Genetic Testing for Cancer Risk: What GPs Should Know as the First Line of Defence

By Rebecca Caeser, Senior Research Fellow; Tasmyn Scriven, Genetic Counsellor; Clin Asst Prof Chiang Jianbang, Consultant; Assoc Prof Joanne Ngeow, Head & Senior Consultant, Cancer Genetics Service, Division of Medical Oncology, NCCS

11/18/2024 1:52:00 PM | Defining Med

The article is contributed/written by National Cancer Centre Singapore

Genetic testing is a crucial component of preventive care when it comes to hereditary cancers – enabling early intervention and gene-directed therapy for both patients and their families. With long-standing relationships with patients, general practitioners (GPs) are ideally placed to recognise when a patient should be referred for genetic testing. The National Cancer Centre Singapore shares what to look out for.

INTRODUCTION

Genetic testing has clinical utility in identifying carriers at increased risk of cancer and providing a genetic diagnosis of a hereditary cancer syndrome.

The options typically involve single or multigene panels depending on the personal and family history of cancer, and usually include clinically actionable genes.

ROLE OF GENETIC COUNSELLING

Due to the clinical, psychosocial, ethical and legal implications associated with genetic testing, patients considering it should receive pre-test and post-test genetic counselling from a genetics specialist/genetic counsellor.

Genetic counselling aims to simplify complex genetic information, explain the implications of a genetic test result, address concerns and discuss test results whilst promoting informed decision-making.

BENEFITS OF GENETIC TESTING FOR CANCER RISK

Genetic testing offers multiple benefits. Identification of a germline pathogenic variant can guide life-saving treatment decisions and gene-directed therapy.¹

Family members are strongly encouraged to also undergo genetic testing once a carrier is identified within a family;¹ this is called cascade testing.

In healthy individuals, this will help them understand their risk of developing cancer which can guide their screening and prophylactic options to reduce and prevent cancer.¹

Family members who are found to not have the genetic fault can then avoid unnecessary check-ups and screening, and it provides peace of mind for those with strong family histories of cancer.

IMPORTANCE OF GENETIC TESTING FOR CANCER RISK

Understanding our genetic make-up has the potential to be one of the most significant developments in clinical medicine.

Genetic testing results allow patients and at-risk family members to make proactive decisions about their health, enabling early intervention and gene-directed preventive measures.

It is therefore imperative for GPs to be able to identify and manage patients with hereditary cancer risks.

Through Singapore’s recent efforts to implement precision medicine, there is hope to create a healthier Singapore, whilst easing the burden on the healthcare system.

CASE STUDY This case study illustrates the importance of genetic counselling and subsequent genetic testing in preventive care.
Genetic counselling Ms Chua* came for a genetic counselling session at the Cancer Genetics Service (CGS) at the National Cancer Centre Singapore (NCCS) as she had been diagnosed with metachronous breast cancer under the age of 50. She has a family history of cancer – her sister and late father were diagnosed with colon cancer. The genetic counsellor explained that her personal and family history of cancer was highly suggestive of a hereditary cancer syndrome and encouraged her to undergo genetic testing. Genetic testing and results Ms Chua was concerned about the cancer risks for her two children and her siblings and decided to pursue genetic testing. Her test results confirmed that she is a carrier of a pathogenic (disease-causing) variant in her MLH1 gene, confirming a diagnosis of Lynch syndrome (LS), which explains her young cancer diagnosis and family history of cancer. This result allowed her doctors to better manage her risks for colon cancer. She had a colonoscopy soon after her diagnosis and is on close surveillance. Familial implications The genetic test result also had familial implications, as her children and siblings had a 50% chance of having the same change in their genetic information. They were offered their own testing to clarify their carrier status. Ms Chua’s youngest brother was initially sceptical as he was active and healthy and did not think these results were relevant to him. His sister and the genetic counsellor explained that genetic testing can refine his future tumour and cancer risks. Early detection for preventive care After several months, Ms Chua’s brother finally decided to proceed with genetic testing and was diagnosed with LS, after discovering he had the same genetic change as his sister. Based on the guidelines for LS, he was referred to have a baseline colonoscopy. The results of the colonoscopy showed that he had a low-grade polyp. This means that if he had delayed genetic testing further, he might have been diagnosed with colon cancer at a later date. Instead, with early detection, he is able to remain healthy and active, and continues his yearly surveillance for colon cancer. *Name has been changed to protect the privacy of the patient

CASE STUDY

This case study illustrates the importance of genetic counselling and subsequent genetic testing in preventive care.

