Renal Cell Carcinoma – Detection of PRCC-TFE3 and Alpha-TFEB Gene Fusions Using RT-PCR on Tissues (Odes 60153 and 60154) Notice of Assessment

Renal Cell Carcinoma – Detection of PRCC-TFE3 and Alpha-TFEB Gene Fusions Using RT-PCR on Tissues (odes 60153 and 60154) Notice of Assessment

June 2013

DISCLAIMER: This document was originally drafted in French by the Institut national d'excellence en santé et en services sociaux (INESSS), and that version can be consulted at http://www.inesss.qc.ca/fileadmin/doc/INESSS/Analyse_biomedicale/Juin_2013/INESSS_Analyse_15.pdf http://www.inesss.qc.ca/fileadmin/doc/INESSS/Analyse_biomedicale/Juin_2013/INESSS_Analyse_16.pdf It was translated into English by the Canadian Agency for Drugs and Technologies in Health (CADTH) with INESSS’s permission. INESSS assumes no responsibility with regard to the quality or accuracy of the translation. While CADTH has taken care in the translation of the document to ensure it accurately represents the content of the original document, CADTH does not make any guarantee to that effect. CADTH is not responsible for any errors or omissions or injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the information in this document, the original document, or in any of the source documentation.

1 GENERAL INFORMATION 1.1 Requestor: Centre hospitalier universitaire de Québec (CHUQ). 1.2 Application Submitted: August 1, 2012. 1.3 Notice Issued: April 12, 2013.

Note: This notice is based on the scientific and commercial information (submitted by the requestor[s]) and on a complementary review of the literature according to the data available at the time that this test was assessed by INESSS.

2 TECHNOLOGY, COMPANY, AND LICENCE(S) 2.1 Name of the Technology Reverse transcription of messenger RNA and amplification (RT-PCR). 2.2 Brief Description of the Technology RT-PCR is used here to detect the production of chimeric messenger RNA generated from a chromosomal translocation. The technique comprises the following four steps: i) the isolation of total RNA from the suspected renal tumour; ii) the reverse transcription of messenger RNA and the synthesis of complementary DNA; iii) amplification by PCR with primers in each of the fusion genes (the PCR product spans the fusion junction); iv) the analysis of amplification products by agarose or polyacrylamide gel electrophoresis. 2.3 Company or Developer In-house protocol from Argani et al. (2002) (PRCC-TFE3) and Kuiper et al. (2003) (Alpha-TFEB)1.  Test kits (PRCC-TFE3): . FFPE RNA kit (Roche Diagnostics) or RNeasy Plus (QIAGEN) . Transcriptor Reverse Transcriptase (Roche Diagnostics) . Taq DNA Polymerase (QIAGEN)  Test kits (Alpha-TFEB): . QIAamp Mini Kit (QIAGEN) . Taq DNA Polymerase (Roche Diagnostics) 2.4 Licence(s): Not applicable. 2.5 Patent, If Any: Not applicable. 2.6 Approval Status (Health Canada, FDA) Not applicable; the kits used have not been approved by Health Canada.

1 Personal electronic communication with Dr. Chantal Courtemanche from the CHU de Québec (March 1, 2013).

2.7 Weighted Value 284.0 (PRCC-TFE3) and 263.0 (alpha-TFEB). Several similar tests were identified in the 2012-2013 Index, representing approximately 30 different codes (translocations associated with lymphomas, leukemias, sarcomas, and other diseases; the weighted values range between 20.0 and 324.0).

