MyHVP Newsletter | Vol. 3. | Issue 2 | Dec 2016

MyHVP Newsletter e m o i r a EduV eople Volume 03 | Issue 02 | December 2016

EducatinagltPhier Nation Towards a He

paign: m a C ss e n re a w A ia m e ss Thala ia Towards Zero Thalassem

EduVariome Program at Universiti Malaysia Medical Sciences, USM Kubang Kerian.

Malaysian Node of Human Variome Kelantan (UMK) iii. Mrs. Afizan Sharina binti Mohamad, Project through the EduVariome ProDeputy President of Kelantan Thalassaemia Socigramme provides education and human service On 6 December 2016, the Malaysian Node of the ety professionals with the knowledge, skills, and Human Variome Project (MyHVP) organised an dispositions to promote health education among EduVariome Program at Universiti Malaysia Kelan- The forum panellists discussed the importance of student community. Thalassemia awareness tan (UMK) with a participation of 200 undergrad- DNA Pre-Marriage screening and current issues on campaign is one such program to create aware- uate students. A forum entitled “Can He Marry screening tests for thalassemia in Malaysia. ness about the importance of pre-marital ge- Me? Uncovering the need for Pre-Marital Genetic netic screening among the public, especially the Screening” was held with Dr. Nik Norliza Nik Has- The first panellist, Assoc. Prof. Dr. Norsarwany youth. In Malaysia, thalassemia is considered as san, a lecturer of the School of Health Sciences, Mohamad, defined ‘thalassemia’ and explained the most common genetics disease as 1 in 20 Ma- USM Kubang Kerian, Kelantan as the moderator. the frequency of the disease among the populalaysians are carriers of the ß-thalassaemia trait. The panel of the forum were as follows: tion. She explained that marriage between carriAs such, educating the public on the importance i.

Assoc. Prof. Dr. Norsarwany Moham- ers is likely to increase by as much as 25% chances of pre-marital genetic screening and how it can ad, Medical Lecturer, Department of Pediatrics, of a child born with Thalassemia disease and 50% affect future generation is key to understanding School of Medical Sciences, USM Kubang Kerian of a child born with a carrier state. thalassemia. ii. Assoc. Prof. Dr. Rosnah Bahar, Medical Lecturer, Department of Hematology, School of | See page 3

The

Contact us: | Secretariat Office: Human Variome Project Malaysian Node & South-east Asian Node School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kota Bharu, Kelantan, Malaysia | Phone :(60) 097676543 / 6531 | Fax: (60) 097676543 | Email : myhvp@usm.my | Website: hvpmalaysia.kk.usm.my

MyHVP Newsletter

Head’s Address

Board of Editors 2016

ISSN: 2550-1747 | Volume 03 | Issue 02 | December 2016

The

Editor in Chief Professor Dr. Zilfalil Alwi

Contents

Malaysian Node of the Human Variome Project (MyHVP) was established on 9th October 2010. Since its inception, MyHVP has attracted a significant number of Malaysian clinicians, scientists, bioinformaticians and researchers to participate in this project. Recently, MyHVP received a strongly-worded statement of support from the Malaysian National Commission for UNESCO (SKUM). SKUM serves as the official link between the Government of Malaysia and UNESCO in helping to implement UNESCO’s programmes and activities in the region. MyHVP is proud to announce the funding from SKUM to implement its public engagement activities of MyHVP as part of the EduVariome program.

02 Head’s Address 06 Calendar of events 03 Report 07 Postgradu 04 When a Geneti- ate cist Writes 08 Photo Diary

The first SKUM-funded EduVariome program was carried out at Universiti Malaysia Kelantan (UMK) on 6 Dec 2016. It was attended by almost 200 undergraduate students from UMK. Another public engagement activity was the Down Syndrome’s Day at the Lion’s Club Kota Bharu.

The full report of these program is featured on page 1 and page 3.

