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Flashcards in Hereditary cancer syndromes Deck (29)
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What is a hereditary cancer syndrome?


  • > 200 hereditary syndromes associated with an increased cancer risk with overall 5-10% cancer cases due to germline variant.
  • Cancers; 80% sporadic, 15-20% familial, 5-10% inherited
  • The expected percentage of cases due to germline pathogenic variants is different in different tumour types/ populations
    • p53: 60-80% v 15% Adrenocortical Ca in <18yrs v >18yrs
    • BRCA1/2: 20% HGSOC (high grade serous ovarian cancer) <50yrs, <5% pancreatic ca


Describe germline vs. sporadic mutations


Germline variants:

  • Pathogenic variant or “Mutation” present in egg or sperm “germ cell”
  • If passed onto offspring: will be present in all cells
  • Results in heritable conditions


Somatic mutations

  • Mutation present in non egg or sperm cell “somatic”
  • Can reproduce abnormality in clonal cells
  • but Non heritable


Describe patterns of inheritance

1. Autosomal dominant

  • The majority of hereditary cancer syndromes are associated with autosomal dominant inheritance pattern 
  • 50% of offspring is affected
  • Incomplete penetrance - not all carriers will develop disease/have phenotype 
  • Can appear to skip a generation if cancers risk is predominantly associated with sex specific cancer e.g. gynaecological cancer and the variant is carried by the male parent. (BRCA1/2)



  • Breast Cancer: BRCA1/2, p53, PALB2, CHEK2, PTEN, CDH1, RAD51C, BRIP1, ATM, STK11, NF1
  • Colon Cancer: Lynch Syndrome-MMR, Familial Adenomatous Polyposis-APC, POLE, POLD1; PeutzJegherSyndrome-STK11; Juvenile Polyposis Syndrome-BMPR1a, SMAD
  • Ovarian Cancer: (epithelial) BRCA/2, RAD51C/D, MMR, BRIP1, PALB2
  • Pancreatic: CDKN2A, BRCA2, PALB2, ?MMR
  • Renal: VHL, BHD-FLCN, Papillary Ca-FH, SDHB, MET, FH, SDHB, SDHC, SDHD, TSC1, TSC2
  • Thyroid: MEN, RET, PTEN
  • Sarcoma: TP53, APC, EXT1, EXT2, RB1

2. Autosomal recessive

  • need to inherit a copy of the affected variant from each parent to develop phenotypic appearance of hereditary cancer syndrome. heterozygous carriers however can still pass to offspring in a single allele manner. 
  • An increased cancer risk may be associated with individuals who are heterozygous for pathogenic variants
  • e.g. 
    • MYH-Attenuated FAP
    • BLM-Bloom Syndrome
    • FANC-FanconiAnaemia
    • ATM-Ataxia Telangectasia


Examples of autosomal dominant hereditary cancer syndrome 

  • Breast Cancer: BRCA1/2, p53, PALB2, CHEK2, PTEN, CDH1, RAD51C, BRIP1, ATM, STK11, NF1
  • Colon Cancer: Lynch Syndrome-MMR, Familial Adenomatous Polyposis-APC, POLE, POLD1; PeutzJegherSyndrome-STK11; Juvenile Polyposis Syndrome-BMPR1a, SMAD
  • Ovarian Cancer: (epithelial) BRCA/2, RAD51C/D, MMR, BRIP1, PALB2
  • Pancreatic: CDKN2A, BRCA2, PALB2, ?MMR
  • Renal: VHL, BHD-FLCN, Papillary Ca-FH, SDHB, MET, FH, SDHB, SDHC, SDHD, TSC1, TSC2
  • Thyroid: MEN, RET, PTEN
  • Sarcoma: TP53, APC, EXT1, EXT2, RB1


Examples of autosomal recessive hereditary cancer syndrome


  • MYH-Attenuated FAP
  • BLM-Bloom Syndrome
  • FANC-FanconiAnaemia
  • ATM-Ataxia Telangectasia


When do you suspect familial cancer syndromes?


