Cancer Genetics

What are the features of genetic predisposition to common cancers?

• Genetic predisposition to common cancers  

• No phenotypic markers 

• Familial clustering  

• Early age at onset  

• Multiple primary tumours  

What are the features of rare familial cancer syndromes?

• Early age of onset 

• Multiple primary tumours  

• Distinct phenotype  

• Clustering of rare cancers  

What is the point of studying familial cancer?

• Provides clues to key rate limiting steps in tumour development  

• Implications for more common sporadic cancers  

• Development of novel therapeutic strategies 

• Accurate assessment of risk often has management implications  

• Increased genetic risk – predictive testing and pre-symptomatic surveillance  

What makes a genetic predisposition more likely?

• Young age at diagnosis  

• Multiple tumours  

• Rare tumours  

• Site of cancer / certain pathology  

• Family history  

What are the features of germline testing?

• Uses blood  

• Confirms presence or absence of germline variant and diagnosis  

• Determine the risk of developing the cancer associated with the variant detected in a family member 

• Access to preventative treatment  

• Determine risk of passing on cancer risks to offspring  

• Useful information for family planning  

What are the features of somatic testing?

• Uses tumour tissue  

• Confirms a particular diagnosis  

• Useful and accurate prognostic information  

• Provides targeted treatment options / access to clinical trials  

• Identify germline variants  

How much breast cancer is genetic?

• 20% of breast cancers are familial  

• Family history is the strongest known risk factor for breast cancer other than age  

What are high risk BC genes?

• 5-10% are due to an autosomal dominant gene  

• High risk and high penetrance cancer predisposition genes  

• BRCA1/2, TP53, PTEN, CDH1, STK11, PALB2  

What are modest and weak BC risks?

• At population level major contribution from weaker genetic susceptibility factors SNPs and environmental influences  

• Modest contribution from moderate genes  

• CHECK2, ATM, RAD51C, RAD51D, NF1  

What is the role of BRCA1?

• Used in homology directed repair  

• Localisation, resection, replication and recombination  

• Repair of double strand DNA breaks 

• Regulation of cell-cycle progression  

What is the structure of BRCA1?

• 17q21, made of 24 exons, exon 11 is largest, codes for 1863aa  

• Population frequency is 1 in 380 

How does BRCA1 impact risk?

• Female lifetime risk of breast cancer between 65-80%  

• Female lifetime risk of ovarian cancer 40-60%  

• Founder mutations – Ashkenazi Jews and Eastern European Polish populations  

How does BRCA1 cause the disease?

• Pathogenic variants throughout gene 

• Mainly truncating or missense in functional domains  

• 20% may be due to large rearrangements  

What is the breast cancer pathology of BRCA1?

• High grade  

• Higher proportion atypical medullary type  

• Pushing margins 

• High mitotic count and lymphocytic infiltrate  

• Enrichment for ER, PR, HER2 negative  

• Triple negative cancer  

• No increase risk of breast cancer in men  

• Increased risk for contralateral breast cancer  

• 70% by the age of 60 

• Biallelic is typically lethal but some patients have a severe phenotype

What is the structure of BRCA2?

• 13q12, 27 exons and pathogenic variants throughout the gene  

• Population frequency of 1 in 280  

What is the BRCA2 risks?

• Lifetime risk of female breast cancer 60-80%  

• 65% risk of contralateral breast cancer increases 2% per year  

• Lifetime risk of ovarian cancer of 10-25%  

• Lifetime risk of male breast cancer 5-10%  

• Lifetime risk of prostate cancer of 20-40%  

• Founder variants in Ashkenazi Jews and Icelandic population  

How does BRCA2 cause disease?

Predominantly protein truncating variants, missense variants in DNA binding/RING binding domains, smaller proportions due to large rearrangements  

What is BRCA2 gene pathology?

• Breast cancers have more sporadic features  

• ER positive, DCIS  

• More typical breast cancer presentation  

• Biallelic mutations in BRCA2 cause FANCD1 a chromosomal fragility syndrome  

• Developmental abnormalities: short stature, microencephaly and radial ray anomalies  

• Predisposes to childhood solid tumours and haematological malignancies  

What are the features of the Manchester scoring system?

• Manual scoring method based on the gender and age of onset of breast/ovarian/pancreatic and prostate cancer  

• Manchester score of 15 for affected individual = 10% a priori chance of PV  

• Manchester score of 20 for unaffected FDR to an affected deceased individual  

How does the Manchester score incorporate tumour pathology?

• Tumour pathology characteristics incorporated  

• Receptor status and grad of the index breast cancer cause  

• For any ovarian case as lone as not related to index through >1 and unaffected woman >60y  

• The higher the score the more likely that a family will have a pathogenic variant in either BRCA1/2  

What is the genetic testing criteria?

