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A Case of Lynch Syndrome with the Deletion of Multiple Exons of the MLH1 Gene, Detected by Next-Generation Sequencing
J Lab Med Qual Assur 2019;41:220-224
Published online December 31, 2019
© 2019 Korean Association of External Quality Assessment Service.

Jinyoung Hong1, Hyunki Kim1, Yong Sang Hong2, Woochang Lee1, Seok-Byung Lim3, Jeong-Sik Byeon4, Sail Chun1, and Won-Ki Min1

Departments of 1Laboratory Medicine, 2Oncology, 3Surgery, and 4Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Correspondence to: Woochang Lee
Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
Tel: +82-2-3010-4506 Fax: +82-2-478-0884 E-mail: wlee1@amc.seoul.kr
Received October 18, 2019; Revised November 7, 2019; Accepted November 9, 2019.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
 Abstract

A 26-year-old man underwent colonoscopy to investigate weight loss and a lesion suspi- cious of colorectal cancer was detected. He had a family history of colorectal cancer and hepatocellular carcinoma. The biopsy result of the lesion showed a well-differentiated adeno- carcinoma of the sigmoid colon and he underwent curative anterior resection of the colon. A microsatellite instability (MSI) test was performed on the resected tumor tissue specimen and it was found to be MSI-high. A next-generation sequencing (NGS)-based hereditary tumor panel test was performed on his peripheral blood to detect the causative germline variant. Neither a pathogenic variant nor a variant of uncertain significance was found in the single nucleotide variant (SNV) and small indel variant analyses. However, a copy number variation (CNV) detection algorithm identified a variant compatible with the deletion of exon 7 to exon 19 of the MLH1 gene. This finding was confirmed to be a true deletion by multiplex ligation-dependent probe amplification. Therefore, the deletion of exon 7 to exon 19 of the MLH1 gene was regarded as the causative pathogenic genetic variant for his colorectal cancer and familial genetic testing was recommended. Therefore, patients with suspected cancer syndromes, including hereditary colorectal cancer, should be tested for germline mutations including CNVs, SNVs, and indels. NGS is a technique that can simultaneously detect SNVs and CNVs and therefore, it has clinical utility for genetic testing for hereditary diseases.

