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Cancer susceptibility syndromes dr. varun
1.
2. All cancer involves changes in genes….
Threshold effect:
During mitosis & DNA replication
mutations occur in the cell’s genetic code
Mutations are normally corrected by DNA repair
mechanisms
If repair mechanism or cell cycle regulation is
damaged
Cell accumulates too many mutations
reaches ‘threshold’
tumour development
3. Somatic mutations
Occur in a single cell in the tissue
Are not passed down to offspring
Sporadic cancers
5. Knudson ‘two-hit’ Model
Sporadic Cancer ONE HIT
(hit=mutation)
Birth: Two non-mutated
copies of the gene
SECOND
HIT
One mutation in one gene;
Second gene non-mutated
Two mutations - one in
each gene
CANCER
6. Knudson ‘two-hit’ Model
Inherited Cancer
Born with one hit
(hit = mutation)
Birth: Two 2 non-
mutated copies of the
gene
SECOND
HIT
One mutation in one gene; One
non-mutated copy
Two mutations - one in
each gene
CANCER
7. Cancer in 2 or more close relatives
(on same side of family)
Early age at diagnosis
Multiple primary tumors
Bilateral or multiple rare cancers
Constellation of tumors consistent with specific
cancer syndrome (e.g., breast and ovary)
8. Personal or family history features
suggestive of hereditary cancer risk
Test can be adequately interpreted
Test result will aid in diagnosis or influence
medical management of the patient and/or
family
J Clin Oncol 2003;21:2397-406
9. Benefits Risks and Limitations
• Identifies high-risk • Does not detect all mutation
individuals • Continued risk of sporadic
• Identifies non-carriers in cancer
families with a known • Efficacy of interventions
mutation unproven
• Allows early detection and • May result in or economic harm
prevention strategies • False sense of security
• May relieve anxiety, and • Change in family dynamics
uncertainity • Discrimination by employer, and
insurer
• Loss of privacy
10. Hereditary Breast Cancer Syndromes
BRCA1, BRCA2, Cowden, Li-Fraumeni
Hereditary Colorectal Cancer Syndromes
HNPCC
FAP
Endocrine Syndromes –
VHL, MEN1, MEN2, FMTC
11.
12.
13.
14. % of Hereditary Breast
Gene Cancer
BRCA1 20%–40%
BOCS
BRCA2 10%–30%
TP53 Li-Fraumenni <1%
PTEN Cowden’s <1%
CHEK2 <1%
Undiscovered genes 30%–70%
ASCO
15. 1 in 800 women in the general population
5-10% of all women with breast CA
18% of women with breast CA <50 and
one close relative with breast CA <50
2% of all women of Ashkenazi Jewish
ancestry
25% of all Ashkenazi Jewish women with
ovarian cancer
16. Tumor suppressor
Tumor suppressor
gene on 17q21
gene on 13q12
Protein has role in
Protein has role in
genomic stability –
genomic stability –has
facilitates DNA repair
a role in meiosis and
by recognition of
repair of double-strand
double strand breaks
breaks
during homologous
recombination ~1,300 different
mutations reported
> 1,200 different
mutations reported
17.
18.
19. Hereditary Cancer Sporadic Cancer
Breast - 41 Breast - 62
Ovarian - 40-50 Ovarian - 60
Prostate - 63 Prostate- 71
20. Multiple cases of breast or ovarian cancer on
same side of family, especially
in closely related relatives
in more than one generation
when breast cancer is diagnosed before age 50
A family member with breast cancer
diagnosed before age 35
A family member with both breast and ovarian
cancers
An Ashkenazi Jewish heritage, particularly with
relatives with breast or ovarian cancer
21. A family member with primary cancer in both
breasts
(especially if before age 50)
A family member with ovarian cancer
A family member with male breast cancer
A family member with an identified
BRCA1 or BRCA2 mutation
22. Positive BRCA1 or BRCA2
test result
Possible testing for
other adult relatives
Increased Lifestyle Chemo- Prophylactic
surveillance changes prevention surgery
23. Breast Cancer
Monthly BSE (begin by age 18) and
Early clinical surveillence (begin by age
25)
Clinical breast examination every 6 months
Mammogram yearly
MRI yearly(ACS 2007)
Prompt evaluation of abnormal findings
24. Ovarian Cancer
No proven metholdology
Annualy or semiannualy (begin by age 25-
35)
Ca-125
Trans vaginal color-doppler ultrasound
Pelvic examination
25. Breast Cancer
Blocking the effects of Oestradiol by Tamoxifen, or
Raloxifen.
Reducing circulating levels of Oestradiol from fat
cells, and adrenal cells by
Aromatase inhibitors (Anastrazole, Letrozole, and
Exemestane ) in postmenopausal women
LHRH agonists (Deslorelin) in premenopausal women,
Deslorelin reduces the risk by stopping estrogen
production from ovaries in, and by reducing breast
density.