Managing Editor Prof. Dr. Wan Zaidah Abdullah Editorial Board Members Prof. Ida Madieha binti Azmi Assoc. Prof. Dr. Muhammad Farid Johan Assoc. Prof. Dr. Endom Ismail Assoc. Prof. Dr Rosnah Bahar Dr. Nik Norliza Bt Nik Hassan Dr. Azlina bt Ahmad Annuar Mr. Abdul Halim Fikri Bin Hashim English Editor Amyzar Alwi

© 2016. All rights reserved. The information in this newsletter is provided by the Malaysian Node of the Human Variome Project (MyHVP) members including South-east Asian Node (HVPSEA Node) for educational / information purpose only. It is not a substitute for professional medical care and medical advice.

The contents express the opinions of the authors who alone are responsible for their view expressed. MyHVP does not accept any legal responsibility for their contents.

Writers, Invited!

MyHVP Newsletter is issued biannually. For the coming issue, we are going to invite the public from various fields and specialties in order to share with us, their experience in dealing with the issues of medicine or biomedicine. Writers may contribute their writing with these following criteria: 1. Length (Max. 1page A4 size, and it may be edited for our use) 2. The committee has the right to share your writing for further issues.

3. To suit the needs of the publication, and your writing won’t be returned 4. Emailed the article to myhvp@usm.my

Published by

Malaysian Node of the Human Variome Project (MyHVP) School of Medical Sciences Universiti Sains Malaysia Health Campus 16150, Kubang Kerian, Kelantan, Malaysia Tel: +6097676531 /6543 | Email: myhvp@usm.my

MyHVP is very committed in its support of the implementation of the Global Globin Challenge (GG2020). GG2020 is a global project aimed at tackling hemoglobanipathies in the low and medium income countries (LMIC) in order to apply recent developments in human genomics involving the systematic collection and sharing of variant data of the hemoglobinopathy genes. LMICS has the highest burden of these diseases and they are being left behind in a form of “genomic divide”. Developing the capacity to generate and to store quality data on variants in these countries, to be shared internationally, is imperative.

Tackling hemoglobinopathies is an ideal

entry point for these countries to develop the necessary infrastructure and expertise that can expand into other areas of health.

GG20020 started in 2014 with the first meeting held at the UNESCO headquarters in Paris. Subsequent meeting was held in Paris but we are hoping that the next GG2020 meeting will be held in Malaysia from May 16 - 17 2017. These annual meetings aim to update the GG2020 Project and to discuss the future plan of the GG2020 project. The GG2020 Challenge hopes to build an evidence base for an efficient management of local treatment, care and eventually cure for these diseases by ensuring a sufficient local capacity in genetics and genomics to deliver services in these countries.

I would like to thank the hardworking editorial board members for the publication of the seventh issue of the MyHVP Newsletter. Last but not least, I invite all academics and researchers from institutions throughout Malaysia to join us in this exciting network of collaboration on a global scale.

Thank you.

Prof. Dr. Zilfalil Alwi Head, Malaysian Node of the Human Variome Project Universiti Sains Malaysia (Health Campus)

MyHVP Newsletter | Dec 2016 | page 2

Report The forum was followed by a lively “Question and Answer” session between the panel members and students. The EduVariome program ended | Continued from page 1 with a quiz to test the students’ understanding of the issues discussed The second panellist was Assoc. Prof. Dr. Rosnah Bahar who expounded during the forum. The prize winners of the quiz each received a RM15 the treatment of thalassemia and thalassemia patient traits. She also meal voucher and a Mc Donald’s shirt sponsored by MC Donald Kota Bhaacknowledged thalassemia as a disease that burdens the patient, his ru. family and the government in the management of the disease. The cost for treatments is expensive and requires deep commitment. She strong- The EduVariome program in UMK was considered a successful start Myly recommended compulsory early screening, as early diagnosis could HVP in its effort to promote awareness-raising talk campaign about the prevent a prolonged suffering. The screening test could be performed in genetic disease of thalassemia, particularly at university level. We hope any clinic under the Malaysian Ministry of Health (MOH). If a person is a the year 2017 would reach a wider audience in our mission to make as carrier, she or he should be discouraged from marrying another a carrier. Malaysian a zero thalassemia nation.

Mrs. Afizan Sharina binti Mohamad, the Deputy President of Kelantan Thalassaemia Society shared a personal story on the burden and coping skills of thalassemia management as a carrier of thalassemia and as a mother of thalassemia patients to her daughter. Her story touched the audience emotionally as she related her daughter’s experience undergo- | Reported by Abdul Halim Fikri bin Hashim, School of Medical Sciences, Universiti Sains ing monthly treatment of blood transfusion including the cost for pur- Malaysia, Health Campus and a members of MyHVP | The Photo Diary is on page 8 chasing the iron chelation therapy.

