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

Abstract 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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7aa2118e78dc497482f0ca5b1ba90ee5
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spelling	oai:doaj.org-article:7aa2118e78dc497482f0ca5b1ba90ee52021-12-02T16:26:30ZPrevalence of cancer susceptibility variants in patients with multiple Lynch syndrome related cancers10.1038/s41598-021-94292-42045-2322https://doaj.org/article/7aa2118e78dc497482f0ca5b1ba90ee52021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94292-4https://doaj.org/toc/2045-2322Abstract 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.Yoon Young ChoiSu-Jin ShinJae Eun LeeLisa MadlenskySeung-Tae LeeJi Soo ParkJeong-Hyeon JoHyunki KimDaniela NachmansonXiaojun XuSung Hoon NohJae-Ho CheongOlivier HarismendyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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 Prevalence of cancer susceptibility variants in patients with multiple Lynch syndrome related cancers
description	Abstract 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.
format	article
author	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
author_facet	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
author_sort	Yoon Young Choi
title	Prevalence of cancer susceptibility variants in patients with multiple Lynch syndrome related cancers
title_short	Prevalence of cancer susceptibility variants in patients with multiple Lynch syndrome related cancers
title_full	Prevalence of cancer susceptibility variants in patients with multiple Lynch syndrome related cancers
title_fullStr	Prevalence of cancer susceptibility variants in patients with multiple Lynch syndrome related cancers
title_full_unstemmed	Prevalence of cancer susceptibility variants in patients with multiple Lynch syndrome related cancers
title_sort	prevalence of cancer susceptibility variants in patients with multiple lynch syndrome related cancers
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/7aa2118e78dc497482f0ca5b1ba90ee5
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Prevalence of cancer susceptibility variants in patients with multiple Lynch syndrome related cancers

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