1. Genome evolution within the individual

2. Genomic mutations Point mutations Deletions Duplications Inversion
Translocation
Changes in chromosome number

3. Genomic mutations Point mutation T A G G C G C G T T C G
A T C C G C G C A A G C
T A G G C G A G T T C G
A T C C G C G C A A G C
Point mutation

4. Cancer Karyotype
clincancerres.aacrjournals.org

5. What are the clonal relationships among metastases?
What is the main research question?
What are the clonal relationships among metastases?

6. Methods:
Deep sequencing of 13 DNA samples from patients with pancreatic adenocarcinoma
DNA
Fragmentation
Paired end sequencing
Mapping

7. Identification of genomic rearrangements using deep sequencing method
Deletion
Duplication
Inversion
Translocation

8. Genomic rearrangements found in the patients

9. Clonal evolution of cancer
Greaves (2010)

10. 2) Primary tumor or metastasis?

11. 2) Primary tumor or metastasis?

12. Clonal relationship among metastasis
Is this metastasis indeed the farthest from the germline?

13. 3) Mutations found in all metastases but not in the primary tumor
In PD3637, eight rearrangements
were not found in the primary pancreatic tumour despite being
present in all metastases (Fig. 3a, b and Supplementary Fig. 10). That all
metastases are so phylogenetically distant from the primary tumour
indicates that one or more driver mutations, which might either be
among the eight rearrangements or among point mutations acquired
contemporaneously, have conferred a selective advantage for metastatic
spread.

14. 3) Mutations found in all metastases but not in the primary tumor
PD3637
PD3640
In PD3637 the primary tumor is closer to the germline then to other metastasis in contrast to PD3640. It can be explained by the 8 mutations, at list one of them could be a driver mutation that allowed the cancer to metastases…. What is driver mutation? ->

15. driver and passenger mutation
Hills and mountains or
driver and passenger mutation

16. Same organ, same mutations?
In PD3827, we identified two overlapping, out-offrame
deletions of exon 6 of PARK2 (Fig. 4b). One was present in all
four lung metastases but no abdominal deposits, whereas the other was
carried by all four abdominal lesions but no lung deposits. Thus, the
two deletions probably arose in separate clones, one of which founded
the lung metastases and the other seeded the abdominal metastases.
Similarly, in PD3828, lung metastases were on a separate branch of the
phylogenetic tree from abdominal lesions (Fig. 4d).
In both patients, the lung lesions were further evolved than the
abdominal metastases, and indeed, the additional rearrangements
targeted cancer genes.
Peritoneal cancer is a rare cancer. It develops in a thin layer of tissue that lines the abdomen. It also covers the uterus, bladder, and rectum. Made of epithelial cells, this structure is called the peritoneum. It produces a fluid that helps organs move smoothly inside the abdomen.
Sometimes people confuse peritoneal cancer with intestinal or stomach cancer. And it's not the same thing as cancers that spread (metastasize) to the peritoneum. Peritoneal cancer starts in the peritoneum. So it is called primary peritoneal cancer
The omentum is a fat pad that lays on top of the intestines. Many peritoneal cancers seed into the omentum. The peritoneal cavity is where all the abdominal organs lie. You can have a peritoneal cancer without seeding into the omentum. There are some cases where the primary source of a tumor is the omentum, but cancer in the omentum usually has a primary tumor located elsewhere

17. Same organ, same mutations?

18. Clonal evolution of cancer
Ma et al.(2012)

19. 4) Fold-back inversion
In comparison with other classes of rearrangement, fold-back inversions
were significantly more likely to be found in all metastases from
that patient (P50.003; Fig. 2c), implying that fold-back inversions
occur early in cancer development, before tumour cells disseminate

20. 4) Fold-back inversion- breakage fusion bridge
cycles predicate specific abnormalities of cell-cycle control, namely
dysregulation of the G1-to-S transition and an intact G2–M checkpoint.
Duplication of DNA breaks in S phase implies that repair was
not required before DNA replication and end-to-end fusion of the
duplicated breaks implies active G2–Msurveillance. End-to-end chromosome
fusions are often seen in association with telomere erosion
and it may be that the double-strand DNA break initiating breakagefusion-
bridge repair results from telomere loss.
Breakage-fusion-bridge cycles, resulting in fold-back inversions, are
often initiated by telomere loss5,18, whereas telomere attrition is not
implicated in the pathogenesis of, for example, interstitial deletions or
tandem duplications21. Telomerase, the gene that maintains telomere
length, shows low expression during early pancreatic carcinogenesis
before markedly increasing expression in the invasive tumour5,18,22.
The genome-stabilizing effects of telomerase re-expression would
therefore have more impact on reducing rates of fold-back inversion
in advanced disease than other classes of rearrangement. In contrast,
our data indicate that other types of rearrangement occur throughout
the cancer life cycle, although the biological pathways underlying these
forms of genomic instability remain unclear

21. Model for the clonal evolution of metastases