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Myriad myPath™ Melanoma is a unique, clinically validated, molecular test using qRT-PCR methodology to provide valuable, additive diagnostic information unavailable from any other test. At Myriad, we’ve seen the power of genetic insight to expose cancer risk and change lives. We set out to answer the need for greater certainty in diagnosing melanoma by developing a 23-gene expression signature that objectively differentiates malignant melanoma from benign nevi with a high degree of accuracy.6 When used in conjunction with the clinical and pathologic work-up, the result is a diagnostic test that increases confidence rather than relying on subjective analysis or poorly validated protocols in these difficult cases.

Innovation that changes lives.

Myriad Genetic Laboratories is a leading molecular diagnostic company dedicated to making a difference in patients’ lives through an understanding of the role genes play in human disease. Using proprietary technology, in-depth research and innovative tests, we answer the most pressing questions for patients and their healthcare providers. Because we believe every patient should be able to know their risk, their path, their plan and their choices regarding disease.

The stakes are too high not to know.

Even the most experienced dermatopathologists with the highest level of conventional diagnostics encounter situations in which a definitive diagnosis can be difficult to provide using histopathology alone.1,2 Due to the subjective nature of histology, standard protocols have been difficult to reproduce and this results in a significant level of discordance and misdiagnosis.1-3

Subjectivity is simply not an option when the consequences of misdiagnosis are so severe.

Early diagnosis is critical for long-term survival. Only 10–15% of patients with advanced disease survive past 5 years.4 With risks this high and misdiagnosis highly possible, it is no surprise melanoma is the 2nd most litigated cancer type for medical malpractice.5

Behind every diagnosis is a patient.

Patients deserve more than ambiguity to determine their best course of treatment. This could mean a disfiguring scar or perhaps avoiding an unnecessary surgery. Yet, arriving at a more definitive diagnosis is sometimes elusive.

Patients deserve more. And so do you.

"The diagnosis of melanoma by conventional methods can be very subjective, and [this assay] provides objective data that could make it an extremely valuable diagnostic tool."

Sancy Leachman, M.D., PhD.
Dept of Dermatology & Melanoma Director,
Knight Cancer Institute, Oregon Health & Science University

To learn more, visit IsThisMelanoma.com and see how Myriad myPath Melanoma can help you answer when your patient asks, “Is this melanoma?”

The stakes are too high not to know.

ДИАГНОСТИКА МЕЛАНОМЫ


     Диагностика меланомы основана на гистологическом исследовании. При этом кроме собственно микроскопического строения оценивается рост во всех направлениях (уровень инвазии), т.к. глубокая инвазия является неблагоприятным признаком, указывающим на высокий риск метастазирования меланомы, как через кровь, так и по лимфатической системе.

    Если врач подозревает меланому, он проводит забор образца клеток из подозрительного участка, для изучения их под микроскопом. Эта процедура называется биопсия кожи. Существует несколько методик биопсии и выбор метода зависит от локализации пораженного участка, его размера и других факторов.  

Myriad myPath™ Melanoma is a unique, clinically validated, molecular test using qRT-PCR methodology to provide valuable, additive diagnostic information unavailable from any other test. At Myriad, we’ve seen the power of genetic insight to expose cancer risk and change lives. We set out to answer the need for greater certainty in diagnosing melanoma by developing a 23-gene expression signature that objectively differentiates malignant melanoma from benign nevi with a high degree of accuracy.6 When used in conjunction with the clinical and pathologic work-up, the result is a diagnostic test that increases confidence rather than relying on subjective analysis or poorly validated protocols in these difficult cases.

Innovation that changes lives.

Myriad Genetic Laboratories is a leading molecular diagnostic company dedicated to making a difference in patients’ lives through an understanding of the role genes play in human disease. Using proprietary technology, in-depth research and innovative tests, we answer the most pressing questions for patients and their healthcare providers. Because we believe every patient should be able to know their risk, their path, their plan and their choices regarding disease.

The stakes are too high not to know.

Even the most experienced dermatopathologists with the highest level of conventional diagnostics encounter situations in which a definitive diagnosis can be difficult to provide using histopathology alone.1,2 Due to the subjective nature of histology, standard protocols have been difficult to reproduce and this results in a significant level of discordance and misdiagnosis.1-3

Subjectivity is simply not an option when the consequences of misdiagnosis are so severe.

