 2015 by John Wiley & Sons, Ltd.Third edition published 2009 © 2009 by John Wiley & Sons, Inc.

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Library of Congress Cataloging-in-Publication Data

Cancer cytogenetics (Heim)   Cancer cytogenetics : chromosomal and molecular genetic aberrations of tumor cells / edited by Sverre Heim, Felix Mitelman. – Fourth edition.       p. ; cm.   Includes bibliographical references and index.

   ISBN 978-1-118-79553-8 (cloth)I.  Heim, Sverre, editor.    II.  Mitelman, Felix, editor.    III.  Title.[DNLM: 1.  Neoplasms–genetics.    2.  Chromosome Disorders–genetics.    3.  Cytogenetics–methods.    QZ 202]   RC268.4   616.99′4042–dc23

        2015015465

A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

Contributors

Sietse M. AukemaInstitute of Human GeneticsUniversity Hospital Schleswig-Holstein Campus KielChristian-Albrechts University KielGermany

Georgia BardiBioAnalytica-GenoType SAMolecular Cytogenetic Research and ApplicationsAthens, Greece

Petter BrandalSection for Cancer CytogeneticsInstitute for Cancer Genetics and InformaticsOlso University HospitalOslo, Norway

Jörn BullerdiekCenter for Human GeneticsUniversity of BremenBremen, Germany

Paola Dal CinDepartment of PathologyBrigham and Women’s HospitalBoston, MA, USA

Thoas FioretosDepartment of Clinical GeneticsUniversity of LundLund, Sweden

David GisselssonDepartment of Clinical GeneticsUniversity of LundLund, Sweden

Susanne M. GollinDepartment of Human GeneticsUniversity of Pittsburgh Graduate School of Public HealthUniversity of Pittsburgh Cancer InstitutePittsburgh, PA, USA

Christine J. HarrisonLeukaemia Research Cytogenetics GroupNorthern Institute for Cancer ResearchNewcastle UniversityNewcastle upon Tyne, UK

Sverre HeimSection for Cancer CytogeneticsInstitute for Cancer Genetics and InformaticsOlso University HospitalOslo, Norway

Bertil JohanssonDepartment of Clinical GeneticsUniversity of LundLund, Sweden

Eeva KettunenHealth and Work AbilitySystems ToxicologyFinnish Institute of Occupational HealthHelsinki, Finland

Sakari KnuutilaDepartment of PathologyHaartman Institute and HUSLABUniversity of Helsinki and Helsinki University Central HospitalHelsinki, Finland

Michelle M. Le BeauSection of Hematology/OncologyUniversity of ChicagoChicago, IL, USA

Nils MandahlDepartment of Clinical GeneticsUniversity of LundLund, Sweden

Fredrik MertensDepartment of Clinical GeneticsUniversity of LundLund, Sweden

Francesca MicciSection for Cancer CytogeneticsInstitute for Cancer Genetics and InformaticsOlso University HospitalOslo, Norway

Lucienne MichauxCentre for Human GeneticsUniversity Hospitals LeuvenUniversity of LeuvenLeuven, Belgium

Felix MitelmanDepartment of Clinical GeneticsUniversity of LundLund, Sweden

Penny NymarkDepartment of ToxicogenomicsMaastricht UniversityMaastricht, The Netherlands;Institute of Environmental MedicineKarolinska InstituteStockholm, Sweden

Harold J. OlneyCentre Hospitalier de l’Universitié de Montréal (CHUM)Université de MontréalMontréal, Quebec, Canada

Ioannis PanagopoulosSection for Cancer CytogeneticsInstitute for Cancer Genetics and InformaticsOlso University HospitalOslo, Norway

Nikos PandisDepartment of GeneticsSaint Savas HospitalAthens, Greece

Reiner SiebertInstitute of Human GeneticsUniversity Hospital Schleswig-Holstein Campus KielChristian-Albrechts University KielGermany

Karen SisleyAcademic Unit of Ophthalmology and OrthopticsDepartment of OncologyThe Medical SchoolUniversity of SheffieldSheffield, UK

Manuel R. TeixeiraDepartment of GeneticsPortuguese Oncology InstitutePorto, Portugal

Peter VandenbergheCentre for Human GeneticsUniversity Hospitals LeuvenUniversity of LeuvenLeuven, Belgium

Preface to the Fourth Edition

Although only six years have passed since the publication of the third edition of Cancer Cytogenetics, the field has undergone marked changes. New information about many tumor types has been gathered using chromosome banding and various molecular cytogenetic techniques, but first and foremost it is the increasing addition of state-of-the-art genomic analyses to the chromosome-level studies of neoplastic cells that has now brought about a more detailed and better understanding of how neoplastic transformation occurs in different disease entities. Inevitably, therefore, this fourth edition contains a wider coverage of the molecular genetic changes that neoplastic cells have acquired than was possible in previous editions. The main focus nevertheless remains unaltered: the genomic aberrations of neoplastic cells as they appear at the chromosomal level of organization. To put the molecular knowledge and studies—especially those involving various ways to search for pathogenetic fusion genes by means of whole genome sequencing—into an integrated molecular genetic–cytogenetic perspective, an entire new chapter was added. Otherwise the overall structure of the book remains the same as it was in the previous edition: the first five chapters, Chapters 1–5, are more generic in nature, Chapters 6–11 deal with hematologic malignancies and lymphomas, and Chapters 12–24 review existing cytogenetic and molecular genetic knowledge on solid tumors.