Keywords : DNA copy number variation, MLH1, Next-generation sequencing
利 濡

26꽭 궓옄 솚옄媛 2媛쒖썡媛 14 kg쓽 泥댁쨷 媛먯냼媛 엳뿀쑝硫, 씠뿉 븳 寃궗瑜 쐞빐 떆뻾븳 옣궡떆寃쎌뿉꽌 빆臾명뵾遺꽑 긽遺 32 cm 遺쐞뿉꽌 醫낆뼇 쓽떖냼寃ъ씠 蹂댁뿬 議곗쭅寃궗瑜 떆뻾븯怨, 議곗쭅寃궗寃곌낵 怨좊텇솕꽑븫쑝濡 諛앺議뚮떎. 솚옄쓽 媛議깅젰뿉꽌뒗 쇅븷븘踰꾩 븘踰꾩媛 옣븫, 븷븘踰꾩媛 媛꾩븫쓣 븪 씠젰씠 엳뼱, Bethesda guideline쓣 留뚯”떆耳 Lynch syndrome씠 쓽떖릺뿀떎. 솚옄뒗 뿉뒪옄寃곗옣븫 吏꾨떒븯뿉 寃곗옣怨 吏곸옣쓽 쟾諛⑹젅젣닠쓣 떆뻾 諛쏆븯쑝硫, 젅젣맂 議곗쭅쓽 蹂묐━寃궗寃곌낵 꽑븫쑝濡 吏꾨떒릺뿀떎. 젅젣맂 꽑븫 議곗쭅뿉꽌 microsatellite instability (MSI) 寃궗瑜 떆뻾븳 寃곌낵, BAT26, D5S346, BAT25, D2S123 留덉빱뿉꽌 MSI 냼寃ъ씠 諛쒓껄릺뿀쑝硫, D17S250 留덉빱뿉꽌뒗 loss of heterozygosity 냼寃ъ씠 諛쒓껄릺뿀떎. 뵲씪꽌 솚옄쓽 MSI 寃궗寃곌낵뒗 留덉빱 5媛 以 4媛 뼇꽦쑝濡 MSI-high濡 뙋젙릺뿀떎. 꽑븫 議곗쭅쓽 硫댁뿭 議곗쭅솕븰뿼깋 寃곌낵 MLH1뿉 빐꽌뒗 쓬꽦씠뿀怨, MSH2뿉 빐꽌뒗 뼇꽦쑝濡 굹궗떎. 씠뿉 뵲씪 DNA 蹂듭젣떎닔援먯젙 (mismatch repair, MMR) 쑀쟾옄쓽 蹂씠媛 쓽떖릺뼱, 솚옄쓽 留먯큹삁븸 寃泥대 씠슜븯뿬 李⑥꽭 뿼湲곗꽌뿴 遺꾩꽍踰(next-generation sequencing, NGS)쓣 湲곕컲쑝濡 븳 쑀쟾꽦 醫낆뼇 쑀쟾옄 뙣꼸寃궗媛 씠猷⑥뼱議뚮떎(Miseq Dx; Illumina, San Diego, CA, USA). 빐떦 NGS 뙣꼸 Lynch syndrome쓽 썝씤 쑀쟾옄濡 븣젮吏 MLH1, MSH2, MSH6, PMS2瑜 룷븿븳 醫낆뼇 諛쒖깮뿉 愿뿬븯뒗 128媛쒖쓽 二쇱슂 쑀쟾옄쓽 뿊넀 뿼湲곗꽌 뿴 쟾泥대 踰붿쐞濡 븯뒗 留욎땄 젣옉 뙣꼸濡, NGS 뙣꼸寃궗寃곌낵, single nucleotide variant (SNV) 諛 옉 겕湲곗쓽 궫엯怨 寃곗떎쓣 寃異쒗븯뒗 븣怨좊━利섏뿉꽌뒗 pathogenic variant굹 variant of uncertain significance뒗 諛쒓껄릺吏 븡븯떎. 洹몃윭굹 read-depth 諛⑹떇쓣 湲곕컲쑝濡 븳 copy number variation (CNV) 寃異 븣怨좊━利(DxSeq Gene Analysis System; Dxome, Seoul, Korea)긽 3踰 뿼깋泥댁쓽 37,053,286-37,092,169 踰붿쐞, 利 NM_000249 transcript 湲곗쑝濡 MLH1 쑀쟾옄쓽 뿊넀 7 遺꽣 뿊넀 19源뚯쓽 踰붿쐞뿉꽌 normalized read depth ratio 媛 0.62濡 寃곗떎씠 쓽떖릺뒗 냼寃ъ씠 愿李곕릺뿀떎(Fig. 1). 솗씤 寃利앹쓣 쐞븯뿬 MLH1 쑀쟾옄뿉 빐 multiplex ligation-dependent probe amplification (MLPA) 寃궗瑜 떆뻾븳 寃곌낵, NGS 뙣꼸寃궗寃곌낵 룞씪븯寃 뿊넀 7遺꽣 뿊넀 19源뚯쓽 寃곗떎냼寃ъ씠 솗씤릺뿀떎(Fig. 2). 뵲씪꽌 MLH1쓽 뿊넀 7-19 寃곗떎 蹂씠媛 솚옄쓽 엫긽뼇긽怨 媛뺥븳 뿰愿꽦쓣 媛吏뒗 蹂씠濡 깮媛곷릺뼱, 솚옄 蹂몄씤뿉 븳 뒫룞쟻 媛먯떆 諛 솚옄쓽 紐⑥튇, 늻굹 諛 異뷀썑 솚옄쓽 옄뿉 븳 쑀쟾옄寃궗瑜 沅뚯쑀븯떎.

Figure 1.

Copy number loss of exon 7 to exon 19 of the MLH1 gene detected by next-generation sequencing. Abbreviation: CNV, copy number variation.


Figure 2.

Multiplex ligation-dependent probe amplification analysis of the MLH1 gene showing a deletion from exon 7 to exon 19.


怨 李

옣븫 솚옄쓽 遺遺꾩 媛議깅젰씠 뾾뒗 寃쎌슦媛 留롮쑝굹, 빟 15%-30%쓽 솚옄뱾 媛議 援ъ꽦썝뱾 以묒뿉 옣븫쓽 媛議깅젰씠 愿李곕릺硫, 씠뒗 媛議깆꽦 옣븫쓣 떆궗븯뒗 냼寃ъ씠떎[1]. 삉븳 옣븫쓽 빟 5% 젙룄뒗 留ㅼ슦 諛쒗쁽꽦씠 넂 쑀쟾꽦 蹂씠 愿젴씠 엳떎[2]. 쑀쟾꽦 옣븫쓽 쑀쟾븰뿉 븳 젙솗븳 씠빐뒗 쐞뿕援 뙆븙, 븫 媛먯떆 諛 삁諛⑹쟾왂쓽 媛쒖꽑, 뼢긽맂 吏꾨떒쟻 · 移섎즺쟻 젒洹쇰쾿쓽 媛쒕컻쓣 쐞빐 留ㅼ슦 以묒슂븯떎[2].