Down Syndrome’s Day at Lions Club of Kota Bharu 17 November 2016, Lions Club of Kota Bharu Reported by Abdul Halim Fikri Hashim

School of Medical Sciences, Universiti Sains Malaysia, Health Campus and a member of MyHVP

On

17 November 2016, the Lions Club of Kota Bharu, the MyHVP and the Malaysian Society of Human Genetics (MSHG) co-organised a talk on basic human genetics and Down Syndrome at Lions Club of Kota Bharu. The talk was held in conjunction with the Community Program of Malaysian Society of Human Genetics with the Down Syndrome Centre Kota Bharu. The program was attended by 40 participants who were mostly parents of Down Syndrome students at the centre.

The program started with a welcome speech by the representative of Lions Club of Kota Bharu followed by a speech by the Head of MyHVP, Prof.

Zilfalil Alwi. The talk on basic human genetics and down syndrome was delivered by Dr. Wan Nur Amalina Wan Zakaria and Dr. Fatimah Azman from the Human Genome Centre, Universiti Sains Malaysia, Kubang Kerian.

During the talk, Dr. Fatimah explained the risk of women giving birth to a child with Down syndrome increases with age because older eggs have a greater risk of improper chromosome division. Down syndrome is a chromosomal disorder caused by an error in cell division and the most common form produces an additional third chromosome 21, or “trisomy 21”. Approximately one in every 700 babies is born with Down Syndrome, or around 6000 births per year.

Dr. Amalina added that since the risk of Down Syndrome is higher in women aged 40 years old and above, screening test known as triple test, is recommended to detect down syndrome. The mother’s blood is checked for a combination of different markers: alpha-fetoprotein (AFP), unconjugated estriol (uE3), and human chorionic gonadotropin (hCG) make up the standard tests. The screening is conducted between the 15th and 20th week of gestation, but it is most accurate between the 16th week and the 18th week.

The program concluded at mid-afternoon with a lunch meal sponsored

by MC Donald Kota Bharu. | The Photo Diary is on page 8

During the “Question and Answer” session MyHVP Newsletter |Dec 2016 | page 3

When a Geneticist Writes Gout and Ethnicity: an Association Analysis of SLC2A9 Variants.

Reported by: Dr. Wan Rohani Wan Taib Institute for Community Health Development (i-CODE), Universiti Sultan Zainal Abidin and a member of MyHVP

Gout

is an inflammatory arthritis due to the formation of monosodium urate crystals in and around articular joints leading to the degradation of osseous tissue. This metabolic disorder is characterized by chronic hyperuricaemia, a condition of elevated serum uric acid (SUA) levels (Terkeltaub, 2010). The prevalence of gouty arthritis differs according to geographic location, nationality, population characteristics and the criteria of metabolic syndrome itself. Genetic factor, together with environmental factor, is believed to play a pivotal role in the gout development. The inheritance of predisposing variant in SLC2A9 gene would increase 30-70% of risk to develop gout (Vitart V et al, 2008). Polymorphisms in this gene were observed in the association susceptibilities of gouty patients among European and Asian populations. The solute carrier family 2, which facilitates the glucose transporter member 9 (SLC2A9) gene, is located on the short (p) arm of chromosome 4. The gene is a high-affinity urate transporter and functions in renal urate reabsorption in the proximal kidney tubule (Anzai et al, 2008). SLC2A9 gene contains 12 transmembrane helices, which similar to a fructose transporter, and is known to transport both fructose and glucose (Manolescu et al, 2007).

The altered proteins offer significant focus in uric acid homeostasis. Involvement of SLC2A9 gene variants with the fractional excretion of urate and the polymorphisms in the gene is believed to affect the urate uptake and lowered urinary urate excretion.

