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Prevalence of cancer susceptibility variants in patients with multiple Lynch syndrome related cancers

 Yoon Young Choi  ;  Su-Jin Shin  ;  Jae Eun Lee  ;  Lisa Madlensky  ;  Seung-Tae Lee  ;  Ji Soo Park  ;  Jeong-Hyeon Jo  ;  Hyunki Kim  ;  Daniela Nachmanson  ;  Xiaojun Xu  ;  Sung Hoon Noh  ;  Jae-Ho Cheong  ;  Olivier Harismendy 
 SCIENTIFIC REPORTS, Vol.11(1) : 14807, 2021-07 
Journal Title
Issue Date
Adult ; Age of Onset ; Aged ; Biomarkers, Tumor / genetics* ; Colorectal Neoplasms / genetics* ; Colorectal Neoplasms, Hereditary Nonpolyposis / genetics* ; Endometrial Neoplasms / genetics* ; Female ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Loss of Function Mutation ; Male ; Microsatellite Instability ; Middle Aged ; Prevalence ; Retrospective Studies ; Stomach Neoplasms / genetics* ; Whole Exome Sequencing
Along with early-onset cancers, multiple primary cancers (MPCs) are likely resulting from increased genetic susceptibility; however, the associated predisposition genes or prevalence of the pathogenic variants genes in MPC patients are often unknown. We screened 71 patients with MPC of the stomach, colorectal, and endometrium, sequencing 65 cancer predisposition genes. A subset of 19 patients with early-onset MPC of stomach and colorectum were further evaluated for variants in cancer related genes using both normal and tumor whole exome sequencing. Among 71 patients with MPCs, variants classified to be pathogenic were observed in 15 (21.1%) patients and affected Lynch Syndrome (LS) genes: MLH1 (n = 10), MSH6 (n = 2), PMS2 (n = 2), and MSH2 (n = 1). All carriers had tumors with high microsatellite instability and 13 of them (86.7%) were early-onset, consistent with LS. In 19 patients with early-onset MPCs, loss of function (LoF) variants in RECQL5 were more prevalent in non-LS MPC than in matched sporadic cancer patients (OR = 31.6, 2.73-1700.6, p = 0.001). Additionally, there were high-confidence LoF variants at FANCG and CASP8 in two patients accompanied by somatic loss of heterozygosity in tumor, respectively. The results suggest that genetic screening should be considered for synchronous cancers and metachronous MPCs of the LS tumor spectrum, particularly in early-onset. Susceptibility variants in non-LS genes for MPC patients may exist, but evidence for their role is more elusive than for LS patients.
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1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hyunki(김현기) ORCID logo https://orcid.org/0000-0003-2292-5584
Noh, Sung Hoon(노성훈) ORCID logo https://orcid.org/0000-0003-4386-6886
Shin, Su Jin(신수진) ORCID logo https://orcid.org/0000-0001-9114-8438
Lee, Seung-Tae(이승태) ORCID logo https://orcid.org/0000-0003-1047-1415
Cheong, Jae Ho(정재호) ORCID logo https://orcid.org/0000-0002-1703-1781
Choi, Yoon Young(최윤영) ORCID logo https://orcid.org/0000-0002-2179-7851
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