As the use of genetic testing increasingly impacts patient outcomes, the role of general practitioners (GPs) in the identification and care of patients at high risk for hereditary cancer becomes even more important. A GP-led model of surveillance provides a convenient and accessible platform to support adherence to screening strategies.

INTRODUCTION

The past decade has seen great strides in our understanding of the genetic basis of human disease. Arguably, the most profound impact has been in the area of cancer genetics, where cancer genes with high-penetrance familial pathogenic variants are increasingly identified. These insights have paved the way for the integration of genetics into mainstream cancer care.

Understanding the hereditary cancer predisposition syndrome that underlies one’s personal and/or family history realises the potential of gene-directed cancer prevention, management and treatment.

HEREDITARY CANCER PREDISPOSITION SYNDROMES

Currently, over 400 hereditary cancer predisposition syndromes have been identified, most of which have an autosomal dominant inheritance pattern. Although many of these are rare syndromes, they account for at least 5–10% of all cancer incidence (Figure 1).

Improving Outcomes with Genetic Testing - SingHealth Duke-NUS Genomic Medicine Centre

A hereditary cancer predisposition syndrome is usually suspected in families with the following characteristics (Figure 2):

  • A strong family history of cancer: Multiple individuals diagnosed with similar types or patterns of cancer on either side (paternal or maternal) of the family
  • Young age of cancer diagnosis: Individuals who are diagnosed with cancer (generally under the age of 50)
  • Multiple cancers: Individuals who are diagnosed with more than one primary cancer
  • Rare tumours or cancers: Unusual types of tumours (e.g., neuroendocrine tumours) or cancers (e.g., sarcoma)

However, due to phenotypic variability, incomplete penetrance, and gender-specific cancer risks, some families with a hereditary cancer predisposition syndrome may not meet these criteria. A negative family history of cancer does not rule out the possibility of a hereditary cancer syndrome.

Improving Outcomes with Genetic Testing - SingHealth Duke-NUS Genomic Medicine Centre

INDICATIONS FOR HEREDITARY CANCER SYNDROMES

Breast cancer​• Hereditary breast and ovarian cancer syndrome
• Cowden syndrome
• Li-Fraumeni syndrome
• Fanconi anaemia
• Neurofibromatosis type 1
• Hereditary diffuse gastric cancer syndrome (lobular histology)
• Peutz-Jeghers syndrome
Ovary/fallopian tube cancer​• Hereditary breast and ovarian cancer syndrome
• Lynch syndrome
Prostate cancer​• Hereditary breast and ovarian cancer syndrome
Pancreatic cancer​• Peutz-Jeghers syndrome
• Hereditary breast and ovarian cancer syndrome
• Hereditary melanoma and pancreatic cancer
​Colorectal cancer​• Familial adenomatous polyposis syndrome
• Lynch syndrome
• Cowden syndrome
• MUTYH-associated polyposis
• Polymerase proof-reading associated polyposis
• Juvenile polyposis syndrome
Endometrial / uterine cancer​• Lynch syndrome
• Cowden syndrome
• Polymerase proof-reading associated polyposis
Gastric cancer​• Hereditary diffuse gastric cancer syndrome
• Lynch syndrome
• Juvenile polyposis syndrome
• Peutz-Jeghers syndrome
Renal cancer​• Von Hippel-Lindau syndrome
• Hereditary leiomyoma renal cell carcinoma
• Birt-Hogg-Dube syndrome
• Cowden syndrome
• Paraganglioma-phaeochromocytoma predisposition syndromes
Thyroid cancer​• Multiple endocrine neoplasia type 2
• Cowden syndrome
​Phaechromocytoma / Paraganglioma​• Von Hippel-Lindau syndrome
• Paraganglioma-phaeochromocytoma predisposition syndromes
• Neurofibromatosis type 1
Leukaemia​• Fanconi anaemia
• Lynch syndrome
​Neuroendocrine tumour​• Multiple endocrine neoplasia type 1
• Von Hippel-Lindau syndrome
Adrenocortical tumour​• Multiple endocrine neoplasia type 1
• Li Fraumeni syndrome
Basal cell carcinoma​• Gorlin syndrome / nevoid basal cell carcinoma syndrome

At the Cancer Genetics Service (CGS) in the National Cancer Centre Singapore (NCCS), we have helped over 400 families identify pathogenic variants associated with a hereditary risk of cancer.

1. Hereditary Breast Cancer

Breast cancer is the most common cancer that afflicts women in Singapore. Almost 25% of breast cancer patients have an underlying breast cancer predisposition syndrome.

Breast cancer genetic testing minimally includes over 20 breast cancer susceptibility genes. Clinically, the most important of these are the BRCA1 and BRCA2 genes. These are high-risk breast cancer genes, where carriers of pathogenic BRCA1/2 variants are predisposed to an increased risk of breast cancer (49–57% vs. general population risk of 12%) and ovarian cancer (18–40% vs. general population risk of 1%).

How to manage individuals at risk of hereditary breast cancer?
Female carriers of a breast cancer susceptibility gene are recommended the following screening and surveillance measures to detect signs of cancer at the earliest and most treatable stage:

  • Annual mammograms and/or breast magnetic resonance imaging (MRIs)
  • 6-monthly clinical breast examination
  • Consider chemo-prevention drugs (e.g., Tamoxifen) on a case-by-case basis to reduce breast cancer risk
  • Consider risk-reducing bilateral mastectomy and/or bilateral salpingo-oophorectomy to reduce breast and ovarian cancer incidence

Treatment implications
Cancers that arise as a result of a germline predisposition are typically managed differently from those that arise sporadically. Patients may undergo more extensive local therapy if they are at an increased risk for metachronous malignancy.