The intronic variant of SLC2A9 (rs11942223) consistently revealed association in the Maoris, Pacific Islanders, New Zealand Caucasians with conferring susceptibility to gout (Hollis-Moffatt et al, 2009). The data was consistent with Malay datasets (p value=0.022, OR=3.542). However, this variant is said to be very rare in the Chinese, Japanese and Solomon Islanders (Tu et al, 2010, Urano et al, 2010). Hence, the effect of this gene differs amongst world populations. The association of rs3733591 (R265H) was also observed in the NZ Maori, Pacific Island and Caucasian case-control sample set (Hollis-Moffatt et 2009) and the data was consistent with the Malay population (p value=0.020, OR=4.834). In the Asia Pacific region, the effect of rs3733591 was observed in the Han Chinese, Solomon Island and Polynesian populations (Phipps-Green et al 2010). In addition to rs3733591 and rs11942223, the rs16890979 (V253I) was also investigated in which the association of this variant with the Caucasians (Li et al, 2007) was reported. Nonetheless, the minor allele of rs16890979 is rare in the Malay population with no significant association. This variant is also uncommon in Han Chinese and Japanese populations (Tu et al 2010, Urano et al 2010). Another SNP tested was rs5028843 which showed susceptibility with significant association in Malays dataset (p value=0.009, OR=4.747). The analysis of 4-marker haplotypes representing rs16890979, rs3733591, rs5028843 and rs11942223, respective-

ly showed that inheritance of the haplotype 1/2/1/1 increases the risk of gout susceptibility effect, and haplotype 1/1/1/1 gives evidence of a protective effect in Malay datasets.

The discrepancy data can be explained by population heterogeneity, the imbalance of sample size, different genetic backgrounds and the unstable gene frequency of polymorphisms thus, suggesting that the gene could have held species characteristics (Zhang et al 2016). Given the accessible proof for population heterogeneity of gout in the association of SLC2A9 variants, a larger sample size with adequately power to detect is required to verify the discrepant results among diverse ethnic populations in future research. In addition, SLC2A9 SNP markers are projected to become useful instruments in detecting risk of gout. Therefore, further research and studies on the combination between genetic and environment factors are needed to develop a better understanding of molecular pathogenesis of gouty arthritis.

References 1.

Zhang X, Yang X, Wang M et al 2016. Association between SLC2A9 (Glut9) gene polymorphisms and gout susceptibility: an update meta-analysis. Rheumatol Int 36:1157-1165.

2.

Urano W, Taniguchi A, Anzai N, Inoue E et al. 2010. Association between GLUT9 and gout in Japanese men. Ann Rheum Dis 69(5):932933.

3.

Hollis-Moffatt JE, Xu X, Dalbeth N, Merriman ME et al. 2009.

Role of the urate transporter SLC2A9 gene in susceptibility to gout in New Zealand Maori, Pacific Island and Caucasian case-control sample sets. Arthritis Rheum 60(11):3485-3492.

4.

Tu HP, Chen CJ, Tovosia S, Ko AM, Lee CH et al. 2010. Associations of a non-synonymous variant in SLC2A9 with gouty arthritis and uric acid levels in Hans Chinese subjects and Solomon Islanders. Ann Rheum Dis 69(5):887-890.

5.

Terkeltaub R. 2010. Update on gout: new therapeutic strategies and options. Nature Reviews Rheumatology 6:30-38.

6.

Li S, Sanna S, Maschio A, Busonero F, Usala G, Mulas A, Lai S, Dei M, OrrĂš M, Albai G, Bandinelli S, Schlessinger D, Lakatta E, Scuteri A, Najjar SS, Guralnik J, Naitza S, Crisponi L, Cao A, Abecasis G, Ferrucci L, Uda M, Chen WM, Nagaraja R: The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts. PLoS Genet 2007, 3:e194.

7.

Vitart V, Rudan I, Hayward C, Gray NK, Floyd J, Palmer CN, Knott SA, Kolcic I, Polasek O, Graessler J, Wilson JF, Marinaki A, Riches PL, Shu X, Janicijevic B, Smolej-Narancic N, Gorgoni B, Morgan J, Campbell S, Biloglav Z, Barac- Lauc L, Pericic M, Klaric IM, Zgaga L, Skaric-Juric T, Wild MyHVP Newsletter | Dec 2016 | page 4

When a Geneticist Writes SH, Richardson WA,Hohenstein P, Kimber CH, Tenesa A, et al: SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 2008, 40:437-442.