Early diagnosis is critical for long-term survival. Only 10–15% of patients with advanced disease survive past 5 years.4 With risks this high and misdiagnosis highly possible, it is no surprise melanoma is the 2nd most litigated cancer type for medical malpractice.5

Target Genes Number of Amplicons Number of Target Mutations Amplicon Locations in Exon(s)
BRAF 1 37 15
NRAS 2 27 2, 3
CDKN2A 1 4 2
MAP2K1 1 4 3
FGFR3 3 9 7, 9, 14
AKT3 2 2 5, 6
KIT 4 27 2, 11, 13, 17
PIK3CA 1 15 11
GNAQ 1 1 5
GNA11 1 1 5
System Control 1 NA NA
Total 18 127  

Behind every diagnosis is a patient.

Patients deserve more than ambiguity to determine their best course of treatment. This could mean a disfiguring scar or perhaps avoiding an unnecessary surgery. Yet, arriving at a more definitive diagnosis is sometimes elusive.

Patients deserve more. And so do you.

"The diagnosis of melanoma by conventional methods can be very subjective, and [this assay] provides objective data that could make it an extremely valuable diagnostic tool."

Sancy Leachman, M.D., PhD.
Dept of Dermatology & Melanoma Director,
Knight Cancer Institute, Oregon Health & Science University

To learn more, visit IsThisMelanoma.com and see how Myriad myPath Melanoma can help you answer when your patient asks, “Is this melanoma?”

The stakes are too high not to know.

REFERENCES

  1. Shoo B, et al. Discordance in the histopathologic diagnosis of melanoma at a melanoma referral center. Am Acad Dermatol; 2010;620751-6.
  2. Lodha S, et al. Discordance in the histopathologic diagnosis of difficult melanocytic neoplasms in the clinical setting. J Cutan Pathol 2008; 35: 349–352.
  3. Cerroni L, et al. Melanocytic tumors of uncertain malignant potential. Am J Surg Pathol; Volume 34, Number 3, March 2010.
  4. American Cancer Society. www.cancer.org. Accessed December 2013.
  5. Pitfalls in the diagnosis of malignant Melanoma: Findings of a risk management panel study. The Doctors Company. www.thedoctors.com/TDC/PressRoom/IntheMedia/CON_ID_001327. Accessed December, 2013.
  6. Data on file
  7. Rock, et al. (2014, Mar) The Clinical Impact of a Gene Expression Signature That Differentiates Benign Nevi from Malignant Melanoma. Poster session presented at the annual meeting of the United States and Canadian Academy of Pathologists, San Diego, CA

 

ДИАГНОСТИКА МЕЛАНОМЫ

 

     Диагностика меланомы основана на гистологическом исследовании. При этом кроме собственно микроскопического строения оценивается рост во всех направлениях (уровень инвазии), т.к. глубокая инвазия является неблагоприятным признаком, указывающим на высокий риск метастазирования меланомы, как через кровь, так и по лимфатической системе.

 

     Если врач подозревает меланому, он проводит забор образца клеток из подозрительного участка, для изучения их под микроскопом. Эта процедура называется биопсия кожи. Существует несколько методик биопсии и выбор метода зависит от локализации пораженного участка, его размера и других факторов. После биопсии на коже остается небольшой рубец. Биопсия кожи проводится под местной анестезией.

 

ДОБРОКАЧЕСТВЕННЫЙ НЕВУС ИЛИ ЗЛОКАЧЕСТВЕННАЯ МЕЛАНОМА?

 

     Во многих случаях при гистолоическом исследовании не удается точно определить что представляет собой меланоцитарное образование. Часто мнения разных специалистов расходятся. Однако, уточнить диагноз можно с помощью молекулярного анализа биопсийного материала.  Известно, что в большинстве случаев меланома имеет характерные повреждения структуры хромосом, называемые делециями или амплификациями. При этом некоторые участки хромосом исчезают, а другие присутствуют во множественном количестве (в норме должно быть две копии каждого участка каждой хромосомы).  Для злокачественной меланомы характерны частые амплификации 1q, 6p, 7p, 7q, 8q, 17q, 20q  и  частые делеции 6q, 8p, 9p, 10p, 10q,  11q. Доброкачественный невус не имеет этих изменений. Эпителиоидный невус иногда имеет изолированные амплификации 11p, 7q.

 

Доброкачественный невус

Злокачественная меланома

 

Определить структурные нарушения в опухоли можно с помощью микроматичного теста ОНКОСКАН. При этом с высокой точностью исследуются все структурные изменения во всех хромосомах.  Для исследования необоодим парафиновый блок.

