Genomic Medicine

Overview

The Laboratory of Genomic Medicine is dedicated to understanding cancer predisposition by studying cancers that clustering within families, young adults and in families with multiple/rare cancer presentations. Our work aims to uncover the genetic factors that increase inherited cancer risk and translate these discoveries into improved clinical care. By integrating clinical genetics, genomics research, and health services research, we connect laboratory discovery to real‑world clinical impact.

Research Areas

Our research centres on both inherited (germline) and somatic mutations that contribute to cancer susceptibility syndromes and rare hereditary disorders. Using state-of-the-art sequencing technologies, we investigate causal sequence variants in the DNA from inherited cells of at-risk individuals, in human tumour genomes, and in the genomes of model organisms. This integrated approach enables us to identify clinically meaningful variants and understand how they drive cancer development.

1. Cancer Risk Associated with Germline Mutations

We define the spectrum of cancer risk associated with inherited mutations, with direct relevance to clinical care. We have led and contributed to landmark studies that established cancer risks and second malignancy profiles associated with PTEN mutations, directly informing international surveillance recommendations for individuals with PTEN Hamartoma Tumor Syndrome (PHTS). This work formed the scientific foundation for hereditary cancer guidelines developed by ASCO, NCCN, and ESMO. In recognition of this expertise, we contribute to global standards in variant interpretation through active participation in NIH ClinGen Expert Panels, including those focused on PTEN, hereditary colorectal cancer, and endocrine cancers. Notably, we were part of the PTEN Variant Curation Expert Panel, the first cancer‑focused panel within ClinGen, where foundational curation principles were developed and subsequently adopted across multiple disease‑specific panels worldwide.

2. Variant Curation and Functional Genomics

Improving genetic variant interpretation is a core component of our research. In addition to long‑standing leadership roles within ClinGen Variant Curation Expert Panels, our team conducts functional genomics studies to resolve Variant of Unknown Significance (VUS). A key example is our work on BAP1 variants, where functional assays in patient‑derived cell lines were used to distinguish pathogenic from benign variants. Our strength lies in translating clinical observations directly into laboratory investigation, ensuring that functional data have immediate relevance for affected families while also contributing to global variant databases and clinical practice.

3. Hereditary Cancer Genomics in Asia

A central theme of our research is defining the genetic epidemiology of hereditary cancers in Singapore and across Asia. Through systematic clinical and genomic studies, we have characterised inherited predisposition to breast, ovarian, and endometrial cancers, as well as soft tissue sarcomas. These studies have filled critical data gaps for Asian populations and have directly informed Singapore Cancer Network guidelines and national healthcare policy. We play a leading role in population genomics as a Lead Principal Investigator of the Health for Life in Singapore (HELIOS) study, a flagship initiative involving 100,000 Singaporeans. This platform enables large‑scale assessment of medically actionable genetic variants and population‑specific allele frequencies, strengthening variant interpretation locally and internationally.

4. Molecular Mechanisms of Cancer Predisposition in Asia

Since 2010, we have led a prospective cohort study titled "Molecular Mechanisms for Cancer Predisposition in Asia," comprising over 7,000 patients and families evaluated through the Cancer Genetics Service at the National Cancer Centre Singapore. This programme is supported by a comprehensive biorepository with samples from more than 4,000 individuals, including blood, serum/plasma, PBMCs, and lymphoblastoid cell lines, representing one of the most extensive hereditary cancer resources in Asian populations. This cohort has enabled detailed characterisation of familial and hereditary cancer spectra and has served as the foundation for multiple high‑impact publications. It also allows rapid initiation of translational and mechanistic studies, supported by strong international collaborations through consortia such as CIMBA, kConFab, and ENIGMA.

5. Long-Read Sequencing to Close the Diagnostic Gap in Hereditary Cancer

Many individuals with strong family histories of cancer and possible hereditary cancers remain resolved, despite genetic testing, because current methods can miss genetic changes. Current short-read sequencing can fail to detect large deletions, duplications, rearrangements, and variants hidden in repetitive DNA regions or challenging regions within genes. Long-read sequencing offers a solution by reading much longer stretches of DNA, allowing detection of variants that short-read sequencing cannot find. This technology can identify missing or extra sequences in BRCA1, BRCA2, and other hereditary cancer genes, and discover hidden mutations that disrupt normal gene function. Long-read sequencing also analyses difficult genes like PMS2 that have nearly identical copies elsewhere in the genome, making them impossible to assess accurately with current methods. This research study will determine whether long-read sequencing can reduce the diagnostic gap in hereditary cancer, improving clinical management decisions for patients and their families with hereditary cancer predisposition.