쑀쟾꽦 옣븫 以 媛옣 쓷븳 寃껋 Lynch syndrome쑝濡, 二쇰줈 옣븫, 寃곗옣븫 諛 뿬꽦쓽 寃쎌슦 옄沅곷궡留됱븫쓽 쐞뿕쓣 利앷 떆궓떎. Lynch syndrome DNA MMR gene쓽 寃고븿씠 쑀쟾 릺뒗 긽깭濡 쁽옱 젙由쎈릺뼱 엳떎. Lynch syndrome쓽 븫 諛쒖깮 寃쏀뼢꽦 mutL homologue 1 (MLH1), mutS homologue 2 (MSH2), MSH6, 洹몃━怨 postmeiotic segregation increased 2 (PMS2)쓽 4媛쒖쓽 二쇱슂 DNA MMR gene쓽 긽뿼깋泥 슦꽦 씠삎젒빀 germline 蹂씠뿉 쓽빐 씪뼱궃떎. 씠 蹂씠뿉 쓽빐꽌 깮꽦릺뒗 떒諛깆쭏쓽 湲곕뒫 긽떎씠 씪뼱굹怨, 궓븘엳뒗 빞깮삎 由쎌쑀쟾옄뿉 湲곕뒫 긽떎 泥댁꽭룷 룎뿰蹂씠媛 씪뼱굹硫댁꽌 MMR system뿉 寃고븿씠 씪뼱굹寃 맂떎. 씠濡 씤빐 泥댁꽦 쑀쟾옄 寃고븿씠 援먯젙릺吏 븡怨 異뺤쟻릺硫댁꽌 Lynch syndrome怨 뿰愿맂 寃껋쑝濡 븣젮吏 븫씠 諛쒖깮븯寃 맂떎. 씠윭븳 醫낆뼇뱾 쟾삎쟻쑝濡 microsatellite repeat legion쓽 tandem repeat쓽 湲몄씠 蹂솕씤 MSI瑜 굹궡寃 맂떎[3]. Lynch syndrome쓽 吏꾨떒뿉 븳 엫긽吏移⑥뿉뒗 Amsterdam criteria Bethesda guidelines for testing of colorectal tumours for microsatellite instability [4]媛 엳쑝硫, 蹂 利앸쓽 솚옄뒗 Bethesda guideline뿉 빐떦븯뿬 Lynch syndrome쑝濡 吏꾨떒븷 닔 엳뿀떎.

Lynch syndrome쓽 룊媛뒗 엫긽쟻 몴쁽삎, 醫낆뼇쓽 蹂묐━븰쟻 냼寃ш낵 쑀쟾쟻 뒪겕由щ떇 寃궗瑜 넻빐 씠猷⑥뼱吏꾨떎. 쁽옱 紐⑤뱺 옣븫 솚옄뿉寃뚯꽌 MSI 寃궗 MMR 떒諛깆쭏쓽 寃곗떎쓣 媛먯븯뒗 硫댁뿭議곗쭅솕븰뿼깋씠 슚쑉쟻씠怨 鍮꾩슜 슚怨쇱쟻씠씪뒗 洹쇨굅媛 留롮씠 엳떎[3]. 硫댁뿭議곗쭅솕븰뿼깋쓣 넻빐 뼱뼡 듅젙 MMR 쑀쟾옄媛 蹂묒쟻 蹂씠瑜 媛吏怨 엳뒗吏 쑀異뷀븷 닔 엳떎. 洹몃윭굹 Lynch syndrome쓽 젙솗븳 썝씤 뙆븙 MMR 쑀쟾옄쓽 deleterious germline variant쓽 寃異쒖쓣 넻빐 媛뒫븯誘濡 씠瑜 媛먯빐 궡뒗 뒫젰 MSI-high, 硫댁뿭議곗쭅솕븰뿼깋 냼寃 벑뿉 쓽빐 쑀쟾꽦 옣븫씠 쓽떖릺뒗 솚옄뿉寃뚯꽌 쑀쟾븰寃 궗瑜 꽑깮븷 븣 以묒슂븳 怨좊젮궗빆씠떎. 쁽옱 Lynch syndrome 怨 愿젴븯뿬 stop codon쓣 留뚮뱶뒗 nonsense 삉뒗 frameshift variant, 븘誘몃끂궛쓽 移섑솚쓣 씪쑝궎뒗 missense variant 벑씠 二쇱슂븳 蹂씠濡 蹂닿퀬릺뼱 엳쑝굹, 蹂 利앸뿉꽌 媛숈씠 MLH1MSH2 쑀쟾옄뿉꽌 겙 겕湲곗쓽 뿊넀 떒쐞쓽 寃곗떎 삉븳 蹂닿퀬릺怨 엳떎. 엫긽쟻쑝濡 Lynch syndrome쓽 뼇긽쓣 蹂댁씠硫 MSI-high 냼寃ъ쓣 蹂댁씠뒗 솚옄쓽 留롪쾶뒗 50%源뚯뿉꽌 4媛쒖쓽 二쇱슂 MMR 쑀쟾옄쓽 蹂씠瑜 寃異쒗빐 궡吏 紐삵븳떎뒗 蹂닿퀬媛 엳떎[5].

