1. The classical model of cancer progression proposed that tumors accumulate driver mutations sequentially through selective sweeps, becoming genetically homogeneous. 2. Recent studies show that tumors are genetically heterogeneous, with multiple clones present. Selective sweeps are rare, and mutations do not necessarily occur in a fixed order. 3. A "Big Bang" model proposes that tumors grow as a single expansion with numerous subclones, not driven by selection. Most mutations arise early in tumor growth.

1. Dr. Anshulekha Patel
Moderator- Dr. (Prof) P.K.Satpathy
Guide-Dr. (Prof) Raghumani Mohanty
GENETIC ORIGINS OF HUMAN
CANCER- RECENT ADVANCES

2. INTRODUCTION
 1916 : Tyzzer first use the term ‘somatic mutation’
to designate events occuring in cancer
progression.
 1954 : Armitage and Doll proposed multi-stage
theory of carcinogenesis
 1971 : Knudson proposed two-hit model of
retinoblastoma
 1990: Fearson and Vogelstein analysed
colorectal tumour progression and provided
support for multistep cancer progression model.

3. ARMITAGE DOLL MODEL

4. KNUDSON’S TWO HIT
HYPOTHESIS

5. THE MULTISTEP CANCER
PROGRESSION MODEL
 Tumors progressively accumulate carcinogenic
mutations or other genetic changes.
 The alterations involve tumour suppressor genes
and oncogenes and occur in a stepwise fashion.
 Multistep cancer progression model emphasises
on the order in which the genetic changes
occur.
 It provides the basis for initiation, growth ,
progression and metastatic spread of cancer.

6. COLORECTAL
TUMORIGENESIS

7. THE MULTISTEP CANCER
PROGRESSION MODEL
 Colorectal cancer
 Pancreatic cancer
 Breast cancer
 During progressive clonal evolution, selectively
advantageous ‘driver’ lesions lead to acquisition
of the phenotypic ‘hallmarks of cancer’.

8. HALLMARKS OF CANCER

9. THE MULTISTEP CANCER
PROGRESSION MODEL
 An initial mutation that confers a selective
advantage is acquired by a cell and leads to
clonal expansion of these cells.
 The first cell is probably a stem cell.
 A further mutation occurs which is again selected
to clonally expand replacing the other cells in the
population- this is called selective sweep.

10. SEQUENTIAL MODEL OF CANCER
PROGRESSION
Subsequent mutations in the key driver genes to cells
within the clone trigger subsequent clonal expansions,
and each clone takes over the entire neoplasm (A
SWEEP TO FIXATION)

11. THE MULTISTEP CANCER
PROGRESSION MODEL
 The accural of driver mutations in this stepwise
fashion underpins the progression to an invasive
or metastatic phenotype.
 In the colon, genetic model involves sequential
mutations in the APC, KRAS and TP53 genes.
 In Barrrett’s oesophagus, early mutation of p16 is
followed by later inactivation of TP53.

12. BARRETT’S OESOPHAGUS

13. BARRETT’S OESOPHAGUS
 The pattern of mutation and clonal expansion as
proposed by Maley et al.
 An initial founder mutation, usually LOH of p16,
provides a cell with a selective advantage and so
it sweeps across the entire Barrett's oesophagus
segment to fixation. Subsequent mutations and
selective sweeps, typically a second hit at the p16
locus or a mutation or LOH of p53 cause later
selective sweeps, sometimes also to fixation. The
linear accumulation of mutations eventually
produces a cancerous clone.

14. COLORECTAL
TUMORIGENESIS

15. COLORECTAL
TUMORIGENESIS

16. COLORECTAL
TUMORIGENESIS

17. COLORECTAL
TUMORIGENESIS

18. COLORECTAL
TUMORIGENESIS
 Based on assumption that all somatic mutations
occurred clonally in an adenoma- present in all its
cells, but beginning with the cell of origin or stem
cell.
 The mutations accumulate within the adenoma by
wave of selective sweeps, which go to fixation
throughout the adenoma.
 So, it follows that adenomas should be ‘
genetically homogenous benign lesion(s)’.

19. PROBLEMS WITH THE
CLASSICAL MULTISTEP
CANCER PROGRESSION
MODEL

20. PROBLEMS WITH THE CLASSICAL
MULTISTEP CANCER PROGRESSION
MODEL
 It suggests there has to be an order in which
mutations occur.
 Clinically this is appealing –might be amenable to
therapeutic attack and milestones of prognosis
 Eg in the progression of Barrett’s oesophagus,
p16 deletion is followed by loss of TP53. So,
TP53 lesion is closer to becoming
cancerous…….?? Such deterministic
progression with a fixed order of selection is
UNLIKELY

21. PROBLEMS WITH THE CLASSICAL
MULTISTEP CANCER PROGRESSION
MODEL
 Tumours develop through variable pathways, and
that the order of mutation/ selection is mainly
stochastic.
 Microenvironment plays an important role in the
selection for mutant genes.
 Driver mutations are detected in normal tissue.
Eg p53 and oncogene mutations in both skin and
nondysplastic colon epithelium in inflammatory
bowel disease.