6. Cancer Risk Prediction Model Using Multi-Modal Data

Early cancer detection through screening can substantially improve treatment outcomes and disease management. However, population-wide screening strategies based primarily on age and gender place increasing pressure on healthcare systems, particularly in rapidly aging Asian populations. This project aims to develop an AI-based cancer risk prediction model that identifies high-risk individuals among cancer-free populations by integrating multimodal data, including sociodemographic, lifestyle and behavioural data, clinical biomarkers, and genomic information. The project seeks to enable more precise risk stratification and support data-driven prioritisation of cancer screening programmes.

7. Investigating Germline Predisposition in Childhood Cancers and Soft Tissue Sarcomas

Childhood cancers and soft tissue sarcomas are rare malignancies that may arise from inherited genetic susceptibility, yet many patients remain genetically unresolved despite current genomic testing approaches. This project investigates germline predisposition in Singaporean childhood cancer and sarcoma cohorts using whole genome sequencing, rare variant analyses, and population-specific genomic data from SG10K to improve variant interpretation in Asian populations. The project also explores graph-based pangenome approaches to enhance detection of variants in difficult-to-map genomic regions and clinically relevant genes that are challenging to resolve using conventional reference genomes. Through the integration of statistical methods, small variant and structural variant analyses, this research aims to identify novel susceptibility genes and improve diagnostic yield for rare cancers.

8. Health Economics and Health Services Research in Hereditary Cancer

Translating genetic testing into national policy requires evidence on clinical benefit, value for money, real-world impact on patients and families, and system-level feasibility. Our programme generates this evidence spanning genetic testing strategies, service delivery, and patient and caregiver outcomes. We developed cost-utility and budget-impact models to compare germline testing strategies for Lynch syndrome (LS) and Hereditary Breast and Ovarian Cancer Syndrome (HBOC), and to evaluate risk-stratified alternatives such as nomogram-based screening. Findings from these models have been submitted to Singapore's Agency for Care Effectiveness to inform national deliberations on subsidising germline genetic testing for hereditary cancer. To address system-level feasibility, we are building system dynamics models of LS and HBOC care that capture workforce capacity, referral bottlenecks, and resource allocation upstream and downstream of testing. To capture real-world impact on patients and families, we are conducting a prospective longitudinal cohort study at the National Cancer Centre Singapore, enrolling over 2,000 patients and caregivers across 19 cancer types. The study measures health-related quality of life, productivity loss, return-to-work, and caregiver burden, providing Singapore-specific data previously unavailable. Alongside these, our group contributes to the international evidence base through systematic reviews and global scoping reviews on cancer genetic testing, screening, service uptake, and patient outcomes.

Cancer Genetics Service

The Cancer Genetics Service (CGS), through the Laboratory of Genomic Medicine, is the clinical arm of the Inherited Cancer and Rare Disease Translational Research Programme at NCCS. CGS is committed to serving as a national centre of expertise in genetic and genomic medicine. Clinical care and research directly inform each other, encompassing:

• Expert genetic risk assessment and counselling
• Genetic and Genomic testing
• Patient education and support

Our integrated model ensures that research discoveries directly inform patient care, while clinical insights drive new research questions.