2019뀈 InSiGHT 뜲씠꽣踰좎씠뒪 湲곗쑝濡 쐞옣愿怨 븫 諛쒖깮뿉 湲곗뿬븯뒗 MMR 쑀쟾옄쓽 likely pathogenic · pathogenic 쑀쟾옄 蹂씠뒗 MLH1뿉꽌 2,868媛, MSH2뿉꽌 4,616媛, MSH6뿉꽌 1,199媛, 洹몃━怨 PMS2뿉꽌 518媛쒓 蹂닿퀬릺뼱 엳떎[6]. MLH1, MSH2, MSH6, PMS2 쑀쟾옄뿉 븳 쟾넻쟻씤 Sanger sequencing SNV 諛 쟻 닔쓽 뿼湲 寃곗떎怨 以묐났쓣 寃궗븷 닔 엳쑝굹, 蹂 利앸뿉꽌 媛숈씠 CNV濡 굹굹뒗 뿊넀 븯굹 씠긽쓽 蹂솕媛 깮湲곕뒗 겙 겕湲곗쓽 寃곗떎怨 以묐났 寃異 빐궪 닔 뾾뒗 븳怨꾩젏씠 엳떎. 蹂 利앸뿉꽌 솗吏꾧궗踰뺤쑝濡 궗 슜븳 MLPA쓽 寃쎌슦, 紐뉗떗-紐뉖갚 媛쒖쓽 뿼湲곗꽌뿴쓣 몴쟻쑝濡 븯뒗 몴吏옄瑜 궗슜븯뿬 떒씪 뿊넀 떒쐞쓽 寃곗떎怨 以묐났쓣 솗씤븯湲곗뿉 醫뗭 湲곕쾿씠굹, 궗슜븯뒗 몴吏옄쓽 媛쒖닔媛 젣븳릺뼱 엳뼱 紐뉖챺 듅젙븳 寃쎌슦뿉 궗슜씠 슜씠븯怨 genome-wide screening 뿉뒗 쟻떦븯吏 븡떎[7].

NGS瑜 씠슜븳 CNV 寃異쒖 paired-end mapping, split read, read depth, de novo assembly of a genome, 洹몃━怨 씠 젒洹쇰갑떇뱾쓽 議고빀쓽 겕寃 떎꽢 媛吏 쟾왂쓣 넻빐 씠猷⑥뼱 吏꾨떎[8]. 씠 以 蹂 利앸뿉꽌 궗슜맂 諛⑹떇 read depth 諛⑹떇씠떎. 씠寃껋 湲곕낯쟻쑝濡 留뚯빟 뼱뼚븳 쑀쟾옄媛 寃곗떎릺嫄곕굹 以묐났릺뿀떎硫, 洹 쑀쟾옄媛 genome뿉 엳뒗 떎瑜 쑀쟾옄뿉 鍮꾪빐꽌 쟻嫄곕굹 留롮 copy 닔瑜 媛吏 寃껋씠怨, sequencing씠 씪뼱궗쓣 븣 鍮꾩쑉쟻쑝濡 떎瑜 쑀쟾옄뿉 鍮꾪빐 쟻嫄곕굹 留롮 利앺룺맂 read 닔瑜 媛吏 寃껋씠씪뒗 썝由щ 湲곕컲쑝濡 븳떎. 臾쇰줎 떎 瑜 thermocycler쓽 궗슜, 떆빟쓽 蹂솕, 닔湲곗옉뾽怨 媛숈 쇅遺쟻 슂씤怨 GC content 벑쓽 궡遺쟻 슂씤뿉 쓽빐꽌 read 닔쓽 蹂솕媛 씪뼱궇 닔 엳湲 븣臾몄뿉, NGS瑜 넻븳 CNV 寃異쒖쓽 젣븳젏씠 엳쓣 닔 엳떎[9]. 洹몃윭굹 NGS뒗 Sanger sequencing 씠굹 MLPA 떖由 븳 踰덉쓽 寃궗濡 留롮 닔쓽 쑀쟾옄뿉 빐 SNV CNV瑜 screening븷 닔 엳뼱, 쑀쟾꽦 옣븫쓣 룷븿븳 뿬윭 醫낆뼇利앺썑援곗뿉꽌 썝씤 쑀쟾옄 蹂씠瑜 뙆븙븯湲곗뿉 쑀슜븳 寃궗踰뺤씠떎.