3 CLINICAL INDICATIONS, PRACTICE SETTINGS, AND TESTING PROCEDURES 3.1 Targeted Patients Individuals with renal cell carcinoma (RCC) whose tumour histopathology suggests the presence of a translocation with TFE3 or TFEB gene fusion. 3.2 Targeted Diseases(s) 3.2.1 Biology Several subtypes of adult RCCs can be distinguished based on histological criteria, the most common being clear cell renal cell carcinoma (CCRCC) (75%). In 2004, the World Health Organization (WHO) established an RCC subtype—based on histological and cytogenetic criteria— bearing an Xp11 translocation (Xp11 translocation RCC) (DeLellis et al., 2004). Xp11 translocation RCCs typically have papillary architecture and are composed of large, clear to eosinophilic cells and medium- or large-sized nuclei with prominent nucleoli. They also show stromal changes such as the presence of psammoma bodies (stratified calcifications) and hyaline nodules. The most commonly observed Xp11 translocations cause the regulating centres of the PRCC and ASPL2 genes to fuse with the coding regions of the ubiquitously expressed transcription factor E3 (TFE3). Another translocation, t(6;11)(p21q12), which generates the Alpha-TFEB3 fusion protein, was described for the first time in 2001, (Argani et al., 2001b). TFEB and TFE3 are members of the MiTF (microphthalmia-associated transcription factor) family (Kuiper et al., 2003). 3.2.2 Epidemiology In children and adolescents, Xp11 translocation RCCs account for approximately 50% of all renal tumours, or between 20% and 70% depending on the authors (Kuroda et al., 2012; Geller et al., 2008; Bruder et al., 2004). In middle-aged adults, Xp11 translocation RCCs are estimated to account for 1.6% of all renal tumours and 15% of the CCRCC subtype (Komai et al., 2009). However, these values are underestimated, as translocations have not been systematically researched (Argani et al., 2007). Some authors suggest that exposure to cytotoxic agents during childhood could significantly increase the risk of developing Xp11 translocation RCC (Argani et al., 2006; Ramphal et al., 2006). As RCCs with t(6;11) rarely occur, only some 30 documented cases exist. 3.2.3 Treatments The first line of treatment involves a radical nephrectomy, or partial nephrectomy if the tumour is superficial. A regional lymphadenectomy is performed when lymph nodes have been affected or when the risk of recurrence is high. For advanced stages of the disease, the first line of treatment is immunotherapy with cytokines (interferon/interleukin-2). If treatment fails, targeted therapies

2 PRCC (papillary renal cell carcinoma) and ASPL (alveolar soft part sarcoma locus) genes are involved in cell cycle control. 3 The function of the Alpha gene, which lacks intron sequences, is unknown.

such as sunitinib or sorafenib4, VEGF (vascular endothelial growth factor) inhibitors, or temsirolimus5, an mTOR kinase inhibitor, may yield a complete response (Kuroda et al., 2012; CEPO, 2010). 3.2.4 Prognosis The prognosis for Xp11 translocation RCCs is not clearly defined and is more dependent on the stage of the disease at the time of diagnosis. Among younger people, Xp11 translocation RCCs appear to be indolent, even in cases of lymph node involvement with no distant metastasis (Armah et al., 2009; Geller et al., 2008; Ramphal et al., 2006). However, the tumours appear to be more aggressive in adults (Argani et al., 2007; Meyer et al., 2007). Xp11 translocation RCCs with ASPL- TFE3 fusions are associated with more advanced stages than are PRCC-TFE3 fusions (Komai et al., 2009; Camparo et al., 2008). However, as Xp11 translocation RCCs with PRCC-TFE3 fusions present a higher risk of recurrence, longer term follow-ups are required (Kuroda et al., 2012). 3.3 Number of Patients Targeted The requestor reports an estimated total volume of 20 tests over the next three years and declares not having conducted any tests (the two translocations combined) from 2011 to 2012. 3.4 Medical Specialties Involved (and Other Professions, If Any) Surgery, oncology, and anatomic pathology. 3.5 Testing Procedure The test is performed on RNA isolated from a biopsy or a formalin-fixed and paraffin-embedded resection of the tumour tissue.