  • Two or more relatives with the same type of cancer on the same side of the family
  • Several generations affected 
  • Earlier ages of cancer diagnosis than what is typically seen for that cancer type
  • Individuals with multiple primary cancers
  • The occurrence of cancers in one family, which are known to be genetically related (e.g. breast and ovarian cancer, or colon and uterine cancer)
  • The occurrence of non-malignant conditions and cancer in the same person and/or family (e.g. Marfanoid habitus and medullary thyroid cancer in multiple endocrine neoplasia type 2B (MEN 2B)).


Describe fouder effect in hereditary cancer syndromes

a high frequency of a specific gene mutatoin in a population founded by a small ancestral group

e.g. ethnic isolation, reduced migration

Ashkenazi Jewish have higher BRCA1/2 mutations. (prevalence is 1/40 c.f. 1/500)



Describe spontaneous germline events 

Rare but can happen 

  • The rate of spontaneous mutations varies according to gene
    • FAP: 15-20% de novo
    • TP53 (Li Fraumini): 15% de novo
    • BRCA1/2: extremely rare
  • Testing of parents still recommended even if family history suggests spontaneous new mutation to rule out genotypic effect (although phenotypically not affected, as this can affect siblings)
  • De-novo mutations
    • Siblings are not at risk-no testing needed
    • Offspring remain at 50% risk


majority of hereditary cancer syndrome are a/w mutations in genes with an active role in _____


e.g. tumour suppressor gene; "gate keeper" genes & "care taker" gene

Tumour suppressor gene: 2 break system

Care taker genes; e.g. MMR, POL E/D: acquired error -> capacity to repair small DNA error in normal somatic cells 


Describe risks of general population risk vs. those with BRCA1/2, PALB2 mutation for breast, ovarian, fallopian tube cancer, primary peritoneal cancer, prostate and pancreatic cancer


Describe risks of general population vs. those with Lynch syndrome or FAP in developing colorectal cancer, ovarian, fallopian tube cancer, primary peritoneal cancer, endometrial cancer, duodenal/ampullary cancer

Lynch syndrome; males have higher CRC than females. estrogen pathway likely protective. 

cancer risk will vary according to gene.

e.g. Lynch syndrome: lower risk for MSH6, PMS2. c.f. higher risk for MHL1 & MSH2. 


Screening for those with hereditary cancer syndromes

  • BRCA1/2, PALB2
  • Lynch syndrome
  • FAP
  • VHL


  • BRCA1/2, PALB2: 
    • Breast Screening to commence at age 25yrs
    • Risk reducing BSO from 40yrs
    • Or 5 years earlier than the youngest person affected
  • Lynch Syndrome
    • MHL1/ MSH2: Screening colonoscopy from 25yrs
    • PMS2/ MSH6: Screening colonoscopy from 30yrs
    • Risk reducing TAH-BSO from 40 yrs
    • Or 5 years earlier than the youngest impacted
  • FAP
    • Screening colonoscopies from 12yrs Or 18 yrs in AFAP until colectomy
  • VHL
    • Annual exam with BP + ocular examination from 2 yrs of age
    • Annual plasma or urine metanephrine screening from 2yrs
    • Annual abdominal screening Alternating US/ MRI from 10yrs


Which mutations lead to higher / lower risk of cancer in Lynch syndrome?

lower risk for MSH6, PMS2.

higher risk for MHL1 & MSH2. 