8.

Phipps-Green AJ, Hollis-Moffatt JE, Dalbeth N, et al. A strong role for the ABCG2 gene in susceptibility to gout in New Zealand Pacific Island and Caucasian, but not M?ori, case and control sample sets. Hum Mol Genet 2010 9.

Manolescu AR, Augustin R, Moley K et al. A highly conserved hydrophobic motif in the exofacial vestibule of fructose transporting SLC2A proteins acts and a critical determinant of their substrate selectivity. Mol Membr Biol 2007: 24 (5-6): 445-463.

Dental Stem Cell and Its Potential Applications Dr. Khairul Bariah Binti Ahmad Amin Noordin School of Dental Sciences, Universiti Sains Malaysia, Health Campus 16150 Kubang Kerian, Kelantan

The

use of stem cells in various research fields has been vastly documented due to their potential as promising therapeutic modulation for different health related problems. Mesenchymal stem cells (MSCs) are stromal cells that were reported for its therapeutic role in various clinical settings, including regeneration of injured tissues [1]. Traditionally MSCs can be found in virtually most fetal and adult tissues, and can potentially self-renew besides its capacity for multiple lineage differentiation. MSCs are usually described as plastic-adherent having fibroblast-like morphology with colony forming capacity, and rapid expansion [2]. Under specific in vivo and in vitro experimental conditions, MSCs have been identified to have multi-lineages differentiation capacity towards osteogenesis, adipogenesis and chondrogenesis lineages. They also have differentiation potential to other cell types including myocytes, cardiomyocytes, hepatocytes, and keratinocytes [3].

In 2000, Gronthos and his team reported their discovery of dental pulp stem cells (DPSCs), hence initiating the search for other dental-derived stem cells sources [4]. Dental stem cells (DSCs) are described as clonogenic, able to self-renew, and capable of differentiating into different kind of cells. DSCs originate from the embryonic source of neural crest ectomesenchyme [5], and are reported to express typical MSCs surface markers. Scientists have documented several types of DSCs which have been successfully isolated, and expanded in vitro: dental pulp stem cells (DPSCs) [4], stem cells from human exfoliated deciduous teeth (SHED) [6], periodontal ligament stem cells (PDLSCs) [7], stem cells isolated from dental follicle precursor cells (DFPCs) [8], stem cells isolated from apical papilla (SCAP) [9], gingiva [10] and stem cells derived from human natal dental pulp (hNDP) [11]. Though embryonic stem cell is vital for clinical applications due to its pluripotency, DSCs has shown promise to be manipulated for clinical applications, since their collection procedures are easily accessible, non-invasive, and most importantly, with few ethical considerations.

Amongst the DSCs, stem cells from human exfoliated deciduous teeth (SHED) have become an attractive alternative for tissue engineering (especially dental tissue engineering), and cell-based regenerative medicine therapy. The use of SHED may have advantages over the use of other stem cells from adult human teeth due to these factors: (1) Higher proliferation rate and increased cell population doublings as compared with stem cells from permanent teeth to facilitate the expansion of these cells in vitro before replantation, (2) Possible retrieval of cells from a tissue that is “disposable�, and readily accessible in young patients, i.e., exfoliated deciduous teeth, and (3) Use of inductive mixtures with different components to successfully differentiate cells in vitro and in vivo into odontoblasts, osteoblasts, chondrocytes, adipocytes and neural cells.

Many reported findings have strengthened the case for the use of SHED in dental pulp tissue engineering. When seeded in scaffolds together with Human Dermal Microvascular Endothelial Cells (HDMEC), SHED are able to form well-vascularised pulp-like tissues with morphology resembling that of a human dental pulp [12]. Using similar approach, a group of researchers showed that SHED differentiated into odontoblast-like cells, expressing three putative markers of odontoblastic differentiation (DSPP, DMP1, MEPE) [13]. Another study showed that SHED seeded in tooth slice differentiated into functional odontoblasts capable of generating new tubular dentin, as demonstrated by tetracycline staining [14]. Additionally, SHED have been shown to differentiate in functional endothelial cells by the same group.