4 TECHNOLOGICAL BACKGROUND 4.1 Nature of the Diagnostic Technology Complementary (confirmation of uncertain cases). 4.2 Brief Description of the Current Technological Context Analytical algorithms leading to the detection of gene translocations may comprise various steps, depending on the clinical and histological characteristics observed. Indeed, on a histological basis alone, the subtle morphological variations and the confusion surrounding the use of descriptive terms in literature can complicate the diagnosis. (Hintzy et al., 2008). Therefore, histopathological diagnoses are strengthened by using IHC to assess specific markers (TFE3 and TFEB). A number of authors consider the combination of histology and IHC to be sufficient, as it has been described as very sensitive and specific (Argani et al., 2007). Karyotyping continues to be the gold standard for detecting chromosomal translocations. FISH has also proven effective and is increasingly used (Zhong et al., 2010). The diagnosis of renal cell carcinomas that generate gene fusions with TFE3 or TFEB relies on the detection of chimeric messenger RNA by RT-PCR or by sequencing of genomic DNA junctions combined with protein overexpression by IHC.

4 Sunitinib is registered on the list of medications published by the RAMQ, but sorafenib is not. Its therapeutic value was rejected in February 2010. 5 Temsirolimus has been registered on the exceptional medications list published by the RAMQ since February 2012.

4.3 Brief Description of the Advantages Cited for the New Technology The RT-PCR technique is widely used, especially in cases of leukemia or sarcoma involving translocations. Indeed, there is a high risk that the junction between the fusion genes will be located inside the long intron sequences. Consequently, fusion genes are more easily detected using messenger RNA, given their smaller size6. It is therefore possible to identify the junction point by using a few primer combinations located within the coding sequences (exons) of the hypothetically fused genes (Argani and Ladanyi, 2005). However, fusions with intronless genes, such as Alpha-TFEB in t(6;11) (p21;q12), can result in chimeric transcripts varying considerably in size and from case to case. Indeed, in several cases of the molecular characterization of Alpha-TFEB fusions, the junctions are dispersed over more than 1.2 kb of sequence. The requestor uses genomic PCR instead of RT-PCR to detect an Alpha-TFEB fusion with several primer combinations.7 4.4 Cost of Technology and Options No relevant information was obtained.

5 EVIDENCE 5.1 Clinical Relevance 5.1.1 Other Tests Replaced No. 5.1.2 Diagnostic or Prognostic Value The literature review identified retrospective case series having as their primary objective the review of the diagnosis of renal tumours and (or) the complete characterization of a few cases. In total, 26 studies on the characterization of renal cell carcinomas involving Xp11 translocations ( Xp11 translocation RCCs ) and TFE3 fusions were examined. Of these, 4 did not involve any genetic or molecular evaluations, 10 involved only cytogenetic characterizations (FISH or karyotype), and 12 involved molecular characterizations using RT-PCR to detect TFE3 gene fusions. Table 1 presents a brief summary of the 12 studies that provided RT-PCR data. Sixty-three tumours with histological features of Xp11 translocation RCCs and TFE3 IHC-positive expression were assessed. For 37 of these, a cytogenetic confirmation of t(Xp11) was obtained by karyotyping or FISH. RT-PCR was used to detect a gene fusion between TFE3 and PRCC, ASPL and PSF in nine, fourteen, and one case, respectively. It should be noted that in several studies, RT-PCR was either used for only one specific fusion or not used for all of the tumours. Briefly, the clinical data revealed a predominance in females (64%) and a median age of 30 years at diagnosis. Upon evaluation, 100% of the tumours tested expressed TFE3 IHC. Subsequent to a median follow-up of 30 months, 50% of patients showed no evidence of the disease. To date, 33 cases have been characterized in which an Alpha-TFEB fusion in t(6;11) (p21;q12) has been detected. Every case is listed in Table 2. In short, the clinical data reveal a predominance in females (58%) and a median age of 29 years at diagnosis. The histology for 10 of the 33 cases does not correspond to the original description provided by (Argani et al., 2001b). None of the tumours

6 The newly transcribed gene is voluminous. Messenger RNA splicing (maturation) causes the deletion of non-coding intron sequences. 7 Personal electronic communication with Dr. Chantal Courtemanche from the CHU de Québec (March 1, 2013).