Studies have also identified BRCA1/2 status as clinically relevant in the selection of therapy for patients already diagnosed with breast cancer. Emerging breast and ovarian cancer research indicates that BRCA1/2 status predicts responsiveness to platinum-based chemotherapy, as well as to inhibitors of poly (ADP-ribose) polymerase (PARP), owing to the ability of these interventions to inhibit DNA repair pathways.

BRCA1/2 germline testing thus has important and expanding roles in treatment planning for subsets of patients with breast cancer. 

2. Hereditary Colorectal Cancer

Colorectal cancer is the most common cancer observed in Singaporean men. Approximately 5–10% of cases are caused by a hereditary cancer predisposition syndrome.

Colorectal cancer genetic testing minimally includes over 19 colorectal cancer susceptibility genes. Clinically, the most important of these are the genes that cause familial adenomatous polyposis (APC) and Lynch syndrome (MLH1, MSH2, MSH6, PMS2, and EPCAM). Patients with familial adenomatous polyposis have a lifetime risk of colorectal cancer above 90%, while patients with Lynch syndrome are predisposed to an increased risk of colorectal cancer (20–47% vs. general population risk of 13–17%) and endometrial cancer (10–36% vs. general population risk of 6.9%).

How to manage individuals at risk of hereditary colorectal cancer?
Carriers of a colorectal cancer susceptibility gene are recommended the following measures to detect signs of cancer early:

  • Annual colonoscopy from age 25
  • Aspirin may decrease colorectal cancer risk, as indicated by preliminary studies
  • Consider risk-reducing colectomy to reduce colorectal cancer incidence

PERSONALISED RISK MANAGEMENT

Perhaps the most important application of genetic testing is in individual cancer risk assessment. For the at-risk individual, identification of pathogenic variants in cancer predisposition genes enables risk reduction via enhanced surveillance or risk-reducing surgery.

Knowing who is at high risk allows us to intensify screening, resulting in early cancer detection and overall cost savings (Figure 3). Correspondingly, unaffected family members can avoid the inconveniences and costs of unnecessary surveillance.

GP-LED MODEL FOR SCREENING AND SURVEILLANCE

We believe that a GP-led model of surveillance for high-risk individuals poses a convenient and accessible platform for the strategies outlined above, increasing patient adherence. We support initiatives to promote multidisciplinary coordinated care, potentially through academic-community partnerships, as these are valuable opportunities to enhance care for our patients.

We welcome any interested GP partners to contact us at cgsgroup@nccs.com.sg or 6436 8000.

​THE CANCER GENETIC SERVICE (CGS) AT NCCS

CLINICAL RESEARCH

The CGS actively contributes to research on a national and international scale. We have multiple ongoing research studies to identify novel pathogenic gene variants that predispose individuals to cancer. We are also involved in health services research to understand the psychosocial impact of hereditary cancer syndromes and are exploring the use of outreach methods to improve accessibility for cancer genetics testing. Lastly, we are also interested in the design of novel drugs tailored for gene-directed targeted treatment of patients with metastatic cancer.

EDUCATION

The team at CGS are strong advocates in raising awareness and providing education to both the public and healthcare professionals. We regularly conduct public outreach programmes to educate the public on hereditary cancers. This is often done in conjunction with our annual ‘Jeans for Genes’ campaign in April to raise awareness on hereditary cancers.

We contribute knowledge through various channels which include GP education forums, multidisciplinary tumour board meetings, clinical rotation training, as well as local and international workshops, conferences and lectures.

In addition to training international aspiring genetics professionals, we are actively involved in the training of medical students, doctors and nurses – where CGS is regarded as a regional and international centre for cancer genetics training.

Medical professionals are welcome to contact us at cgsgroup@nccs.com.sg or 6436 8000 if they are interested to partner with us, find out more about our educational and training opportunities, or refer a patient or family with a cancer predisposition syndrome to any of our research programmes.


Jeanette Yuen is a Genetic Counsellor at the National Cancer Centre Singapore. She received her Masters of Genetic Counselling from the University of Sydney, where she studied the use of internet-based platforms to facilitate population screening. She has a keen interest in hereditary cancer syndromes and related health services research to improve patient outcomes through genetic counselling and testing.

GPs who would like more information on this topic, please contact Ms Yuen at jeanette.yuen.x.y.@nccs.com.sg.

Dr Chiang Jianbang is an Associate Consultant in Medical Oncology, National Cancer Centre Singapore (NCCS). He completed his internal medicine residency at Singapore General Hospital and senior residency in medical oncology at NCCS. He works with a dedicated team of geneticists and genetic counsellors in the Cancer Genetics Service at NCCS. He hopes to empower patients, family members and healthcare professionals with cancer genetics knowledge to improve personal and public health. His interests are in cancer genetics and lymphoproliferative disorders.

GPs who would like more information on this topic, please contact Dr Chiang at chiang.jianbang@singhealth.com.sg.

Associate Professor Joanne Ngeow is a Senior Consultant in Medical Oncology, National Cancer Centre Singapore (NCCS) and Associate Professor at Lee Kong Chian School of Medicine, Nanyang Technological University. She heads the NCCS Cancer Genetics Service with an academic interest in hereditary cancer syndromes and translational cancer genetics. Her current clinical and research focus revolves around understanding cancer predisposition by studying cancers clustered in families, young adults with cancers and patients with multiple or rare cancers.

GPs who would like more information on this topic, please contact Prof Ngeow at joanne.ngeow.y.y@singhealth.com.sg.

GPs can call the SingHealth Duke-NUS Genomic Medicine Centre for appointments at the following hotlines:
KK Women's and Children's Hospital: 6692 2984
National Cancer Centre Singapore: 6436 8288