Cancer

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CancerMolecular Network DiseaseCheng shujun,
Gao yanning, Zhang kaitai, Xiao TinCancer
Institute, Chinese Academy of Medical Sciences,
Peking Union Medical College
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Fortune Magazine, March 22,2004
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• Personalized Therapy
• progress and challenge

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• Breast cancer patients with the same stage can
  have markedly different treatment responses. The
  clinical behaviour (such as lymph node status and
  histological grade) fail to classify accurately
  outcome. Chemotherapy or hormonal therapy reduces
  distant metastases by one-third, however 70-80
  of these patients would not developed distant
  metastases without the adjuvant treatment, these
  patients may not benefit from the treatment, and
  may potentially suffer from the side effects.
• (Nature, 2002,VOl.415, 530)

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• Breast cancer patients with the same stage can
  have markedly different treatment responses. The
  clinical behaviour (such as lymph node status and
  histological grade) fail to classify accurately
  outcome. Chemotherapy or hormonal therapy reduces
  distant metastases by one-third, however 70-80
  of these patients would not developed distant
  metastases without the adjuvant treatment, these
  patients may not benefit from the treatment, and
  may potentially suffer from the side effects.
• (Nature, 2002,VOl.415, 530)

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• FDA News
• FOR IMMEDIATE RELEASEP07-13February 6, 2007
  Media Inquiries
• .
• The MammaPrint test uses the latest in molecular
  technology to predict whether existing cancer
  will metastasize (spread to other parts of a
  patient's body).
• 70 genes activity confers information about the
  likelihood of tumor recurrence.

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• Imatinib(Glivec) Chronic myelogenous
  leukemia(CML) Bcr-abl tyrosine kinase inhibitor
  . CML patients have high-expression of Bcr-abl
  fusion protein.
• Gefitinib (Iressa) (epidermal growth factor
  receptop tyrosine kinase inhibitor)
• Lung adenocarcinoma patients with relatively
  high frequency of EGFR gene mutation
• Herceptin Breast cancer Her2 monoclonal
  antibody
• Ttumor regression 11-26 for unselected
  breast cancer patients, 34 for HER2-positive
  breast cancer patients
• ( Nature Review cancer, 2006, 6 735-741)

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• Wood,LD,et.al(Science,2007,Nov.16,Vol.3181108)
  
• isolated DNA from 11 breast and 11 colorectal
  tumors and determined the sequences based on
  exons representing 20,857 transcript from
  18,191gene. Any gene that was mutated in the
  tumor but not in normal tissue from the same
  patients was analyzed in 24 additional tumors.
• Pathway rather than individual genes appear to
  govern the course of tumorigenesis. Disruption of
  a pathway by mutation in any one of its genetic
  components would presumably lead to similar
  changes in growth. The lt15 driver mutation in an
  individual tumor likely reflect alterations in a
  similar number of pathways.

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A few gene mountains are mutated in a large
proportion of tumors most genes are mutated in
lt5 of tumors represented as hills?????????????
, (Science 2007,318 1108)
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• Greenman,C et al(Nature, 2007,446153-)reported
  1,000 somatic mutations found in the coding exons
  of 518 protein kinase genes in 210 diverse human
  cancers. There was substantial variation in the
  number and pattern of mutations in individual
  cancer. Most somatic mutations are likely to be
  passengers that do not contribute to
  oncogenesis. However, there was evidence for
  driver mutation contributing to the development
  of the cancer studied in approximately 120 genes.

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Thomas,RK et al.(Nature genetics,2007,39347-)dete
rmined 238 known oncogen mutation across 1,000
human tumor samples of 17 cancer types. Of 17
oncogens analyzed, they found 14 to be mutated at
least once, and 298(30) samples carried at least
one mutation
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Sian jones, et al, Scienceexpress, 2008, Sep. 4,
1-10 ???24?????20661??????Pancreatic cancer
contain an average of 63 genetic alterations, the
majority of which are point mutations. These
alterations defined a core set of 12 cellular
signaling pathways
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• 1). Wood,LD,et.al determined the ???????? DNA
  sequences based on exons of 20,857 transcript
  from 18,191gene. (Science,2007,Nov.16,Vol.3181108
  )
• 2). Thomas RK,et al ??17??? 238?oncogenes
  ???(Nature genetics, 2007 39 153-)
• 3). Greenman,Cet al. ??210???????? 518
  protein kinase gene exons ???
• ( Nature, 2007, 446 153-)
• The mutated genes in two colorectal tumors
  overlap to only a small extent
• Pathway rather than individual genes appear to
  govern the course of tumorigenesis.
• Disruption of a pathway by mutation in any one of
  its genetic components would presumably lead to
  similar changes in growth.
• The differences are likely to be the basis for
  the wide variation in tumor behavior and
  responsiveness to therapy
• the acquisition of numerous somatic mutations,
  each with a small fitness advantage, may also
  drive tumourigenesis

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• Molecular lesions that occur in early stage of
  cancer or in precursor lesions are more likely to
  have a direct influence on cancer occurrence and
  progression than those that accumulate at the
  later stage of cancer development. Among the
  latter, many alterations may be considered as
  passengers .