tested expressed TFE3 IHC, whereas 100% expressed TFEB and approximately 90% expressed HMB45, MelanA and cathepsin K. Cytogenetic confirmation of t(6;11) (p21;q12) with FISH or karyotyping and molecular confirmation of an Alpha-TFEB fusion by RT-PCR or genomic PCR were obtained in 70% and 49% of cases, respectively. Following a median follow-up of 36 months, 88% of patients showed no evidence of the disease. Two of the patients enrolled died of their disease. 5.1.3 Therapeutic Value Meyer et al. (2007) examined five cases of Xp11 translocation RCCs in adults aged 18 to 41 years (mean age of 32.6 years) (diagnosis was confirmed by cytogenetics and TFE3 IHC). Of these, 3 (60%) showed metastases in the colon, brain, liver, or lungs. To conclude, two patients were lost to follow-up, one died after 20 months, one was in palliative care after 10 months, and one was still alive after 24 months (Meyer et al., 2007). These data are supported by those of Argani et al. (2007), who investigated 28 cases involving patients aged 22 years to 78 years, all of which were confirmed by TFE3 IHC. During long-term follow-up, one third of patients with the disease died within 12 months of diagnosis (Argani et al., 2007). In 2010, Malouf et al. conducted a study of 21 patients with metastatic Xp11 translocation RCC who had received targeted therapy (the diagnosis was confirmed by cytogenetics and TFE3 IHC). The authors observed a progression-free survival of 8.2 months for the group that received sunitinib (n = 11) compared with 2 months for the group treated with immunotherapy (n = 9); p = 0.003 (Malouf et al., 2010). Klatte et al. (2012) used IHC and genetic analyses to evaluate patients aged 40 or younger who had a tumour with Xp11 translocation RCC histology (n = 75). The objectives of this study included determining the necessity of using genetic analyses, as opposed to IHC analyses, to diagnose Xp11 translocation RCCs. In total, 17 of the 75 tumours analyzed (23%) showed strong nuclear TFE3 staining (3+). Genetic analyses performed with FISH and RT-PCR (solely for ASPL-TFE3) confirmed two cases of Xp11 translocation RCC with an ASPL-TFE3 fusion. During a mean follow-up of 44 months, a total of 85 patients died of their disease, including six of the 17 with TFE3+. The overall survival rate after five years for patients with TFE3+ IHC status was 62% compared with 90% for patients with TFE3- status (significant only in univariate analysis where p = 0.032) (Klatte et al., 2012).

Table 1: Diagnostic Confirmation of a Renal Carcinoma Associated With Xp11 Translocation and TFE3 Gene Fusion Using RT-PCR

STUDY CASES HISTOLOGY TFE3+ IHC CYTOGENETICS RT-PCR (TFE3 FUSION) N CASES WITH SURVIVAL REVIEWED Xp11 RCC T(Xp11) DATA Zhong et al., 2012 121 ND 11 6 ASPL: 2, PSF: 1 6 Ohe et al., 2012 1 1 1 1 5 fusions: 0 1 Klatte et al., 2012 848 75 17 2 ASPL: 2 2 Kuroda et al., 2011 41 41 5 ND 5 fusions: 0 0 Hung et al., 2011 8 8 8 ND PRCC: 1 5 Kuroda et al., 2009 1 1 1 failed 5 fusions: 0 1 Komai et al., 2009 443 7 7 4 PRCC: 1, ASPL: 1 7 Argani et al., 2006 2 2 2 2 PRCC: 1, ASPL: 1 1 Sangkhathat et al., 2005 1 1 ND 1 PRCC: 1 1 Argani et al., 2002 11 11 11 10 PRCC: 2 4 Argani et al., 2001a 480 8 ND 3 ASPL: 8 8 Sidhar et al., 1996 3 3 ND 3 PRCC: 3 0 TOTAL 1,960 cases 158 cases 63 cases 32 cases 24 cases 36 cases

Table 2: Diagnostic Confirmation of a Renal Cell Carcinoma With an Alpha-TFEB Gene Fusion in t(6;11) (p21q12) Using RT-PCR.