 

МОЛЕКУЛЯРНЫЙ ПРОФИЛЬ МЕЛАНОМЫ

Исторически сложилось так,  что меланома классифицируется в соответствии с клиническими-анатомическими и гистологическими характеристиками.   При этом кроме собственно микроскопического строения оценивается рост во всех направлениях (уровень инвазии). За последние десять лет, стало очевидно, что подмножества меланомы могут быть дополнительно определены на молекулярном уровне. Критерием такой классификации являетя наличие "драйверных" мутаций в некоторых онкогенах, в том числе BRAF , GNA11 , GNAQ , KIT , MEK1 (MAP2K1) , и NRAS  ( Таблица 1; рис. 1). Такие "драйверные" мутации приводят к активации мутантных сигнальных белков, которые вызывают и поддерживают развитие опухоли.

 

Мутации в BRAF , GNA11 , GNAQ , KIT ,  MEK1 (MAP2K1) , и NRAS можно найти в примерно 70% всех меланом.Кроме того, мутации в CTNNB1 также были описаны в меланомах. Эти мутации встречаются редко одновременно в том же опухоли. Распределение мутаций зависит от места происхождения, а также в отсутствии или в присутствии солнечного хронического повреждения.

 

В настоящее время доступны или разрабатываются лекарственные препараты -таргетные молекулярные ингибиторы для пациентов имеющих конкретные мутации.

 

Тест на наличие мутаций в меланоме дает возможность исследовать все онкогены, для которых установлена связь с прогнозом и ответом нкак на таргетные препараты, так и на обычные химиотерапевтические средства.


Mutation

Biology

Targeted Therapy

Comments

BRAF gene

ARUP Test

BRAF Codon 600 Mutation Detection by Pyrosequencing2002498

  • BRAF is a protein involved in the MAPK pathway, which includes BRAF/MEK/ERK signaling
  • Activates pathway, mediates growth signaling, links with factor receptors (eg, tyrosine kinases), leading to cell growth and depression of immune regulation of cancer cells
  • >80% mutations substitute glutamic acid for valine at codon 600, resulting in V600E mutation
    • Other mutations – V600K, V600R, V600D

BRAF V600E inhibitors – vemurafenib (PLX4032) and dabrafenib (GSK2118436)

MEK inhibitors in phase I and II trials – AZD6244, GSK112012

  • 40-50% of melanomas (Solas, 2013)
  • Molecular genetic testing required if therapy directed at BRAF V600E mutation is being considered
  • Associated with melanomas of intermittent acute sun-damaged skin, younger age (<55 yrs), and poorer prognosis compared to BRAFand NRAS wild type melanomas
  • Resistance develops in all patients
    • Resistance to BRAF inhibitors develops downstream, not at the initial mutation site
  • Combining BRAF with MEK inhibition may improve outcome

RAS family of genes

(NRAS, KRAS,HRAS)

ARUP Test

NRAS Mutation Detection by Pyrosequencing   2003123

  • NRAS is a protein involved in the MAPK pathway
  • Most mutations are in NRAS gene
  • Mutation leads to defective GTPase activity with uncontrolled cell proliferation
  • Most common mutations are located in codons 12, 13, and 61
  • Mutation is generally mutually exclusive of BRAF mutation

None available yet

Clinical trials combining BRAF with MEK, ATK, and  PI3K inhibitors

  • 15-20% of melanomas (Solus, 2013)
  • Associated with thicker tumors, higher mitotic rate, and worse prognosis than BRAF mutation orBRAF/NRAS wild type

KIT gene

ARUP Test

KIT Mutations, Melanoma2002695

  • KIT gene encodes for type III transmembrane receptor tyrosine kinase, which is involved in regulation of MAPK and PI3K pathways
  • Mutations function as oncogene
  • Exons 9, 11, 13, 14, 17, 18
  • Most common mutations are located in exon 11

Tyrosine kinase inhibitors (TKIs) – imatinib; dasatinib in clinical trials

  • Rate of occurrence dependent on type of melanoma
    • Most common in acral lentiginous, sun-damaged skin or mucosal melanomas
  • Molecular genetic testing should be performed if TKIs are being considered
    • KIT IHC staining does not predict mutation status or sensitivity to TKIs
    • Exons 11, 13 most likely to have response to TKIs
  • Resistance develops in most patients with a secondary mutation in KIT gene

PDGFRA gene

ARUP Test

KIT Mutations, Melanoma2002695

  • PDGFRA gene provides instructions to create platelet-derived growth factor
  • Rare in melanoma
  • Most common mutations in exons 12, 14, 18