Current Projects

Selected Publications

1. Ngeow J^. United by Unique: reimagining future cancer care through precision health and prevention. Singapore Medical Journal 67(2):p 109-110, February 2026. | DOI: 10.4103/singaporemedj.SMJ-2026-081 (IF: 3.3)
2. Fitriyah NH, Yuen J, Chua ZY, Ngeow J^, Benvenuti D^. Investigating narrative styles in animated patient stories to increase public awareness and genetic literacy in a multiethnic Asian population. Patient Educ Couns. 2026 Apr;145:109480. doi: 10.1016/j.pec.2026.109480. Epub 2026 Jan 12. PMID: 41564567. (IF: 3.1)
3. Saxena A, Phay R, Chiang J, Wong FY, Yuen J, Ishak D, Tasnim S, Ngeow J^. Does financial subsidy equalise cancer genetic testing uptake across socioeconomic groups? A retrospective observational study in Singapore. BMJ Open. 2025 Dec 5;15(12):e107513. doi: 10.1136/bmjopen-2025-107513. PMID: 41360469; PMCID: PMC12684128. (IF: 2.4)
4. Fok RW, Lim SW, Letchimy D, Chiang J, Yuen J, Lim TQ, Chua ZY, Liong SZ, Yang GM, Tan NC, Lee ES, Ngeow J^. Assessing the Feasibility and Acceptability of a Colorectal Cancer Risk Prediction Tool in Primary Care to Increase Screening Uptake in Singapore: A Multi-Methods Pilot Study. J Prim Care Community Health. 2025 Jan-Dec;16:21501319251397205. doi: 10.1177/21501319251397205. Epub 2025 Dec 11. PMID: 41382976; PMCID: PMC12701228. (IF: 2.7)
5. Yuen J, Li ST, Courtney EK, Karthikeyan M, Scriven T, Binte Ishak ND, Goh HX, Lim T, Zhang Z, Chiang J, Kanesvaran R, Dent R, Ngeow J^. Inefficiencies in precision medicine: can genetic counsellors (GC) be the solution? The experience from the first GC-led cancer genetics service in Asia. J Med Genet. 2025 Nov 21;62(12):776-782. doi: 10.1136/jmg-2025-110995. PMID: 40908109. (IF: 3.7)
6. Tan YY, Tasnim S, Fadzil MFB, Ng XR, Wong SK, Manski-Nankervis JE, Sung JJ, Ngeow J^. Risk-based screening programmes for cancer diagnosis: A systematic review with narrative synthesis. Ann Acad Med Singap. 2025 Oct 7;54(10):644-663. doi: 10.47102/annals-acadmedsg.202598. PMID: 41197028. (IF: 8.7)
7. Ngeow J^, Chiang J, Astiazaran-Symonds E, Balmaña J, Cass I, Kommoss FKF, Foulkes WD, James PA, Katcher A, Klugman S, Livinski AA, Mak JS, Voian N, Wick MJ, Tischkowitz M, Pal T, Stewart DR, Hanson H; ACMG Professional Practice and Guidelines Committee. Management of individuals with heterozygous germline pathogenic variants in RAD51C, RAD51D, and BRIP1: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2025 Nov;27(11):101557. doi: 10.1016/j.gim.2025.101557. Epub 2025 Oct 7. PMID: 41070818; PMCID: PMC12862869. (IF: 6.2)
8. Goshayeshi L, Eu EW, Ramesar R, Goldberg P, Tan YB, Algar U, Manisekaran RG, Li ST, Caeser R, Boutall A, Goshayeshi L, Monahan KJ, Ngeow J. Comparative insight: hereditary colorectal cancer registries in Iran, Singapore, and South Africa. Fam Cancer. 2025 Sep 5;24(4):70. doi: 10.1007/s10689-025-00494-4. PMID: 40911264. (IF: 2.3)
9. Lim A, Chua ZY, Loh C, Suresh PD, Yuen J, Kartikeyan M, Zewen Z, Chiang J, Koh MJA, Fong NWY, Tan ES, Ngeow J^. Identifying the unmet needs of patients with neurofibromatosis type 1 in Singapore. J Med Genet. 2025 Jun 4:jmg-2025-110702. doi: https://doi.org/10.1136/jmg-2025-110702. Epub ahead of print. PMID: 40467291. (IF 3.7)
10. Soon JJH, Wu J, Ishak NDB, See WQ, Dorosan M, Yuen J, Tan AWL, Ong MEH, Lam SSW, Wee HL, Chiang J, Ngeow J^. Leveraging Electronic Health Records to Examine the Real-World Rates of Cancer Genetics Referrals in a Singapore Health Care Cluster. JCO Oncol Pract. 2026 Jan;22(1):91-99. doi: 10.1200/OP-24-00858. Epub 2025 Apr 15. PMID: 40233285; PMCID: PMC12815468. (IF: 4.7)
11. Que FVF, Ishak NDB, Li ST, Yuen J, Shaw T, Goh HX, Zhang Z, Chiang J, Yeo SY, Chew LL, Thng CH, Ngeow J^. Utility of Whole-Body Magnetic Resonance Imaging Surveillance in Children and Adults With Cancer Predisposition Syndromes: A Retrospective Study. JCO Precis Oncol. 2025 Mar;9:e2400642. doi: 10.1200/PO-24-00642. (IF: 5.3)