CASE SEX AGE TYPICAL TFEB TFE3 GENETIC/MOLECULAR FOLLOW- STATUS REFERENCES (YEARS) HISTOLOGY CONFIRMATION UP (MO) 1 M 18 Y + - CG, RT-PCR, G-PCR 18 NED Argani et al., 2001b 2 F 14 Y + ND CG, RT-PCR, G-PCR ND ND Kuiper et al., 2003 3 F 42 Poorly described ND ND CG, RT-PCR, G-PCR ND ND Kuiper et al., 2003 4 F 17 Poorly described ND ND CG, RT-PCR, G-PCR ND ND Kuiper et al., 2003 5 F 18 Y + ND CG, FISH, RT-PCR 18 NED Davis et al., 2003 6 F 9 Y + ND RT-PCR, G-PCR ND ND Argani et al., 2005 7 M 33 Y + ND RT-PCR, G-PCR ND ND Argani et al., 2005 8 F 54 Y + - CG, FISH, RT-PCR 36 NED Martignoni et al., 2005 9 F 24 Y ND - RT-PCR, G-PCR 36 NED Hora et al., 2009 10 M 26 N + - RT-PCR, G-PCR 6 NED Zhan et al., 2010 11 M 57 Y + - RT-PCR, G-PCR 8 NED Inamura et al., 2012 12 M 37 N + - CG, RT-PCR, G-PCR 120 DOD Inamura et al., 2012 13 M 47 N + - CG, RT-PCR, G-PCR 12 NED Inamura et al., 2012 14 F 54 Y ND - CG, FISH, RT-PCR 36 NED Petersson et al., 2012 15 F 31 Y + - FISH, G-PCR 6 NED Rao et al., 2012 16 M 30 N + - FISH, G-PCR 31 NED Rao et al., 2012 T 57% F Mean: 30 YES: 56% 100% 0% RT or G-PCR (100%) Mean: 18 NED: 91% 9 different articles FISH or CG (69%) Abbreviations: AWD = alive with disease; CG = cytogenetics; DOD = died of disease; F = female; M = male; MO = months; N = no; ND = not determined; NED = no evidence of disease; T = total; Y = yes.

5.2 Clinical Validity

COMPONENT PRESENCE ABSENCE NOT APPLICABLE Sensitivity x Specificity x Positive predictive value (PPV) x Negative predictive value (NPV) x Likelihood ratio (LR) x ROC curve x Accuracy x

Klatte et al. (2012) used RT-PCR and FISH as gold standards for a study on the clinical validity of TFE3 IHC. The sensitivity and specificity of TFE3 IHC in the diagnosis of Xp11 translocation RCCs were 100% (2/2) and 79% (58/75), respectively. Although the authors did not test other translocations than ASPL-TFE3 with RT-PCR, they maintain that FISH would have detected an Xp11 translocation that generates a fusion of TFE3 with another gene (for example, PRCC). 5.3 Analytical (or Technical) Validity No information available. 5.4 Recommendations for Listing in Other Jurisdictions  National Comprehensive Cancer Network (NCCN) (2013): No case management recommendation specific to Xp11 translocation RCCs (V1. 2013).  European Society for Medical Oncology (ESMO) (2012): No case management recommendation specific to Xp11 translocation RCCs (Escudier et al., 2012).  European Association of Urology (2010): No prognostic marker is currently recommended for routine clinical use. (Ljungberg et al., 2010).

6 ANTICIPATED OUTCOMES OF INTRODUCING THE TEST 6.1 Impact on Material and Human Resources No relevant information available. 6.2 Economic Consequences of Introduction Into Quebec’s Health Care and Social Services System The economic consequences have not been evaluated. 6.3 Main Organizational, Ethical, and Other (Social, Legal, Political) Issues The ASPL-TFE3 gene fusion is recognized as the most common and aggressive form. This fusion is not considered in this application. Reliable and effective treatments have not yet been developed for Xp11 translocation RCCs (Klaassen et al., 2012).

