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General genomics

Dr Sarah Taylor, GatewayC GP Lead, speaks to Dr Fiona Lalloo, Consultant Clinical Geneticist, about cancer genetics.

Key points:

    • There are 2 types of genetic mutations:
      • Somatic mutations – these are mutations which are confined to the tumour and are useful to direct treatment 
      • Germline mutations – these are mutations which affect every cell in the body. This can affect treatment but can also cause a predisposition to malignancies for the patient and members of their family
    • Patients with germline mutations need referral to a genetics service. This is normally done by the oncology team, but primary care practitioners may be asked to refer family members
    • In that case it useful to know the name of the affected patient, the type of cancer and where they are being treated
    • Many cancers are environmental but 1-5% of cancers have a germline mutation
    • There are some cancer syndromes which have specific clusters of cancer types.


The National Genomic Test Directory lists the referral criteria for genetic testing for patients
who are concerned about a family history of cancer

Factors which increase the probability of a germline mutation are:

  • cancers occurring at young age
  • individuals with more than one primary
  • clusters of cancer within a family

Many cancers are environmental, but 1-5% of cancers have a germline mutation.

There are some cancer syndromes which have specific clusters of cancer types.

Genomic testing in Wales

While the National Genomic Test Directory is owned, controlled and maintained by NHS England, the Welsh Health Specialised Services Committee (WHSSC) approve funding of genomic testing in line with the criteria identified in the Test Directory and implementation of these tests is being clinically prioritised in collaboration with a range of clinicians through the All Wales Medical Genomics Service.

Pancreatic Ductal Adenocarcinoma (PDAC)

Pancreatic Ductal Adenocarcinoma (PDAC) accounts for more than 90% of exocrine pancreatic cancers. Unlike other cancer types such as breast and colorectal, there is currently no consensus on the molecular subtypes of pancreatic cancer. Although mutations
predominately occur in KRAS, CDKN2A, SMAD4 and TP53 genes, modern genomic analysis of PDAC reveal high tumour heterogeneity with a multitude of mutated genes at low prevalence. As such, there are a multitude of classifications published based on genomic
aberrations, transcriptomics, and epigenetics, but its associated relevance in clinical practice has yet to be defined.

Currently, there is no routine screening or tumour molecular profiling of PDAC. However, there is growing evidence that identifying ‘actionable’ genetic alterations where patients go on to receive therapy can improve overall survival by up to 1 year.

Familial Pancreatic Ductal Adenocarcinoma

Approximately 10% of patients with pancreatic cancer are familial and result from germline mutations. Individuals with 1 first degree relative with PDAC have a two-fold risk of developing the disease; this risk rises to up to seventeen-fold if there are
3 or more first degree relatives with PDAC. The genetic basis for PDAC is its association with known inherited syndromes (see table below).


Susceptible gene

Increased risk of PDAC

Cystic Fibrosis


5-6-fold increase

Familial Adenomatous Polyposis (FAP)


4-fold increase

Familial Atypical Multiple Mole Melanoma (FAMMM)


13-22-fold increase

Hereditary Non-Polyposis Colorectal Cancer (HNPCC) / Lynch Syndrome

DNA mismatch repair genes,MLH1, MSH2, MSH6, PMS1, PMS2

9-fold increase

Hereditary Pancreatitis


40-55% lifetime risk

Peutz-Jeghers Syndrome


11-36% risk

BRCA1/BRCA2 Mutation


3-10-fold increase, 10% lifetime risk

PALB2 Mutation


1-3% of patients have this gene

Figures taken from Pancreatic Cancer Action Network.

Currently, NICE guidance recommends surveillance for pancreatic cancer for individuals with hereditary pancreatitis,
Peutz-Jeghers Syndrome, and those with an affected first degree relative and who exhibit BRCA1, BRCA2, PALB2 mutations or familial atypical multiple mole melanoma (FAMM) syndrome. Surveillance should also be considered for those with Lynch Syndrome
and any affected first degree relative, and to those with 2 or more affected first-degree relatives across 2 or more generations.

Additional resources

Link: National Genomic Test Directory, NHS EnglandLink: All Wales Medical Genomics ServiceLink: NCI Dictionary of Genetic Terms, National Cancer Institute
Link: Pancreatic cancer and genomics, HEE Genomics Education Programme (2019)
Link: NICE NG85 guidance – Pancreatic cancer in adults: diagnosis and management, NICE (2018)

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