The findings from SHED have paved way for further studies on its use, other than the use of other DSCs in tissue repair, and personalized medicine. SHED are easily obtained by non-invasive procedures, and can be isolated, cultured and expanded in vitro. | See page 6 MyHVP Newsletter |Dec 2016 | page 5

When a Geneticist Writes | Continued from page 5 SHED also has been successfully differentiated in vitro and in vivo into odontoblasts, osteoblasts, chondrocytes, adipocytes and neural cells, besides showing low immune reactions or rejection following transplantation. Furthermore, SHED have been reported for its capacity to remain undifferentiated and stable after long-term cryopreservation, hence making it easily accessible for further downstream manipulations.

References: [1] Togel F, Westenfelder C. The role of multipotent marrow stromal cells (MSCs) in tissue regeneration. Organogenesis 2011; 7(2): 96-100.

[2] Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea?pig bone marrow and spleen cells. Cell Prolif 1970; 3(4): 393-403.

[3] Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8(4): 315-7.

[4] Gronthos S, Mankani M, Brahim J, Robey PG, Shi S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America; 2000; 97(25): 13625-30.

[5] Kaukua N, Shahidi MK, Konstantinidou C, Dyachuk V, Kaucka M, Furlan A, et al. Glial origin of mesenchymal stem cells in a tooth model system. Nature 2014; 513(7519): 551-54.

[6] Miura M, Gronthos S, Zhao M, Lu B, Fisher LW, Robey PG, et al. SHED - Stem cells from human exfoliated deciduous teeth. J Dent Res. 2003;82:B305-B. [7] Seo BM, Miura M, Gronthos S, Bartold PM, Batouli S, Brahim J, et al. Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet 2004; 364(9429): 149-55.

[8] Sonoyama W, Liu Y, Yamaza T, Tuan RS, Wang S, Shi S, et al. Characterization of the apical papilla and its residing stem cells from human immature permanent teeth: A pilot study. J Endod. 2008; 34(2): 166-71.

[9] Morsczeck C, Gotz W, Schierholz J, Zellhofer F, Kuhn U, Mohl C, et al. Isolation of precursor cells (PCs) from human dental follicle of wisdom teeth. Matrix Biol. 2005;24(2):155-65.

[10] Zhang QZ, Shi SH, Liu Y, Uyanne J, Shi YF, Shi ST, et al. Mesenchymal stem cells derived from human gingiva are capable of immunomodulatory functions and ameliorate inflammation-related tissue destruction in experimental colitis (vol 183, pg 7787, 2009). J Immunol. 2010;184(3):1656-.

[11] Karaoz E, Dogan BN, Aksoy A, Gacar G, Akyuz S, Ayhan S, et al. Isolation and in vitro characterisation of dental pulp stem cells from natal teeth. Histochem Cell Biol. 2010; 133(1): 95-112.

[12] Cordeiro M.M., Dong Z., Kaneko T., Zhang Z., Miyazawa M., Shi S 2008. Dental pulp tissue engineering with stem cells from exfoliated deciduous teeth. Journal of Endodontics 34: 962-969.

[13] Casagrande L., Demarco F.F., Zhang Z., Araujo F.B., Shi S., Nor J.E 2010. Dentin-derived BMP-2 and odontoblast differentiation. Journal of Dental Research 89: 603-608.

[14] Sakai V.T., Zhang Z., Dong Z., Neiva K.G., Machado M.A., Shi S., Santos C.F., Nรถr J.E 2010. SHED differentiate into functional odontoblasts and endothelium. Journal of Dental Research 89: 791-796.

Calendar of Events 5 Feb - 7 Feb 2017 | Human Genome Meeting 2017

Barcelona, Spain 16 May - 17 May 2017 |Annual Meeting of Global Globin Challenge 2020 (GG2020) Kuala Lumpur, Malaysia 27 May - 30 May 2017 | The European Human Genetics Conference 2017

Copenhagen, Denmark

MyHVP Newsletter | Dec 2016 | page 6

Postgraduate Hereditary Colorectal Cancer: An Insight into Diagnosis and Challenges Wan Khairunnisa Wan Juhari1, Assoc. Prof. Dr Andee Dzulkarnaen Zakaria2

Department of Paediatrics, 2Department of Surgery, School of Medical Sciences, Universiti Sains Malaysia

1

It

was generally assumed that hereditary factors played no role in common cancers until a research by an American oncologist, Henry T. Lynch reported a hereditary form of colorectal cancer (Steinke et al. 2013). However, there are known genetic risk factors for many common cancers. The hereditary tumour syndromes are known to be caused by a single, highly-penetrant genetic alteration or mutation and associated with a substantially increased risk of certain tumours. At present, the diagnosis of these hereditary tumour syndromes poses particular challenges for clinical, genetic, and pathological evaluation and require specific screening measures.