To date, no monitoring algorithm has been developed to manage renal cell carcinomas involving translocations (Klaassen et al., 2012). As these tumours are more often diagnosed in young adults, the authors propose a long-term monitoring algorithm.  Every 6 months post-diagnosis for up to 24 months: anamnesis, physical examination, lab tests, thoracic and abdominal CT scan.  2.5 years post-diagnosis: anamnesis, physical examination, lab tests, and thoracic CT scan.  3 years, 4 years, and 5 years post-diagnosis: anamnesis, physical examination, lab tests, thoracic and abdominal CT scan.  Between 6 years and 10 years post-diagnosis: anamnesis, physical examination, lab tests, annual thoracic CT scan; and abdominal CT scan every two years.  Annually thereafter: anamnesis, physical examination, lab tests, and imaging, if clinically indicated.

7 INESSS NOTICE IN BRIEF Renal Cell Carcinoma — Detection of PRCC-TFE3 and Alpha-TFEB Gene Fusions Using RT-PCR on Tissues (Codes 60153 and 60154)

Status of the Diagnostic Technology:  Established (in an experimental context)  Innovative  Experimental (for research purposes only)  Replacement of technology : , which becomes obsolete

INESSS Recommendation:  Keep test in the Index  Remove test from the Index  Reassess test when the Canadian Kidney Cancer Forum's conclusions will be available The current Canadian Kidney Cancer Forum's objective is to determine the role of molecular tests in genetic counselling for kidney cancer. The final report will be available within two to three weeks.

Additional Recommendation:  Draw connection with listing of drugs, if companion test  Production of an optimal use guide  Production of indicators, when monitoring is required

APPENDIX A

CASE SEX AGE CG RT-PCR TNM FOLLOW-UP TX STATUS REFERENCES (MO) 1 M 30 + PRCC ND ND ND ND Sidhar 1996 2 F 21 + PRCC ND ND ND ND Sidhar 1996 3 F 45 + PRCC ND ND ND ND Sidhar 1996 4 F 8 + ASPL 1 48 None NED Argani 2001 5 M 2 + ASPL 3 144 CT, IT AWD Argani 2001 6 F 7 Failed ASPL 3 84 None NED Argani 2001 7 F 17 + ASPL 3 30 ND NED Argani 2001 8 M 17 ND ASPL 3 13 ND NED Argani 2001 9 F 17 ND ASPL 4 24 CT DOD Argani 2001 10 F 15 ND ASPL 3 15 IT AWD Argani 2001 11 M 4 ND ASPL 3 2 ND NED Argani 2001 12 M 15 + PRCC 1 108 None NED Argani 2002 18 M 9 ND PRCC 3 2 ND AWD Argani 2002 23 M 2 + PRCC 1 12 None NED Sangkhathat 2005 24 M 16 + ASPL 3 24 None NED Argani 2006 25 M 22 + PRCC 3 ND None ND Argani 2006 27 M 40 + PRCC 2 92 None NED Komai 2009 29 F 24 + ASPL 4 14 IT AWD Komai 2009 33 F 68 ND None ND 3 None NED Kuroda 2009 34 F 20 ND PRCC 4 ND ND AWD Hung 2011 42 F 74 ND None 1 ND ND ND Kuroda 2011 43 M 60 ND None 3 ND ND ND Kuroda 2011 44 M 50 ND None 1 ND ND ND Kuroda 2011 45 F 78 ND None 1 ND ND ND Kuroda 2011 46 M 67 ND None ND ND ND ND Kuroda 2011 47 F 57 + None ND 18 None NED Ohe 2012 48 M 5 + ASPL 4 54 CT, IT NED Klatte 2012 49 F 45 + ASPL 1 96 None NED Klatte 2012 50 F 38 + ASPL ND 21 ND AWD Zhong 2012 51 F 65 + ASPL ND 19 ND AWD Zhong 2012 53 F 45 + PFS ND 5 ND DOD Zhong 2012 T 64% F Median 32 + 14 ASPL I 15 Median: 30 NED 50% : 30 7 II 5 none III 16 1 PFS IV 6 8 PRCC