Genetic counselling

Ms Chua* came for a genetic counselling session at the Cancer Genetics Service (CGS) at the National Cancer Centre Singapore (NCCS) as she had been diagnosed with metachronous breast cancer under the age of 50.

She has a family history of cancer – her sister and late father were diagnosed with colon cancer. The genetic counsellor explained that her personal and family history of cancer was highly suggestive of a hereditary cancer syndrome and encouraged her to undergo genetic testing.

Genetic testing and results

Ms Chua was concerned about the cancer risks for her two children and her siblings and decided to pursue genetic testing.

Her test results confirmed that she is a carrier of a pathogenic (disease-causing) variant in her MLH1 gene, confirming a diagnosis of Lynch syndrome (LS), which explains her young cancer diagnosis and family history of cancer.

This result allowed her doctors to better manage her risks for colon cancer. She had a colonoscopy soon after her diagnosis and is on close surveillance.

Familial implications

The genetic test result also had familial implications, as her children and siblings had a 50% chance of having the same change in their genetic information. They were offered their own testing to clarify their carrier status.

Ms Chua’s youngest brother was initially sceptical as he was active and healthy and did not think these results were relevant to him. His sister and the genetic counsellor explained that genetic testing can refine his future tumour and cancer risks.

Early detection for preventive care

After several months, Ms Chua’s brother finally decided to proceed with genetic testing and was diagnosed with LS, after discovering he had the same genetic change as his sister. Based on the guidelines for LS, he was referred to have a baseline colonoscopy.

The results of the colonoscopy showed that he had a low-grade polyp. This means that if he had delayed genetic testing further, he might have been diagnosed with colon cancer at a later date. Instead, with early detection, he is able to remain healthy and active, and continues his yearly surveillance for colon cancer.

*Name has been changed to protect the privacy of the patient

WHEN GPs SHOULD SUSPECT HEREDITARY CANCER AND REFER FOR GENETIC TESTING

GPs should suspect a hereditary cancer syndrome when a patient presents with the following characteristics:^2-6

A strong family history of cancer (two or more relatives with similar types or patterns of cancer, on one side of the family)
Rare tumours and/or non-malignant conditions
Younger age of cancer diagnosis compared to what is usually seen for that cancer type (aged under 60)
Multiple primary cancers over their lifetime

GPs should consult the National Comprehensive Cancer Network (NCCN) and eviQ guidelines on when to refer individuals for genetic testing.^{3, 5, 7}

Cancers that should be referred to CGS
Diagnosis: >10% 'Mendelian' contribution	Genetic loci
Retinoblastoma	RB1
Adrenocortical or choroid plexus carcinoma, hypodiploid acute lymphocytic leukaemia, anaplastic rhabdomyosarcoma	TP53
Phaeochromocytoma/paraganglioma	VHL, NF1, RET, SDHx
Retinal or cerebellar haemangioblastoma, endolymphatic sac tumour (ELST)	VHL
Optic glioma, malignant peripheral nerve sheath tumour, juvenile myelomonocytic leukaemia (JMML)	NF1
Medullary thyroid cancer	RET
Atypical teratoid/malignant rhabdoid tumour	INI1/SMARCB1
Ovarian small cell carcinoma of hypercalcaemic type	SMARCA4
Acoustic or vestibular schwannomas	NF2
Pulmonary pleuroblastoma	DICER1
Hepatoblastoma	APC