蹂 利앸뿉꽌뒗 MLH1쑀쟾옄쓽 7踰 뿊넀뿉꽌 19踰 뿊넀源뚯瑜 踰붿쐞濡 븯뒗 겕湲곌 겙 寃곗떎씠 諛쒓껄릺뿀떎. 씠 蹂씠뒗 Human Gene Mutation Database (HGMD)뿉 벑濡앸릺吏 븡 蹂씠씠굹, HGMD뿉 벑濡앸맂 1,237媛 蹂씠 以 156媛쒓 gross deletion쑝濡, 蹂 利앸 媛숈 뿊넀 떒쐞쓽 寃곗떎 MLH1 쑀쟾옄쓽 蹂묒쟻 蹂씠쓽 10% 씠긽쓣 李⑥븯怨 엳떎. 뵲씪꽌 MSI-high濡 MMR gene쓽 蹂씠媛 쓽떖릺뒗 옣븫 솚옄뿉 빐 쑀쟾쟻 寃궗瑜 떆뻾븷 븣, CNV瑜 寃異쒗븷 닔 엳뒗 寃궗踰뺤쓣 궗슜븯吏 븡쑝硫 긽떦닔쓽 솚옄뿉꽌 씠긽냼寃ъ쓣 넃爾 솗吏꾩쓣 뼱졄寃 븷 쐞뿕씠 엳떎. 삉븳 븳 뿰援ъ뿉꽌 77紐낆쓽 엫긽 쟻쑝濡 Lynch syndrome씠 쓽떖릺硫 醫낆뼇 議곗쭅뿉꽌 MSH2 떒諛깆쭏쓽 寃곗떎씠 엳뿀쑝굹, MSH2 삉뒗 MSH6쓽 蹂씠媛 諛쒓껄릺吏 븡 솚옄瑜 긽쑝濡 genome 踰붿쐞쓽 CNV 遺꾩꽍쓣 떆뻾븯쓣 븣, 깉濡쒖슫 썑蹂 쑀쟾옄쓽 媛뒫꽦씠 엳뒗 쑀쟾옄뱾쓣 諛쒓껄븷 닔 엳뿀떎뒗 蹂닿퀬媛 엳뼱[10], CNV 遺꾩꽍 媛議깆꽦 옣 醫낆뼇뿉 븳 쑀쟾쟻씤 씠빐瑜 蹂대떎 꼻엳뒗 뜲 湲곗뿬븷 닔 엳쓣 寃껋쑝濡 깮媛곷맂떎.

寃곕줎쟻쑝濡, 醫낆뼇 議곗쭅뿉 븳 MSI testing 삉뒗 硫댁뿭議곗쭅 솕븰뿼깋 寃궗 벑쓣 넻빐 쑀쟾꽦 옣븫씠 쓽떖릺뒗 솚옄뿉寃뚯꽌 썝씤 뙆븙쓣 쐞븳 쑀쟾븰寃궗瑜 떆뻾븷 븣, 諛섎뱶떆 CNV쓽 寃異쒖쓣 룷븿븯뒗 寃궗踰뺤쓣 궗슜븯뿬빞 븷 寃껋씠떎. 씠윭븳 愿젏뿉꽌 쁽옱 꼸由 떆뻾릺怨 엳뒗 NGS뒗 醫낆뼇利앺썑援곗쓣 씪쑝궎뒗 떎닔쓽 쑀쟾옄뿉 빐 SNV CNV瑜 룞떆뿉 寃궗븷 닔 엳뒗 엫긽쟻 떦꽦씠 엳뒗 寃궗踰뺤쑝濡, 쑀쟾꽦 옣븫 솚옄뿉寃뚯꽌 떆뻾씠 쟻洹뱀쟻쑝濡 怨좊젮릺뼱빞 븷 寃껋씠떎.

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