TKIs

  • Best response for V658A
  • Better response for crenolanib compared to imatinib
  • Exons 12, 14, 18 in PDGFRA gene may be associated with TKI sensitivity
PTEN gene
  • Functions as  lipid phosphatase regulating PI3K/AKT pathways
  • Mutation causes high-level activation of pathway with unregulated cell growth and proliferation
  • Mutation is generally mutually exclusive of NRAS  gene mutations, but usually inclusive for BRAF gene mutations
Multiple classes of inhibitors in phase I and II trials – PI3K, AKT, mTORC1, dual PI3K/mTOR inhibitors  


TARGET GENES

Target Genes Number of Amplicons Number of Target Mutations Amplicon Locations in Exon(s)
BRAF 1 37 15
NRAS 2 27 2, 3
CDKN2A 1 4 2
MAP2K1 1 4 3
FGFR3 3 9 7, 9, 14
AKT3 2 2 5, 6
KIT 4 27 2, 11, 13, 17
PIK3CA 1 15 11
GNAQ 1 1 5
GNA11 1 1 5
System Control 1 NA NA
Total 18 127  
 

Myriad myPath™ Melanoma

Myriad myPath™ Melanoma is a unique, clinically validated, molecular test using qRT-PCR methodology to provide valuable, additive diagnostic information unavailable from any other test. At Myriad, we’ve seen the power of genetic insight to expose cancer risk and change lives. We set out to answer the need for greater certainty in diagnosing melanoma by developing a 23-gene expression signature that objectively differentiates malignant melanoma from benign nevi with a high degree of accuracy.6 When used in conjunction with the clinical and pathologic work-up, the result is a diagnostic test that increases confidence rather than relying on subjective analysis or poorly validated protocols in these difficult cases.

Innovation that changes lives.

Myriad Genetic Laboratories is a leading molecular diagnostic company dedicated to making a difference in patients’ lives through an understanding of the role genes play in human disease. Using proprietary technology, in-depth research and innovative tests, we answer the most pressing questions for patients and their healthcare providers. Because we believe every patient should be able to know their risk, their path, their plan and their choices regarding disease.

The stakes are too high not to know.

Even the most experienced dermatopathologists with the highest level of conventional diagnostics encounter situations in which a definitive diagnosis can be difficult to provide using histopathology alone.1,2 Due to the subjective nature of histology, standard protocols have been difficult to reproduce and this results in a significant level of discordance and misdiagnosis.1-3

Subjectivity is simply not an option when the consequences of misdiagnosis are so severe.

Early diagnosis is critical for long-term survival. Only 10–15% of patients with advanced disease survive past 5 years.4 With risks this high and misdiagnosis highly possible, it is no surprise melanoma is the 2nd most litigated cancer type for medical malpractice.5

Behind every diagnosis is a patient.

Patients deserve more than ambiguity to determine their best course of treatment. This could mean a disfiguring scar or perhaps avoiding an unnecessary surgery. Yet, arriving at a more definitive diagnosis is sometimes elusive.

Patients deserve more. And so do you.

"The diagnosis of melanoma by conventional methods can be very subjective, and [this assay] provides objective data that could make it an extremely valuable diagnostic tool."

Sancy Leachman, M.D., PhD.
Dept of Dermatology & Melanoma Director,
Knight Cancer Institute, Oregon Health & Science University

To learn more, visit IsThisMelanoma.com and see how Myriad myPath Melanoma can help you answer when your patient asks, “Is this melanoma?”

The stakes are too high not to know.

REFERENCES

  1. Shoo B, et al. Discordance in the histopathologic diagnosis of melanoma at a melanoma referral center. Am Acad Dermatol; 2010;620751-6.
  2. Lodha S, et al. Discordance in the histopathologic diagnosis of difficult melanocytic neoplasms in the clinical setting. J Cutan Pathol 2008; 35: 349–352.
  3. Cerroni L, et al. Melanocytic tumors of uncertain malignant potential. Am J Surg Pathol; Volume 34, Number 3, March 2010.
  4. American Cancer Society. www.cancer.org. Accessed December 2013.
  5. Pitfalls in the diagnosis of malignant Melanoma: Findings of a risk management panel study. The Doctors Company. www.thedoctors.com/TDC/PressRoom/IntheMedia/CON_ID_001327. Accessed December, 2013.
  6. Data on file
  7. Rock, et al. (2014, Mar) The Clinical Impact of a Gene Expression Signature That Differentiates Benign Nevi from Malignant Melanoma. Poster session presented at the annual meeting of the United States and Canadian Academy of Pathologists, San Diego, CA
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