Cancer susceptibility syndromes dr. varun


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  • 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.
  • Cancer susceptibility syndromes dr. varun

    1. 1. 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
    2. 2. Somatic mutations Occur in a single cell in the tissue Are not passed down to offspring Sporadic cancers
    3. 3. Germline mutations May be passed to offspring Inherited cancer syndromes
    4. 4. 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 geneCANCER
    5. 5. 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 geneCANCER
    6. 6.  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)
    7. 7.  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
    8. 8. 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
    9. 9.  Hereditary Breast Cancer Syndromes  BRCA1, BRCA2, Cowden, Li-Fraumeni Hereditary Colorectal Cancer Syndromes  HNPCC  FAP Endocrine Syndromes – VHL, MEN1, MEN2, FMTC
    10. 10. % of Hereditary BreastGene CancerBRCA1 20%–40% BOCSBRCA2 10%–30%TP53 Li-Fraumenni <1%PTEN Cowden’s <1%CHEK2 <1%Undiscovered genes 30%–70% ASCO
    11. 11.  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
    12. 12.  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
    13. 13. Hereditary Cancer Sporadic CancerBreast - 41 Breast - 62Ovarian - 40-50 Ovarian - 60Prostate - 63 Prostate- 71
    14. 14.  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
    15. 15.  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
    16. 16. Positive BRCA1 or BRCA2 test resultPossible testing forother adult relatives Increased Lifestyle Chemo- Prophylacticsurveillance changes prevention surgery
    17. 17. 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
    18. 18. Ovarian Cancer No proven metholdology Annualy or semiannualy (begin by age 25- 35)  Ca-125  Trans vaginal color-doppler ultrasound  Pelvic examination
    19. 19. 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.
    20. 20. 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.
    21. 21.  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
    22. 22. 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
    23. 23. 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.
    24. 24. HNPCC is associated with germline mutations in any one of at least four genes
    25. 25.  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
    26. 26. Cancer Site General Lynch Pop Syndrome Colon 5-6% 80% Avg age dx 44 ~75% right-sidedEndometrium 2-3% 40-60% Stomach 1% 13% Ovaries 1-2% 12% Lesser increased risks for:small bowel, hepatobiliary tract, urinary tract, and brain cancers
    27. 27.  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
    28. 28. 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 BxENDOMETRIUM 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
    29. 29.  Chromosome 5, APC gene High penetrance Characterized by:  Early onset  >100 adenomatous polyps  Variant form:  Attenuated FAP may occur with >10 but <100 polyps.
    30. 30.  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:
    31. 31.  ~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
    32. 32.  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
    33. 33.  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
    34. 34.  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
    35. 35. • 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.