• NGTD defines what testing is commissioned and who is eligible  

• Separate components for cancer/somatic testing compared to rare/inherited disease  

• Testing is based on whether the result is likely to have clinical utility for the patient or family  

• NGDT is regularly updated so have to check the current criteria  

What is the VHR programme?

• Breast screening – VHR programme  

• MRI screening from 25 to 50 years above 50 depends on breast density  

• Mammography 40 to 70 years, considered between 30-39  

• Over 70 can self refer for annual mammograms  

What is the mastectomy reducing risk?

• Bilateral risk reducing mastectomy for over 30% risk  

• Residual breast cancer risk post surgery is less than 5%  

• Survival advantage thought to be small and diminishes with age  

• Contralateral mastectomy can be considered for those who have had breast primary  

What is endocrine reducing risk?

• Risk reducing endocrine therapy  

• Options for BRCA2 carriers but not BRCA1 due to high risk of triple negative breast cancer  

How is ovarian screening done?

• Not currently recommended in routine practice  

• No evidence based screening programme  

What is ovarian risk reducing surgery?

• Offer when child-bearing complete from 35-40  

• RRBSO should be considered for all women with fitness and co-morbidities  

• Need to consider HRT if pre-menopausal  

What is PALB2?

• Integral part of the BRCA complex required for homologous recombination repair  

• Recurrent variants account for more than half of variants reported  

• Majority truncating and pop frequency of 1 in 770 

How does PALB2 increase risk?

• Up to 45-65% lifetime risk of breast cancer form females  

• Majority of breast cancers are ER+ some are TNT 

• Increased risk of contralateral breast cancer  

• Male breast cancer has 1% increased risk by 80  

• Ovarian cancer risk around 5% by 80 

• Pancreatic cancer risk is unclear around 2-3% by 80 

What impact does PTEN have?

• Germline variant causes Cowden Syndrome or PTEN-hamartoma tumour syndrome up to 85% BC  

• High incidence of fibrocystic breast disease  

What role does STK11 have?

Germline variant causes Peutz Jeghers syndrome – 45-55% increase risk 

What risk does CDH1 have?

Germline pathogenic variants cause Hereditary Diffuse Gastric Cancer, and women have 40-55% lifetime risk 

What risk does TP53 have?

 

• Germline variant causes Li Fraumeni syndrome  

• Very early age of BC onset 80-90% development chance  

What is the moderate risk for breast cancer?

• ¼ to 1/7 women will develop breast cancer  

• From 20y is between 17-30%  

• 10 year risk between 40-50 is 5-8%  

• There are genes known to cause a moderately increased risk  

• CHECK2, ATM, RAD51C, RAD52D  

• Some additional cancer risks for some genes have their own management implications  

What are the features of CPG and cancer?

• If there is no CPG in those with a family history of breast cancer  

• Risk assess on basis of family history  

• Use tools such as CanRisk  

• Has other risk factors such as hormonal factors, BMI, alcohol  

What are the features of Lynch syndrome?

• 2-4% all CRC  

• 1 in 200 people are heterozygous for the pathogenic variant in the MMR gene 

• Mean age of cancer is 45 – 67 in general population  

• Often ascending colon (70%), and multifactorial (25%)  

• Pathological characteristics 

• Often mucinous, lymphocytic infiltrate 

What are the features of VHL disease?

• Clinical diagnostic criteria first developed in 1964 

• Rare and affects 1 in 36000  

• De novo in 20% of cases  

• Mean onset age is 20s and 97% present by 65  

What are the features of RCC in VHL?

• Predominantly clear cell, occurs in 70% by 60  

• Frequently multi-centric and bilateral  

• Develop from precursor lesions present in both kidneys  

• Leading cause of mortality  

• Survival associated with tumour size  

• Ideally nephron sparing surgery  

• Role of ablation when tumours small/ surgery not possible  

• Aim is to postpone need for dialysis  

What are the features of somatic variants?

• Common in oncology practice to perform tumour sequencing using large cancer panels  

• For pathogenic sequence variants in cancer susceptibility genes idenfied on tumour only sequencing  

• Unclear if they are somatic or germline in origin  

What are the features of ESMO?

• Recommendations regarding germline focused analyses of tumour only sequencing data  

• Indications for germline follow-up testing  

• Guidance on patient given information giving and consent  

What are the features of ctDNA?

• Mother had a ctDNA test  

• Circulating tumour DNA tests allow for the detection of genetic changes in tumour cells via blood test  

• Test detects DNA from cancer cells that can be found circulating in the blood  

• Done for breast cancer, NSCLC and cancer of unknown primary origins