Fenretinide ( vitamin A) In premenopausal women
under the age of 40
.
26. Ovarian Cancer
Oral contraceptives have been shown to decrease
the risk of ovarian cancer in the general population.
In women with mutations in BRCA1 or BRCA2 that
risk reduction was also documented, with 60%
reduction (RR=0.4) with use of 6 years or more.
Narod SA, Risch H, Moslehi R, et al. NEJM 1998, Aug 13;339(7):469-71.
Fisher B, Costantino JP, Wickerman DL, et al. JNCI, 1998; 90(18):1371-1388.
27. Cowden’s (TP53) – 25-50% breast ca risk
Oral lesions, GI hamartomas, benign breast dz
Thyroid, uterine lesions or CA, macrocephaly
Li-Fraumeni (PTEN)– breast ca < age 40
Often childhood cancers
sarcoma, leukemia, brain adrenocortical CA
HDGC(CDH1) -gastric, lobular breast and
colon cancers
Lower risk genes: ATM, PALB2, CHEK2
28.
29.
30. Two common syndromes:
Lynch syndrome
Also known as Hereditary Non Polyposis Colorectal
Cancer or HNPCC
~2 - 5% of colorectal cancer
Prevalence of 1 in 200 - 2,000*
Familial Adenomatous Polyposis (FAP)
<1% of colorectal cancer
Prevalence of 1 in 8,000 – 14,000*
Autosomal dominant inheritance
*Prevalence depends on population
31. when mutated
Lynch syndrome (HNPCC):
Mutations in DNA repair genes lead to an
accumulation of mutations which may result
in malignancy.
FAP:
Mutations in a tumour suppressor gene
cause an increase in cell proliferation and a
decrease in cell death.
32.
33. HNPCC is associated with germline mutations
in any one of at least four genes
34. Early but variable age at CRC
diagnosis (~45 years)
Tumor site in proximal colon
predominates
Patients rarely exhibit polyps,
making early detection difficult
Extracolonic cancers:
endometrium , ovary, stomach,
urinary tract, small bowel, bile
ducts, sebaceous skin tumors
35. Cancer Site General Lynch
Pop Syndrome
Colon 5-6% 80%
Avg age dx 44
~75% right-sided
Endometrium 2-3% 40-60%
Stomach 1% 13%
Ovaries 1-2% 12%
Lesser increased risks for:
small bowel, hepatobiliary tract, urinary tract, and brain cancers
36. Individuals with colorectal or endometrial
cancer diagnosed <50
Individuals with 2 Lynch syndrome related
cancers diagnosed at any age
Includes multiple synchronous or metachronous
colorectal cancers
Individuals with colorectal or endometrial
cancer who have a 1st degree relative with any
Lynch associated malignancy
One of the cancers dx < 50
Relatives of individuals with a known Lynch
syndrome mutation
Modified from Bethesda Guidelines JNCI 89:1758-1762
37. Recommendations for Individuals with Lynch Syndrome
Cancer Site Procedure Age to Begin Interval
COLON1 Colonoscopy 20-25 Every 1-2 years
or 5-10 yrs before the until age 40;
earliest CRC dx in the annually
family; whichever is
younger
thereafter
Endometrial Bx
ENDOMETRIUM and/or 30-35 Every 6-12
& OVARIES2 Transvaginal months
ultrasound and
CA-125
STOMACH3 EGD 30-35 Every 1-2 yrs
URINARY Ultrasound and 30-35 Every 1-2 yrs
TRACT3 Urine Cytology
1 Sub-total colectomy could be considered (not standard of care)
2 Could also consider prophylactic hysterectomy and BSO
3 Some advocate only if there is a positive family hx of these types of cancers
38. Chromosome 5, APC gene
High penetrance
Characterized by:
Early onset
>100 adenomatous polyps
Variant form:
Attenuated FAP may occur with >10 but <100
polyps.
39. Colorectal adenomatous polyps begin to appear at
an average age of 16 years (range 7-36 years)
Average age at diagnosis: 34-43 years, when >95%
have polyps
Age Individuals with colon
cancer
21 7%
45 87%
50 93%
From: http://www.genetests.org
40. ~50-90% develop small bowel polyps
lifetime risk of small bowel malignancy is 4-
12%
~50% develop gastric polyps
~10% gastric cancer
~10% develop desmoid tumours
41. Colon
Annual sigmoidoscopy or colonoscopy beginning at
age 10-15 yrs
Prophylactic colectomy following polyp detection
w/continued surveillance of rectum/ileal pouch
Consider use of NSAIDs to decrease polyp burden
Duodenum/stomach
EGD age 25, repeat 1-3 yrs depending on findings
Hepatoblastoma
Abdominal U/S & AFP every 6 mos from birth to 5
yrs.