Hereditary nonpolyposis cancer (HNPCC), also known as the Lynch syndrome, is said to be the most common hereditary form of colorectal cancer (Lynch et al. 2009). HNPCC is a genetic disease of autosomal dominant inheritance caused by a mutation in any one of four genes of the DNA mismatch repair (MMR) system: MLH1, MSH2, MSH6 and PMS2 genes. The prevalence in the general population is about 1 in 500, and it causes about 2% to 3% of all colorectal cancers (Steinke et al. 2013). As the mutation is usually inherited from one parent, every cell in the body initially carries both a defective copy of the gene and a fully functional copy that maintains DNA repair in cells. A cell develops a DNA repair defect only when its second copy of the gene becomes non-functional (Knudson’s two-hit hypothesis) as a result of a random mutation. The DNA repair defect causes an increase in the frequency of somatic mutations in the cell line and therefore an acceleration of malignant degeneration. However, some mutations in MMR genes whose consequences for the risk of cancer remain unclear (“unclassified variants”) are a major, and as yet known to be unresolved problem (Steinke et al. 2013).

HNPCC patients frequently develop colorectal cancer before the age of 50 (the average age at onset of disease: 45 years), and approximately one-third of patients were known to develop another HNPCC-typical tumour within 10 years (Lynch et al. 2009). In many cases, there is often an increased frequency of similar tumours in the patient’s family. The diagnosis of HNPCC involves two steps. If colorectal cancer is suspected (because a patient develops cancer at an unusually young age or because of family history), the tumour tissue is analysed for evidence of deficient mismatch repair of either micro - satellite instability or loss of mismatch repair protein expression. If such evidence is found, a genetic mutation is sought. However, the diagnosis of patients with HNPCC has become a challenging task and not always easy to identify. The factors may usually come from incomplete family history of poorly informed individuals about the disease of their relatives thus, leading to incomplete penetrance of MMR mutations. The method of identifying mismatch repair mutation in a patient was thought to depend heavily on family findings. Although the HNPCC screening itself is not yet fully established in some institutions, the realities of raising awareness for testing patients with colorectal cancer for HNPCC must be understood along with the full spectrum of carrying various strategies for establishing the diagnosis and testing family members. The enhancement of genetic testing, genetic counselling, peri-management involving multidisciplinary team such as surgery, oncology, rehabilitation and allied health team should be considered to improve the outcome and survival of patients with HNPCC. References: Steinke, V., Engel, C., Büttner, R., Schackert, H. K., Schmiegel, W. H., & Propping, P. (2013). Hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome. Dtsch Arztebl Int, 110(3), 32-8.

Lynch, H. T., Lynch, P. M., Lanspa, S. J., Snyder, C. L., Lynch, J. F., & Boland, C. R. (2009). Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clinical genetics, 76(1), 1-18.

Special Acknowledgment We would like to thank the Malaysian National Commission for UNESCO (SKUM) for supporting the Malaysian Node of the Human Variome Project (MyHVP) for EduVariome Program.

MyHVP Newsletter |Dec 2016 | page 7

Photo Diary Key events in the second half of 2016 All photograps below were taken during November - December 2016

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Photo 3 - 7

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Prof Zilfalil Alwi’s (Head of MyHVP) visit at National Research Centre, Cairo

Down Syndrome’s Day at Lion Club Kota Bharu Kelantan

The First INASHG Conference - Symposium “Recent Developments of Human Genetics: From Hopes to Reality”

EduVariome Program at Universiti Malaysia Kelantan (UMK)

8 - 9 November 2016

17 November 2016

26 - 28 November 2016

6 December 2016

Cairo, Egypt

Kelantan, Malaysia

Semarang, Indonesia

Kelantan, Malaysia MyHVP Newsletter | Dec 2016 | page 8