Cancers are classified as rare when they affect less than 15 per 100,000 people per year. Despite being termed “rare”, these cancers are more common than you think! According to the National Cancer Institute (USA), rare cancers as a group account for approximately 27% of all cancers and are responsible for 25% of all cancer deaths. Rare cancers are also most commonly found amongst teenagers and younger adults – targeting a vulnerable patient population with tremendous psychosocial needs.
With fewer resources available, cultivating a deeper understanding on rare cancers has been challenging. In contrast to more common cancers, some subtypes of rare cancers may only affect single patients over several years. For example, we previously described the genetic basis for a young patient with Gitelman syndrome together with a polyposis syndrome leading to colorectal cancer (1). Finding the right treatment plan is therefore difficult as there are limited resources we can refer to. For these cancer types, there are extremely limited treatment options available. With the lack of patient samples available, there is also scarcity of animal and cell line models available for research purposes (2).
In order to tackle these issues, we recently started the STARLIGHT Initiative, a research effort for the study of rare cancers in Singapore. We aim and aspire to increase our knowledge of rare cancers by deep molecular profiling and modelling their biological behavior, and to develop means to improve patient outcomes. Using multi-sequencing platforms, we can dive deep into the genetic makeup of the cancers and understand their driving forces. By identifying the key targets, clinicians will then have a better understanding on the mechanisms of the rare cancer under study and will be able to design better treatment plans for such patients in future.
Figure 1. Mission, Vision and Values of the STARLIGHT Initiative
We recently described a rare occurrence of sarcomatoid renal cell carcinoma (sRCC) in a patient with known autosomal dominant polycystic kidney disease (ADPKD). We applied multiregion whole exome sequencing and whole transcriptomic sequencing to investigate intratumoral molecular heterogeneity. Through this work, we identified mutations shared across different histological constituents in the tumor as well as mutations unique to the individual components. We observed dichotomous evolutionary pathways in the development of epithelioid and spindle compartments, involving early mutations in TP53 and ATM/CTNNB1/NF2, respectively. Wnt, PI3K-mTOR, and MAPK signaling pathways, known key mechanisms involved in ADPKD development, featured prominently in the sarcomatoid component, thereby suggesting that common pro-oncogenic signals are present between ADPKD and sRCC (Figure 2) (3).
Figure 2. Mutational heterogeneity in a case of SRCC from ADPKD
Research plays an essential role in broadening our knowledge. It is an ongoing process which requires the collaborative efforts of not only the researchers, but with the clinicians, patients, and their families. Given its importance, we are working to expand the STARLIGHT Initiative and develop it into a national level research framework (Figure 3).
Figure 3. Framework for Rare Cancer Research
References
1. Chan JY, Toh MR, Chong ST, Ishak NDB, Kolinjivadi AM, Chan SH, Lee E, Boot A, Shao-Tzu L, Chew MH, Ngeow J. Multiple neoplasia in a patient with Gitelman syndrome harboring germline monoallelic MUTYH mutation. NPJ Genom Med. 2020 Sep 18;5:39. doi: 10.1038/s41525-020-00146-9.
2. Ng DYX, Li Z, Lee E, Kok JST, Lee JY, Koh J, Ng CC, Lim AH, Liu W, Ng SR, Lim KS, Huang XX, Hong JH, Guan P, Sim Y, Thike AA, Nasir NDM, Li S, Tan PH, Teh BT, Chan JY. Therapeutic and immunomodulatory potential of pazopanib in malignant phyllodes tumor. NPJ Breast Cancer. 2022 Apr 1;8(1):44. doi: 10.1038/s41523-022-00413-1.
3. Lee E, Guan P, Lim AH, Loh JW, Tan GF, Loh T, Ng DYX, Lee JY, Goh S, Liu W, Ng CC, Teh BT, Chan JY. Multiregion sequencing of sarcomatoid renal cell carcinoma arising from autosomal dominant polycystic kidney disease. Mol Genet Genomic Med. 2022 Mar;10(3):e1853. doi: 10.1002/mgg3.
Ms Elizabeth Lee
Research Officer, Cancer Discovery Hub
National Cancer Centre Singapore