22. PROBLEMS WITH THE CLASSICAL
MULTISTEP CANCER PROGRESSION
MODEL
 Selective sweeps are rare in human tumours.
 Studies on Barrett’s oesophagus supported
concept of small, localised clonal expansions.

23. INTRATUMOUR
HETEROGENEITY

24. PROBLEMS WITH THE CLASSICAL
MULTISTEP CANCER PROGRESSION
MODEL
•Multiple clones exist throughout the follow-up period.
•In only one case, a clone grew to dominate the Barrett’s
segment without real evidence that the clone swept to
fixation.

25. PROBLEMS WITH THE CLASSICAL
MULTISTEP CANCER PROGRESSION
MODEL
 In colorectal adenomas progressing to
carcinomas, there are no selective sweeps.
 Adenomas are not genetically homogenous but
they show a complex regional genetic structure,
with segregated clones that correlate with the
histological appearances.

26. PROBLEMS WITH THE CLASSICAL
MULTISTEP CANCER PROGRESSION
MODEL
 Genetic mosaicism is a feature of most, if not all,
cancers.
 Kidney cancer
 Lung cancer
 Breast
 Glioma
 Leukemia
 Ovary
 Genetic differences are observed between
primary tumour and associated metastases.

27. Assumption made in the classical multistep
cancer progression model- that mutations
sequentially spread throughout the tumour,
creating a genetically homogenous lesion in
which all cells share the same mutations- are
inconsistent with currently available data.

28. A BIG BANG
 A new proposed model of colorectal cancer
growth.

29. A BIG BANG
 Colorectal cancers grow as a single(clonal) expansion
rather than evolving sequentially via multiple selective
sweeps.
 Composition of subclones that naturally arise within
the single expansion do not experience stringent(
differential) selection. That means tumour are
heterogenous. Acquiring a new driver mutation
doesnot trigger a selective sweep.
 Because of lack of selection, the timing of mutation,
rather than selection, is main determinant of clone
size within the tumour. Mutations arising early will
tend to have large subclones and those arising late
will form clones of restricted size.

30. A BIG BANG
 The Big Bang model was postulated to explain
the results of a detailed genetic analysis of
intratumour diversity in colorectal cancers and
adenoma.
 The spatial distribution of point mutations and
copy number alterations across different regions
of these tumours was recorded and
computational modelling approach was used to
determine the most likely way in which tumour
would progress.

31. A BIG BANG
 The computational analysis revealed that sequential
model was extremely unlikely to explain the
obsereved spatial distribution of subclones.
 It predicted that all the sizeable subclones arose early
during the cancer expansion, and their size was not
determined by their fitness.
 But it is based on the fact that a tumour consists of an
almost innumerable population of cells. 1 cm3 tumour
is lower size limit of clinical detection but already
contains one billion cells.

32. A BIG BANG

33. After initiation, a tumor grows predominantly as a single expansion
numerous heterogeneous subclones.
ITH results from private alterations (colored arrowheads) that contin
accumulate owing to replication errors.

34. ABSTRACT OF BIG BANG
ARTICLE
 What happens in early, still undetectable human
malignancies is unknown because direct observations are
impractical. Here we present and validate a 'Big Bang'
model, whereby tumors grow predominantly as a single
expansion producing numerous intermixed subclones that
are not subject to stringent selection and where both public
(clonal) and most detectable private (subclonal) alterations
arise early during growth. Genomic profiling of 349
individual glands from 15 colorectal tumors showed an
absence of selective sweeps, uniformly high intratumoral
heterogeneity (ITH) and subclone mixing in distant regions,
as postulated by our model. We also verified the prediction
that most detectable ITH originates from early private
alterations and not from later clonal expansions, thus
exposing the profile of the primordial tumor. Moreover,
some tumors appear 'born to be bad', with subclone
mixing indicative of early malignant potential. This new
model provides a quantitative framework to interpret tumor
growth dynamics and the origins of ITH, with important
clinical implications.

35. AVENUE FOR FUTURE
RESEARCH
 Clinically, the Big Bang model raises the question
of whether cancers are ‘ born to be bad.’
 If the clonal composition of the tumour is
essentially fixed from the outset of tumour growth,
then the early events will determine the prognosis
of tumour and its sensitivity to treatment.
 In Authors’ opinion Big Bang dynamics could
apply equally well in other tumour types but is still
undetermined.