Histological differences of breast cancer of BRCA1/2 mutations

- histology

- grade

- steroid receptors

- HER2


  • Histology
    • Majority are ductal carcinomas of no-special type
    • Atypical medullary carcinomas more common in BRCA1
  • Grade
    • Largely higher grade for both BRCA1/2
    • BRCA2: lack tubules and lower mitotic counts
    • BRCA1: high mitotic count, pleomorphic, high tubule
  • Steroid Receptors
    • BRCA1-more likely to be ER and PgR negative (~90%) compared with sporadic breast cancers (~30%) 
    • BRCA2-not significantly different to sporadic cancers
  • Her2: Both BRCA1 and BRCA2 cancers rarely overexpress or show amplification of HER2


Describe ovarian cancer pathology in BRCA, PALB2, RAD51C, BRIP1, RAD51D mutations

- type of cancer

- grade

- p53 staining

- histology

- origin


  • An excess of serous adenocarcinomas 
  • If you have a BRCA1 mutation >90% of tumors are HGSOC (high grade serous ovarian cancer)
  • ~50% in women without a BRCA1
  • Higher grade (majority G3, remainder G2)
  • Associated with complete or complete absent p53 staining (all or nothing)
  • Not associated with mucinous histology
  • Many may originate from tubal origin


Hereditary genetic mutations of ovarian cancer

BRCA, PALB2, RAD51C, BRIP1, RAD51D mutations


Describe assessment of mismatch remair proteins

by immunohistochemistry


IHC can be utilised to determine expression of mismatch repair proteins, whereby indicating MMR function.

Germline v somatic v methylation; can be distinguished by BRAF & Methylation assay

MLH1 methylation possible as denovo -> silencing of MLH1 -> MMR deficient phenotype


Histological features of lynch syndrome related CRC

- histology

- well/poorly differentiated

- R/L sided etc


  • Mucinous histology
  • Poor differentiation
  • Right sided
  • Lymphocytic infiltrate
  • Expanding growth pattern
  • Absence of intraglandular neutrophil-rich ‘dirty’ necrosis
  • dMMR CRC can be predicted using the presence of any three of these factors (sens.98% spec. 48%) 


Mismatch repair deficiency in CRC

- mostly due to what

- which stage is common

  • mainly due to MLH1 & PMS2 loss
  • Most due to acquired MLH1 methylation
  • 3% due to germline MMR mutations (Koopman 2009) 
  • More commonly seen in stage II than stage III
  • ~4% stage IV


How do you differentiate if CRC is due to germline mutations or acquired methylation?

somatic BRAF mutations can be tested to differentiate if germline mutations are present vs. acquired methylation 

  • Somatic V600E mutation in 63% cases associated with MLH1 methylated CRC (c.f. lynch)
    • Associated with loss of expression of MLH1 and PMS2 on IHC
    • ?<1% in Lynch Colorectal Cancers
  • Causal relationship between CIMP CRCs and BRAF mutations is unclear but a useful means of differentiating Lynch from CIMP dMMR tumours in CRC
  • cannot differentiate cause of dMMR in non-CRC e.g. endometrial, gastric or small bowel in lynch -> need to use methylation assay, rather than BRAF testing 
  • Methylation testing assesses MLH1 methylation in tumour in comparison to surrounding normal tissue. If surrounding normal tissue also MLH1 methylation; due to constitutional methylation which is very very rare 

i.e. if you see V600E mutation, highly unlikely to be Lynch syndrome


Targeting surgical mx of hereditary cancer syndromes


- lynch


- breast cancer a/w BRCA


  • VHL: 
    • Nephron sparing surgery given the high likelihood of multiple and bilateral renal cancers
  • Lynch Syndrome: 
    • subtotal colectomy v hemi colectomy should be discussed
  • FAP: Colectomy v proctocolectomy
    • Attenuated v non attenuated
    • Colonic polyposis
    • Rare families with gastric polyposis only
  • BRCA related breast cancer
    • esp if BRCA1, risk of 70% of new contralateral primary breast cancer in 5-10 years; consider mastectomy
    • Risk of new breast primary is dependent on age at diagnosis (esp <50yo)
    • Systemic therapies reduce the risk of both local recurrence and new breast primaries
    • Oophorectomy reduces new breast cancer (as well as ovarian cancer) risk in women premenopausal at diagnosis