In all the chapters of this edition, we have strived to emphasize the clinical impact of the various acquired rearrangements, be it diagnostic or prognostic, as much as possible. Cancer cytogenetics has come of age as one of the several means whereby different neoplastic diseases could and should be diagnosed—especially hematologic disorders, malignant lymphomas, and tumors of bone and soft tissue but also increasingly other solid tumors—and it is imperative that cancer cytogeneticists communicate these aspects of their work to the pathologists and clinicians who are in direct charge of the patients. The closer the dialogue with other diagnosticians and clinicians, the more useful the karyotype and other cytogenetic and molecular findings will be in the risk assessment and choice of therapy for individual patients.

At the same time, cancer cytogenetics remains pivotal in the examination of neoplastic cells for research purposes. Chromosome banding analysis is a robust and unbiased method whereby global genetic information can be obtained at the cytogenetic level. All molecular examinations of tumor cells should ideally be viewed against the background of knowledge about the tumor karyotype.

A large number of experts have helped us write the various chapters of Cancer Cytogenetics, Fourth Edition. They have done a better job than we ever could even if we had had unlimited time on our hands, and we are profoundly grateful to all of them. The heterogeneity inevitable resulting from multiple authorship reflects reality within the scientific community and we choose to see it as an advantage rather than a disadvantage. We have nevertheless strived to impart a recognizable common format on the various organ-specific chapters so as to comply with the overall plan of the book. It is our hope that those who read and use this book will agree with us that the final result does the field of cancer cytogenetics the credit that is its due.

Sverre Heim

Felix Mitelman

Oslo and Lund, December 2014

CHAPTER 1How it all began: cancer cytogenetics before sequencing

Felix Mitelman1and Sverre Heim2

1Department of Clinical Genetics, University of Lund, Lund,Sweden

2Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway

The role of genetic changes in neoplasia has been a matter of debate for more than 100 years. The earliest systematic study of cell division in malignant tumors was made in 1890 by the German pathologist David von Hansemann. He drew attention to the frequent occurrence of aberrant mitoses in carcinoma biopsies and suggested that this phenomenon could be used as a criterion for diagnosing the malignant state. His investigations as well as other studies associating nuclear abnormalities with neoplastic growth were, a quarter of a century later, forged into a systematic somatic mutation theory of cancer, which was presented in 1914 by Theodor Boveri in his famous book Zur Frage der Entstehung maligner Tumoren. According to Boveri’s hypothesis, chromosome abnormalities were the cellular changes causing the transition from normal to malignant proliferation.

For a long time, Boveri’s remarkably prescient idea, the concept that neoplasia is brought about by an acquired genetic change, could not be tested. The study of sectioned material yielded only inconclusive results and was clearly insufficient for the examination of chromosome morphology. Technical difficulties thus prevented reliable visualization of mammalian chromosomes, in both normal and neoplastic cells, throughout the entire first half of the 20th century.

During these “dark ages” of mammalian cytogenetics (Hsu, 1979), plant cytogeneticists made spectacular progress, very much through their use of squash and smear preparations. These techniques had from 1920 onward greatly facilitated studies of the genetic material in plants and insects, disclosing chromosome structures more reliably and with greater clarity than had been possible in tissue sections. Around 1950, it was discovered that some experimental tumors in mammals, in particular the Ehrlich ascites tumor of the mouse, could also be examined using the same squash and smear approach. These methods were then rapidly tried with other tissues as well, and in general, mammalian chromosomes were found to be just as amenable to detailed analysis as the most suitable plant materials.

Simultaneously, tissue culturing became more widespread and successful, one effect of which was that the cytogeneticists now had at their disposal a stable source of in vitro grown cells. Of crucial importance in this context was also the discovery that colchicine pretreatment resulted in mitotic arrest and dissolution of the spindle apparatus and that treatment of arrested cells with a hypotonic salt solution greatly improved the quality of metaphase spreads. Individual chromosomes could now be counted and analyzed. The many methodological improvements ushered in a period of vivid expansion in mammalian cytogenetics, culminating in the description of the correct chromosome number of man by Tjio and Levan (1956) and, shortly afterward, the discovery of the major constitutional human chromosomal syndromes. Two technical breakthroughs around the turn of the decade were of particular importance: the finding that phytohemagglutinin (PHA) has a mitogenic effect on lymphocytes (Nowell, 1960) and the development of a reliable method for short-term culturing of peripheral blood cells (Moorhead et al., 1960).

Cytogenetic studies of animal ascites tumors during the early 1950s, followed soon by investigations of malignant exudates in humans (Figure 1.1), uncovered many of the general principles of karyotypic patterns in highly advanced, malignant cell populations: the apparently ubiquitous chromosomal variability within the tumor, surmised by pathologists since the 1890s; the stemline concept, first defined by Winge (1930); and the competition between stemlines resulting in labile chromosomal equilibria responsive to environmental alterations. The behavior of malignant cell populations could now be described in Darwinian terms: by selective pressures, a dynamic equilibrium is maintained, but any environmental change may upset the balance, causing shifts of the stemline karyotype. Evolution thus occurs in tumor cell populations in much the same manner as in populations of organisms: chromosomal aberrations generate genetic diversity, and the relative “fitness” imparted by the various changes decides which subclones will prevail.

Figure 1.1 Camera lucida drawing of tumor cell mitosis from one of the first (early 1950s) human cancerous effusions submitted to detailed chromosome analysis. The modal number was 75. The stemline also contained numerous abnormal chromosome shapes

(Courtesy of Prof. Albert Levan).