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• Next-generation sequencing
• CancerWhole Genome Sequencing

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Recurring mutations found by sequencing an acute
myeloid leukemia genome. N Engl J Med. 2009 Sep
10361(11)1058-66

• 38-year-old man of European ancestry
• DNA samples from the patients bone marrow
  sample and a normal skin- biopsy specimen
  obtained
• The AML genome that we sequenced contains
  approximately 750 point mutations,
• We identified 12 acquired (somatic)
  mutations within the coding sequences of genes
  and 52 somatic point mutations in conserved or
  regulatory portions in the tumor sample. Four of
  the 64 mutations occurred in at least 1
  additional AML sample in 188 samples that were
  tested

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A comprehensive catalogue of somatic mutations
from a human cancer genomePublished online 16
December 2009.Nature 08658

• we have sequenced the genomes of a
  malignant melanoma and a lymphoblastoid cell line
  from the same person
• We identified 33,345 somatic base
  substitutions.
• A total of 32,325 were single-base and
  510 were double-base substitutions

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A small-cell lung cancer genome with complex
signatures of tobacco exposure/nature Published
online 16 December 2009

• .
• Using massively parallel sequencing
  technology, we sequenced a small-cell lung
  cancer cell line, NCI-H209, NCI-BL209 (an
  EpsteinBarr-virus-transformed lymphoblastoid
  line has been generated from the patient. ) to
  explore the mutational burden associated with
  tobacco smoking.
• A total of 22,910 somatic substitutions
  were identified, including 134 in coding exons.
• One mutation for every 15 cigarettes
  smoked.

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• Cancer Molecular network disease caused by
  cellular abnormal growth and differentiation
  related to developmental genome

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PNAS, 2007,1048685-
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Gene Expression Profiles in Different Phases of
Human Lung Embryonic Development and
Tumorigenesis
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Development landscape
(41k probes)
Mid FL
Early FL
Adult L
Embud
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The dynamic gene expressing patterns in human
developmental process
DNA Replication
DNA Replication Pre-Initiation
DNA strand elongation
E2F mediated regulation of DNA replication
E2F transcriptional targets at G1/S
FOXM1 transcription factor network
FoxO family signaling
G1/S Transition
G2/M Checkpoints
G2/M DNA damage checkpoint
G2/M Transition
M Phase
M/G1 Transition
Mitotic Metaphase/Anaphase Transition
Mitotic Prometaphase
Mitotic Prophase
Mitotic Spindle Checkpoint
Mitotic Telophase /Cytokinesis
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Clinical Significance

• The expression level of these genes was
  correlated with survival cancer patients.
• Type of cancers
• Adenocarcinoma of the lung(242 samples)
• 117, 125 samples
• Brain Cancer(268 samples)
• Breast Cancer(1077samples)
• 249, 159, 179, 286 samples

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P 0.041
Overall survival analysis of 49 lung ADC patients
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Survival analysis of stage I lung ADC patients
the relationship between the development
related genes and the prognosis of stage I lung
ADC patients.
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Survival analysis of glioma patients The
relationship between the development related
genes and the overall survival of patients with
glioma.
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The expression level of development related genes
was associated with the relapse-free survival of
the breast cancer patients, which was confirmed
in 7 independent datasets, involving 1300 samples.
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The expression level of development related genes
was associated with the overall survival of the
breast cancer patients, which was confirmed in 3
independent datasets.
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The expression level of development related genes
was associated with both the overall survival and
the relapse-free survival of the breast cancer
patients without lymph note metastasis (N0).
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For the patients treated with Tamoxifen, the
expression level of the development related genes
was associated with their prognoses.
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The expression level of the development related
genes was also associated with the prognoses of
the patients not treated with Tamoxifen.
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The expression level of development related genes
was associated with the Elston Histologic Grade
of breast cancer. Most patients with Grade 1
breast cancer (good prognosis) had a lower
expression level of the development related
genes. And most patients with Grade 3 (bad
prognosis) had a higher expression level.
However, the patients with Grade 2, whose
prognosis was unpredictable according to Elston
Histologic Grade, could still be divided into two
groups with different expression level of
development related genes.
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And the prognosis of the two groups of Elston
Grade 2 patients was significantly different.
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Cancer prevention and treatment (present and
future)

• High-risk individual--Precancerous
  lesions--invasive cancer
• Future
  present
• prevention (life
  style) Surgery
• Network drugs
  radiotherapy
• Vaccine
  chemotherapy
• 
  
  new-therapy

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• Key Steps for cancer research in the Future
• To intensify clinical investigation on human
  cancer and set up tumor tissue banks(
  translational study).
• To establish high-throughput platforms for fast
  analysis of genes, proteins, cell structures and
  functions through a synthetic approach.
• Systematic analysis of both clinical and basic
  research data with bioinformatics.

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• Thank you