Figure 1

Suggested criteria for when GPs should refer for genetic testing
1. Hereditary breast and ovarian cancer syndrome (HBOC)	• Breast cancer diagnosed at or under 50 years of age • Triple-negative breast cancer • Multiple primary breast cancers (either in one or both breasts) • Male breast cancer • Breast cancer diagnosed at any age in an individual of Ashkenazi Jewish ancestry • Ovarian cancer (including fallopian tube cancer or peritoneal cancer) • Metastatic or high-grade prostate cancer • Pancreatic cancer • Two or more relatives on the same side of the family meeting any of the criteria above • A previously identified pathogenic (disease) causing variant in BRCA1, BRCA2 or PALB2 gene in the family
2. Lynch syndrome (LS)	• Colorectal or endometrial cancer and any of the following: 1. Diagnosis under 50 years 2. A synchronous or metachronous LS-related cancer at any age 3. One first- or second-degree relative with an LS-related cancer diagnosed under 50 years 4. ≥2 first- or second-degree relatives with an LS-related cancer at any age • A previously identified LS pathogenic variant in the family • Identification of a tumour with MMR deficiency determined by polymerase chain reaction (PCR), next-generation sequencing (NGS) or immunohistochemistry (IHC) diagnosed at any age • Family history of any of the following: 1. ≥1 first-degree relative with a colorectal or endometrial cancer diagnosed under 50 years 2. ≥1 first-degree relative with a colorectal or endometrial cancer and a synchronous or metachronous LS-related cancer at any age 3. ≥2 first- or second-degree relatives with LS-related cancer including one diagnosed under 50 years 4. ≥3 first- or second-degree relatives with LS-related cancer at any age • Increased model-predicted risk (e.g. PREMM5, MMRpro, MMR predict) for LS
3. Familial adenomatous polyposis (FAP)	• Recommend genetic testing if there is a personal history of ≥1 of the following criteria: 1. Personal history of ≥20 cumulative adenomas 2. A previously identified FAP pathogenic variant in the family 3. Multifocal/bilateral congenital hypertrophy of retinal pigment epithelium (CHRPE) 4. Family history of polyposis and family unwilling/unable to have testing • Consider genetic testing if there is a personal history of ≥1 of the following criteria: 1. Between 10-19 cumulative adenomas 2. Desmoid tumour 3. Hepatoblastoma 4. Papillary thyroid cancer 5. Unilateral CHRPE 6. Family history of polyposis

Suggested criteria for when GPs should refer for genetic testing

1. Hereditary breast and ovarian cancer syndrome (HBOC)

• Breast cancer diagnosed at or under 50 years of age

• Triple-negative breast cancer

• Multiple primary breast cancers (either in one or both breasts)

• Male breast cancer

• Breast cancer diagnosed at any age in an individual of Ashkenazi Jewish ancestry

• Ovarian cancer (including fallopian tube cancer or peritoneal cancer)

• Metastatic or high-grade prostate cancer

• Pancreatic cancer

• Two or more relatives on the same side of the family meeting any of the criteria above

• A previously identified pathogenic (disease) causing variant in BRCA1, BRCA2 or PALB2 gene in the family

2. Lynch syndrome (LS)

• Colorectal or endometrial cancer and any of the following:

1. Diagnosis under 50 years

2. A synchronous or metachronous LS-related cancer at any age

3. One first- or second-degree relative with an LS-related cancer diagnosed under 50 years

4. ≥2 first- or second-degree relatives with an LS-related cancer at any age

• A previously identified LS pathogenic variant in the family

• Identification of a tumour with MMR deficiency determined by polymerase chain reaction (PCR), next-generation sequencing (NGS) or immunohistochemistry (IHC) diagnosed at any age

• Family history of any of the following:

1. ≥1 first-degree relative with a colorectal or endometrial cancer diagnosed under 50 years

2. ≥1 first-degree relative with a colorectal or endometrial cancer and a synchronous or metachronous LS-related cancer at any age

3. ≥2 first- or second-degree relatives with LS-related cancer including one diagnosed under 50 years

4. ≥3 first- or second-degree relatives with LS-related cancer at any age

• Increased model-predicted risk (e.g. PREMM5, MMRpro, MMR predict) for LS

3. Familial adenomatous polyposis (FAP)

• Recommend genetic testing if there is a personal history of ≥1 of the following criteria:

1. Personal history of ≥20 cumulative adenomas

2. A previously identified FAP pathogenic variant in the family

3. Multifocal/bilateral congenital hypertrophy of retinal pigment epithelium (CHRPE)

4. Family history of polyposis and family unwilling/unable to have testing

• Consider genetic testing if there is a personal history of ≥1 of the following criteria:

1. Between 10-19 cumulative adenomas

2. Desmoid tumour

3. Hepatoblastoma

4. Papillary thyroid cancer

5. Unilateral CHRPE

6. Family history of polyposis

Figure 2

When to refer a patient for genetic testing for the three most common hereditary cancer syndromes in Singapore^{3, 4, 5, 7}

CANCER GENETICS SERVICE

The Cancer Genetics Service (CGS) at National Cancer Centre Singapore provides individualised cancer risk assessment, genetic counselling and testing services for a broad range of genetic and hereditary conditions. This helps tailor clinical management and treatment for the individual and paves the way towards personalised medicine.

CGS serves as a single unified platform coordinating patient care, research and education of genomic medicine.