36. PUNCTUATED EQUILIBRIA AND
HOPEFUL MONSTERS
Sequential model
assumes that the driver
mutations accrue
sequentially (phyletic
gradualism)
Big bang model is an
example of punctuated
equilibrium. Large
phenotypic leaps occur
suddenly in a static
population

37. PUNCTUATED EQUILIBRIA AND
HOPEFUL MONSTERS
 Punctuated equilibria evolutionary model is a
model purely of the pattern of phenotypic change
in a population.
 It makes no comment on pattern of genotypic
change.
 Genotypic phenotype relationship is complex.
1. Small genotype changes can have large
phenotypic consequences.(eg. single base pair
change in APC cause Hereditary polyosis
syndrome)
2. Cell’s phenotype is defined in conjunction with

38. PUNCTUATED EQUILIBRIA AND
HOPEFUL MONSTERS
 Individuals with grossly altered genomes are
referred to as ‘hopeful monsters’.
 ‘Hopefulness’ derives from the chance that the
alterations will provide significant increase in
fitness to the mutated individual.
 Question arises: Is the development of a hopeful
monster a plausible cause of Big Bang????

39. GENETIC INSTABILITY,
CHROMOSOMAL CATASTROPHES AND
CONSPIRING CLONES
 85% of colon cancers show chromosomal
instability (CIN) in the form of loss and gain of
whole chromosome arms.
 15% show increased point mutations that lead to
defect in mismatch repair (MMR) or defect in
other DNA replication and repair enzymes.
 Both causes elevated rates of ongoing genetic
change, and increase the rate at which driver
mutations accrue.

40. MICROSATELLITE INSTABILITY
(MSI)
 MSI is a result of defects in the mismatch repair
proteins (genes) hMSH2,
hMLH1,hPMS1,hPMS2,and hMSH6.
 MSI-H cancers tend to be diploid and have wild
type p53 compared with MSS cancers.
 MSI-H present at a lower stage and have better
survival.
INSTABILITY IN TUMOUR
CELLS
NIH classification
30% (≥ 2 of 5 microsatellites) MSI-H
10-30% MSI-L
<10% MSS

41. GENETIC INSTABILITY,
CHROMOSOMAL CATASTROPHES AND
CONSPIRING CLONES
 A steady accural of mutations could underpin
punctuated evolution if certain conditions are met
1. Driver mutation must be rare enough that
periods of time sufficient for a selective sweep
elapse between each sequential driver
mutation.
2. The accrual of a single new driver mutation
must cause a significant change in phenotype.

42. GENETIC INSTABILITY,
CHROMOSOMAL CATASTROPHES AND
CONSPIRING CLONES
 A new class of mutational processes is identified
by whole genome sequencing that cause
enormous changes to the genome in a single or
very few cell divisions.
 Chromothripsis - Shattering of chromosomes
into many parts and their (partial) reassembly into
a different order.
 Chromoplexy – interleaved chromosomal
alterations that involve multiple chromosomes.

43. GENETIC INSTABILITY,
CHROMOSOMAL CATASTROPHES AND
CONSPIRING CLONES
Chromothripsis can be seen in at least 2-3 % of all cancers
across many subtypes and is present in 25% of bone
cancers.

45. GENETIC INSTABILITY,
CHROMOSOMAL CATASTROPHES AND
CONSPIRING CLONES
 Kataegis is a process of clustering of somatic point
mutations in localised regions of the genome.
 HYPOTHESIS : A chromosomal catastrophe in the
form of chromothripsis, chromoplexy or kataegis leads
to generation of a hopeful monster and subsequent
initiation of a Big Bang.
 Drivers of clonal expansion in tumours can be a
growth factor produced by one clone and used by
another. Hence, phenotypic changes need not be
elicited by genotypic changes in the expanding clone

46. CONCLUSION
 Colorectal adenomas considered to be precursor
to colorectal cancer may be sitting static for 10-
15 years and progress through punctuated
genetic events to eventually develop the invasive
phenotype or may not progress.
 Once invasion occurs there is a ‘flat’ clonal
expansion and progression to advanced
carcinoma can be quite rapid.
 The fact that genetic progression occurs in
spatially segregated clones is immaterial-

47. CONCLUSION
 Question arises: in patients with resected
adenomas by looking at the genotype/phenotype
of the index adenoma(s) can we predict future
cancer risk ??
 Whether or not imminent Big Bang can be
detected before the ‘explosion’ happens??
 The answer is further research.

48. CONCLUSION
 In Barrett’s oesophagus, most Barrett’s segments
are non-progressors.
 Genetic progression in Barrett’s oesophagus
does not progress in selective sweeps . The
individual clones expand independently and can
be a focal event.
 Barrett’s segments can be long-over 10cm and
even the most invasive screening/ surveillance
protocols cannot be expected to pick up such
localised events.

49. Finding the right model for cancer
progression could be rate limiting
for the design of appropriate
methods of preventing and
treating cancer

50. TAKE HOME MESSAGE
 Most pre-malignant and preinvasive lesions
(DCIS, colorectal adenomas, Barrett’s
oesophagus) will not progress to malignancy.
 The main driver mutations occur early in the
neoplastic process in many tumour types
suggesting tumour is ‘borne to be bad’.
 Tumour progression can be very fast, may be the
basis of ‘interval cancers’- missed on surveillance
in Barrett’s oesophagus.
 Future research is needed to identify rapidly
progressive pre-malignant and pre-invasive
lesions in order to tailor therapy appropriately

51. THANK
YOU