12. Nguyen T, Bora N, JYe J, Chong S.T, Sutopo R.C, Mu Y, Ngeow J^. In-silico and in-vitro mutational analysis to investigate the structure and pathogenicity of POT1 missense variants. NAR Molecular Medicine. 2025, 2; ugaf004. Doi: 10.1093/narmme/ugaf004 (IF: 16.1)
13. Yuen J, Zhou S, Caeser R, Venkatramani M, Bte Ishak DN, Li ST, Zhang Z, Chiang J, Chan SH, Ngeow J^. Multi-locus inherited neoplasia alleles syndromes in cancer: implications for clinical practice. Eur J Hum Genet. 2025 Mar;33(3):289-296. doi: 10.1038/s41431-025-01785-1. (IF: 4.6)
14. Chiang J, Chua Z, Chan JY, Sule AA, Loke WH, Lum E, Ong MEH, Graves N, Ngeow J^. Strategies to improve implementation of cascade testing in hereditary cancer syndromes: a systematic review. NPJ Genom Med. 2024 Apr 3;9(1):26. doi: 10.1038/s41525-024-00412-0. (IF: 4.8)
15. Ho WK, Hassan NT, Yoon SY, Yang X, Lim JMC, Binte Ishak ND, Ho PJ, Wijaya EA, Ng PP, Luccarini C, Allen J, Tai MC, Chiang J, Zhang Z, See MH, Thong MK, Woo YL, Dunning AM, Hartman M, Yip CH, Mohd Taib NA, Easton DF, Li J, Ngeow J^, Antoniou AC^, Teo SH^. Age-specific breast and ovarian cancer risks associated with germline BRCA1 or BRCA2 pathogenic variants - an Asian study of 572 families. Lancet Reg Health West Pac. 2024 Feb 5;44:101017. doi: 10.1016/j.lanwpc.2024.101017. (IF:8.1)
16. Chiang J, Ngeow J^. Challenges with mainstreaming genetic testing for metastatic prostate cancer treatment in Singapore. Official Journey of the Academy of Medicine, Singapore, 52(3), 111–113. (IF 8.7)
17. Ishak ND, Shaw T, Li ST, Yuen J, Goh HX, Chua ZY, Suresh P, Que FVF, Zhang Z, Chiang J, Ngeow J^. Cancer patients' experience of receiving variant of uncertain significance results: An Asian perspective. Journal of Genetic Counseling. (IF 2.7)
18. Kolinjivadi AM, Chong ST, Choudhary R, Sankar H, Chew EL, Yeo C, Chan SH, Ngeow J^. Functional analysis of germline RAD51C missense variants highlight the role of RAD51C in replication fork protection. Hum Mol Genet. 2023 Apr 6;32(8):1401-1409. doi: 10.1093/hmg/ddac281. (IF: 3.2)
19. Chan SH, Bylstra Y, Teo JX, Kuan JL, Bertin N, Gonzalez-Porta M, Hebrard M, Tirado-Magallanes R, Tan JHJ, Jeyakani J, Li Z, Chai JF, Chong YS, Davila S, Goh LL, Lee ES, Wong E, Wong TY; SG10K_Health Consortium; Prabhakar S, Liu J, Cheng CY, Eisenhaber B, Karnani N, Leong KP, Sim X, Yeo KK, Chambers JC, Tai ES, Tan P, Jamuar SS, Ngeow J^, Lim WK^. Analysis of clinically relevant variants from ancestrally diverse Asian genomes. Nat Commun. 2022 Nov 5;13(1):6694. doi: 10.1038/s41467-022-34116-9. (IF: 17.7)
20. Chan SH, Ni Y, Li ST, Teo JX, Ishak NDB, Lim WK, Ngeow J^. Spectrum of Germline Mutations Within Fanconi Anemia-Associated Genes Across Populations of Varying Ancestry. JNCI Cancer Spectr. 2021 Jan 5;5(1):pkaa117. doi: 10.1093/jncics/pkaa117.
21. Chiang J, Chia TH, Yuen J, Shaw T, Li ST, Binte Ishak ND, Chew EL, Chong ST, Chan SH, Ngeow J. Impact of Variant Reclassification in Cancer Predisposition Genes on Clinical Care. JCO Precis Oncol. 2021 Nov;5:577-584. doi: 10.1200/PO.20.00399. (IF: 4.9)
22. Shaw T, Chan SH, Teo JX, Chong ST, Li ST, Courtney E, Ishak D, Sankar H, Ang ZLT, Chiang J, Loh M, Zhou L, Lee SC, Yeh HY, Kolinjivadi AM, Lim WK, Ngeow J. Investigation into the origins of an ancient BRCA1 founder mutation identified among Chinese families in Singapore. Int J Cancer. 2021 Feb 1;148(3):637-645. doi: 10.1002/ijc.33241. Epub 2020 Aug 21. PMID: 32745242. (IF: 4.7)
23. Courtney E, Chok AK, Ting Ang ZL, Shaw T, Li ST, Yuen J, Ngeow J. Impact of free cancer predisposition cascade genetic testing on uptake in Singapore. NPJ Genom Med. 2019 Sep 13;4:22. doi: 10.1038/s41525-019-0096-5. PMID: 31531230; PMCID: PMC6744424. (IF: 5.7)
24. Yuen J, Lee SY, Courtney E, Lim J, Soh H, Li ST, Chen Y, McAllister M, Fenwick EK, Ngeow J^. Evaluating empowerment in genetic counseling using patient‐reported outcomes. Clinical Genetics, 97(2), 246–256. (IF 4.1)
25. Toh MR, Low CE, Chong ST, Chan SH, Ishak NDB, Courtney E, Kolinjivadi AM, Rodrigue A, Masson J-Y, Ngeow J^. Missense PALB2 germline variant disrupts nuclear localization of PALB2 in a patient with breast cancer. Familial Cancer, 19(2), 123–131. (IF 1.9)