Clinical research

CGS actively contributes to research on a national and international scale. It has multiple ongoing research studies to identify novel pathogenic gene variants that predispose individuals to cancer. It is also involved in health services research to understand the psychosocial impact of hereditary cancer syndromes, and is exploring the use of outreach methods to improve accessibility for cancer genetics testing. CGS is 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 of raising awareness and providing education to both the public and healthcare professionals. CGS regularly conducts outreach programmes to educate the public on hereditary cancers. This is often done in conjunction with its annual ‘Jeans for Genes’ campaign in April to raise awareness for such cancers.

CGS contributes 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, the service is 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.

Campaigns and events

The ‘Living with’ series of events are specially organised for patients and their families living with a hereditary cancer syndrome that predisposes them to certain cancer risks.

These events are important in facilitating support networks for patients and their families. Connecting with others facing similar challenges can provide emotional support and practical advice, improving coping mechanisms and resilience.

Our yearly Hereditary Cancer Syndrome Awareness and Family Days include:

March: Living with Lynch Syndrome
May: Living with Li-Fraumeni Syndrome
May: Living with Neurofibromatosis
October: Living with hereditary breast and ovarian cancer syndrome

10 years of delivering individualised care CGS is celebrating its 10th anniversary this year. This marks a decade of delivering individualised patient care, participating in clinical research as well as engaging in education and campaigns.

HOW GPs CAN REFER A PATIENT

To refer a patient with a cancer predisposition syndrome to any of CGS’ research programmes, partner with us or learn more about our educational and training opportunities, GPs can contact us at:

Cancer Genetics Service, National Cancer Centre Singapore
Tel: 6436 8000 / 6436 8288
Email: [email protected]

REFERENCES

Rahner N, Steinke V. Hereditary cancer syndromes. Dtsch Arztebl Int. 2008;105(41):706-14.
Nagy R, Sweet K, Eng C. Highly penetrant hereditary cancer syndromes. Oncogene. 2004;23(38):6445-70.
NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. 2020.
Vasen HFA. Progress Report: New insights into the prevention of CRC by colonoscopic surveillance in Lynch syndrome. Fam Cancer. 2022;21(1):49-56.
NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal
Ngeow J, Shaw, T., Li, S-T., Xuan, G.H., Tan, V. A GUIDE TO GENETIC TESTING FOR HEREDITARY BREAST & OVARIAN CANCER: National Cancer Centre Singapore; 2020.
Eviq Cancer Treatments Online > Cancer Genetics > Risk Management [press release]. 2021.

Rebecca Caeser
Senior Research Fellow, Cancer Genetics Service,
Division of Medical Oncology, National Cancer Centre Singapore

Rebecca Caeser is a Senior Research Fellow at the National Cancer Centre Singapore and has ten years of research experience in oncology. She received her PhD from the University of Cambridge before joining the Memorial Sloan Kettering Cancer Centre in New York as a Postdoctoral Researcher. She has a strong interest in precision health, with the aim of improving patients’ health on a population level.

Tasmyn Scriven
Genetic Counsellor, Cancer Genetics Service,
Division of Medical Oncology, National Cancer Centre Singapore

Tasmyn Scriven is a Genetic Counsellor at the National Cancer Centre Singapore. She received her Master of Science (Medicine) in Genetic Counselling at the University of Witwatersrand, South Africa. Ms Scriven has a passion for empowering patients with knowledge and psychosocial support as they navigate their cancer journey.

Clin Asst Prof Chiang Jianbang
Consultant, Division of Medical Oncology, National Cancer Centre Singapore;
SingHealth Duke-NUS Blood Cancer Centre;
SingHealth Duke-NUS Genomic Medicine Centre

Clinical Assistant Professor Chiang Jianbang is a Consultant in the Division of Medical Oncology, National Cancer Centre Singapore (NCCS). He focuses on cancer genetics in NCCS and works with a team of dedicated geneticists and genetic counsellors. He hopes to empower patients, family members and healthcare professionals with cancer genetics knowledge to improve personal and public health. His interests are in clinical cancer genetics, genomic medicine and implementation science.

Assoc Prof Joanne Ngeow
Head & Senior Consultant, Cancer Genetics Service,
Division of Medical Oncology, National Cancer Centre Singapore;
Deputy Head & Service Chief, Cancer Genetics,
SingHealth Duke-NUS Genomic Medicine Centre;
Senior Consultant, Paediatric Brain and Solid Tumour Programme & Visiting Consultant, KK Breast Centre,
KK Women’s and Children’s Hospital

Associate Professor Joanne Ngeow is a Senior Consultant in the Division of 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.

GP Appointment Hotline: 6436 8288

GPs can call scan visit the website for more information about the department.