Targeting cancer mx by systemic therapy in hereditary cancer syndromes


  • Many of the germline mutations associated with DNA repair pathway (BRCA, PALB2, ATM etc) -> allow potential molecular targeted agents
  • Altered susceptibility to chemotherapy agents
    • DNA repair deficient tumours increase sensitivity to platinum salts
    • dMMR CRC (Lynch Syndrome) have reduced sensitivity to 5-FU chemotherapy
    • dMMR EC have reduced chemotherapy sensitivity
  • Development of targeted therapies e.g. PARP inhibitors
  • Immunotherapy e.g. MMR deficient tumours more likely to respond than MMR proficient tumours (including Lynch syndrome)


Discuss ovarian cancer mx in setting of BRCA mutation


BRCA mutation predicts for prolonged platinum sensitivity

if relapsed disease -> can still re-trial platinum. If unsuccessful, can trial PARP inhibitors with significant improvement in progression free survival. 


Describe Homologous recombination genes

Without proper homologous recombination, chromosomes often incorrectly align for the first phase of cell division in meiosis. Decreased rates of homologous recombination cause inefficient DNA repair, which can also lead to cancer.


HR genes not restricted to BRCA

Germline HR mutations: 22.6%

somatic HR mutations: 7.6%

Of these, BRCA1 > 2 are most common, however other HR mutations exist e.g. ATM. 


WHen is PARP inhibitor beneficial? 

BRCA related tumours in not just ovarian, but also breast, prostate and pancreatic cancer



Describe risk assessment in familial cancer clinic


  • Family history documentation by family members
  • Confirmation of the cancers in the family
    • Cancer Council Victoria Registry
    • Death Certificates
    • Pathology reports
    • Medical records
  • Estimation of the likelihood of there being a Hereditary Cancer Syndrome and a gene to test for!
    • Combination of pathology review, IHC, pedigree review, colonoscopy reports, dermatology reviews
    • Probability Modelling programs: BOADICEA, MANCHESTER


Describe genetic testing in familial cancer clinics

- who is offered genetic testing

- singel gene vs. panel testing 


  • Genetic Testing is offered if the risk of a mutation is more than 10%
  • Generally genetic testing for cancer genes starts in someone who has had cancer
  • Is offered to the individual most likely to have the mutation within the family if…..
    • Is still alive 
    • Happy to have genetic testing
    • Medicare rebate for Breast/ Ovary 
    • Clinic funded testing for non medicarerebatable
  • Single Gene vs Panel Testing
    • Most conditions are now associated with a number of genes 
    • Technologies allow multiple genes to be assessed using the one sample
    • Targeting the panels to the condition


Describe mainstreamed genetic testing in oncology (genetic tests ordered by non-geneticists)

- indications

- current availability


  • The provision of genetic testing by a non genetics specialist
    • Patients with HGSOC ~15% chance of germline BRCA1/2 mutation <70yrs
    • Treatments altered on the basis of presence of a mutation
  • Allows genetic testing to be provided to patients in their own unit during chemotherapy visits
  • Currently available:
    • All HGSOC (non mucinous)
    • All TNBC (50yrs) or MANCHESTER score of >15
  • NOT for predictive testing in families where there is a known pathogenic variant


Discuss actions following genetic tests in oncology

- negative test result

- positive test result 

- variant of uncertain significance


  • Negative Test Result:
    • No pathogenic variant identified
      • May not exclude hereditary cancer risk 
      • No genetic test for relatives
    • Risk assessment based on family history (FHx)
  • Positive Test Result: 
    • Pathogenic variant identified
    • Gene fault that is the likely cause of the patient’s cancer
    • The result implies an increased risk of another primary cancer. 
    • Other members of her family can be tested for the same gene fault.
  • Variant of uncertain significance: 
    • No gene test available for family members
    • Risk assessment will be based on FHx