NCCN Practice Guidelines & Gastroenterology 2003; 124 AGA Statement
42. Prophylactic colectomy is necessary for patients
with FAP once polyps develop
Colectomy may become necessary in patients with
AFAP if polyps become too numerous to manage via
colonoscopy
43. Lifetime polyp burden of 20 to 100, usually more
proximal located
Polyps may not appear until mid life
Lifetime risk of CRC = 80%
Extracolonic tumors occur at same rate as FAP
Surveillance:
annual colonoscopy starting late teens or early 20’s
EGD every 1 to 3 years beginning around age 25
44. • 5-10% of cancers are Hereditary.
• Hereditary cancers are caused by germ-
line mutation.
• Life time risk for cancer is significantly high
in an individual with positive mutant genes.
• Possible to diagnose mutant genes.
Possible to prevent cancer by high
surveillance, chemoprevention, and
surgical intervention.
Editor's Notes
When these mutations Occur in a single cell in the tissue they are called Somatic mutations eg in breast tissueThese mutations Are not passed down to offspring These cause Sporadic cancers
On the other hand if mutation occurs in egg or sperm then it is called Germline mutationsThese mutations May be passed to offspring And causes Inherited cancer syndromes
In individuals with cancer susceptible genes Moreover it Besides thisAnd Also during life time there is high risk of development of 2nd or 3rd primary cancer
When we should suspect Hereditary Cancer Syndromes If there is Cancer in 2 or more close relatives (on same side of family)Or cancer develop at an early ageIf there are Multiple primary tumors or Bilateral or multiple rare cancersMoreover if there is presence of various combinations
Benefits, Risks, and Limitationsof geneTesting are as followsBenefits includes that these tests identifies But some risks and limitations associated with teses tests includes that Even if these tests results are negative still there is continued risk of sporadic cancer Even if these tests results are positive Efficacy of further interventions unprovenMoreover They can cause False sense of securityChange in family dynamicsDiscrimination by employer, and insurerLoss of privacy
Some important hereditary cancer syndromes includes
Although most of the cases of breast and ovarian cancers are sporadic still About 5-10% of cancers are hereditary
And out of those about 40 % cases are associated with BRCA 1 and 30% with brca 2And Still 27% cases are associated with undiscovered genes
Normally brca 1 and 2 mutations found in 1 out of 800 women in general population but And its prevalence Increases to 5-10% in women with breast CancerAnd if breast cancer develop before age of 50 then in 18% women brca1 and 2 mutations are found
Brca 1 and 2 both are Tumor suppressor gene 1 on ch. 17 and 2 on chr. 13And there are about >2500 mutations have been identified in thses Tumor suppressor gene
With brca 1 there is 50-85% inc risk of breast cancer dev. And that is even at an early ageMoreover risk of development of second primary breast cancer is about 40-60%Risk of ovarian cancer dev. Is about 15-45%Besides there there is inc. risk of dev. Of other cancers too
Similarly brca 2 is associated with inc.risk of dev. Of breast cancer by 50-85%Second primary by 40-60%And moreover there is inc. risk dev. too
Average age of diagnosis of cancers in hereditary syndromes is about 2 decade earlier
And if genetic test results show positive brca 1 or 2 mutation then further management includes
For active surveillance of brca mutation carrier individuals recommendations are Monthly bse which should be begin by age of 18And if there is any abnormal finding then Prompt evaluation of those findings should be done
And for prevention of ovarian cancer recommendations includes
Various risk reduction surgeries should be offered to individuals with brca mutation carriers includeswhich
Some medical interventions which have been tried and advised in brca mutation carrier individuals includes either we can block effects of estradiolOr can reduce circulating levels of Oestradiol
Ocp use has shown risk reduction of dev. Of ovarian cancer in brca mutation carrier individuals similar to the general population
Although About 65-85% cases of crc are sporadic still about 5% patients of crc are associated with hnpcc and 1% with fap
In individuals with hnpcc mutation risk of dev. Of crc is about 70-80% while in cases of fap lifetime risk of crc is 100%
In case of lynch syndrome life time risk of dev. Of crc is about 80% which is only 5-6% in gen. populationSimilarly risk of endometrium cancer is 40-60% in comparison of 2-3% in gen. populationThere is also significant inc. risk of stomach and ovarian cancerAnd lesser inc. risk of
Various Recommendations for Individuals with Lynch Syndrome includeColonoscopy every 1-2 yrly until age of 40 and annually thereafter and it should be started with age of
eosphagogastroodudenoscopy
About in natureAnd these are caused by And because of these mutations their life time risk of cancer development is significantly high Now a days it is Possible to diagnose mutant genesAnd we can prevent these cancers by high surveillance, chemoprevention, and surgical intervention.