APPENDIX B Table B1: Diagnostic Confirmation of a Renal Carcinoma With Alpha-TFEB Gene Fusion in t(6;11) (p21q12) (All Cases). CASE SEX AGE HISTOLOGY TFEB TFE3 GENETICS FOLLOW- STATUS REFERENCES UP (MO) 1 M 18 Y + - CG, RT-PCR, G-PCR 18 NED Argani et al., 2001b 2 M 10 Y + - CG 53 NED Argani et al., 2001b 3 F 14 Y + ND CG, RT-PCR, G-PCR ND ND Kuiper et al., 2003 4 F 42 Poorly ND ND CG, RT-PCR, G-PCR ND ND Kuiper et al., 2003 described 5 F 17 Poorly ND ND CG, RT-PCR, G-PCR ND ND Kuiper et al., 2003 described 6 F 18 Y + ND CG, FISH, RT-PCR 18 NED Davis et al., 2003 7 F 20 Y + ND CG 30 NED Argani et al., 2005 8 F 9 Y + ND RT-PCR, G-PCR ND ND Argani et al., 2005 9 M 33 Y + ND RT-PCR, G-PCR ND ND Argani et al., 2005 10 F 42 Poorly + - CG 36 AWD Martignoni et al., described 2005 11 F 54 Y + - CG, FISH, RT-PCR 36 NED Martignoni et al., 2005 12 F 6 N + ND CG 3 NED Argani et al., 2006 13 F 34 Y + - CG 50 NED Camparo et al., 2008 14 M 36 N + - CG 3 DOD Camparo et al., 2008 15 F 9 Poorly + - CG 42 NED Geller et al., 2008 described 16 M 22 Y ND - No analyses 60 NED Hora et al., 2009 17 F 24 Y ND - RT-PCR, G-PCR 36 NED Hora et al., 2009 18 F 39 Y ND - No analyses 17 NED Hora et al., 2009 19 M 22 N + - No analyses 36+ NED Suarez-Vilela et al., 2011 20 M 26 N + - RT-PCR, G-PCR 6 NED Zhan et al., 2010 21 M 57 Y + - RT-PCR, G-PCR 8 NED Inamura et al., 2012 22 M 37 N + - CG, RT-PCR, G-PCR 120 DOD Inamura et al., 2012 23 M 47 N + - CG, RT-PCR, G-PCR 12 NED Inamura et al., 2012 24 F 20 Y ND - No analyses 60 NED Petersson et al., 2012 25 F 54 Y ND - CG, FISH, RT-PCR 36 NED Petersson et al., 2012 26 M 17 N + ND No analyses 36+ ND Zhong et al., 2012 27 F 31 Y + - FISH, G-PCR 6 NED Rao et al., 2012 28 M 21 Y + - FISH 22 NED Rao et al., 2012 29 F 37 Y + - FISH 34 NED Rao et al., 2012 30 F 36 Y + - FISH ND ND Rao et al., 2012 31 M 30 N + - FISH, G-PCR 31 NED Rao et al., 2012 32 F 29 N + - FISH 55 NED Rao et al., 2012 33 M 30 N + - FISH 36 NED Rao et al., 2012 T 58% F Median: 19 Y, 10 N 100% 0% RT or G-PCR (49%) FISH Median: 36 NED: 88% 16 different articles 29 or CG (70%) Abbreviations: AWD = alive with disease; CG = cytogenetics; DOD = died of disease; F = female; M = male; MO = months); N = no; ND = not determined; NED = no evidence of disease; T = total; Y = yes.

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