NTHL1 is a recessive cancer susceptibility gene

Anna K. Nurmi; Liisa M. Pelttari; Johanna I. Kiiski; Sofia Khan; Mika Nurmikolu; Maija Suvanto; Niina Aho; Tiina Tasmuth; Eija Kalso; Johanna Schleutker; Anne Kallioniemi; Päivi Heikkilä; FinnGen

doi:10.1038/s41598-023-47441-w

NTHL1 is a recessive cancer susceptibility gene

Anna K. Nurmi, Liisa M. Pelttari, Johanna I. Kiiski, Sofia Khan, Mika Nurmikolu, Maija Suvanto, Niina Aho, Tiina Tasmuth, Eija Kalso, Johanna Schleutker, Anne Kallioniemi, Päivi Heikkilä, FinnGen

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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Abstract

In search of novel breast cancer (BC) risk variants, we performed a whole-exome sequencing and variant analysis of 69 Finnish BC patients as well as analysed loss-of-function variants identified in DNA repair genes in the Finns from the Genome Aggregation Database. Additionally, we carried out a validation study of SERPINA3 c.918-1G>C, recently suggested for BC predisposition. We estimated the frequencies of 41 rare candidate variants in 38 genes by genotyping them in 2482–4101 BC patients and in 1273–3985 controls. We further evaluated all coding variants in the candidate genes in a dataset of 18,786 BC patients and 182,927 controls from FinnGen. None of the variants associated significantly with cancer risk in the primary BC series; however, in the FinnGen data, NTHL1 c.244C>T p.(Gln82Ter) associated with BC with a high risk for homozygous (OR = 44.7 [95% CI 6.90–290], P = 6.7 × 10^–5) and a low risk for heterozygous women (OR = 1.39 [1.18–1.64], P = 7.8 × 10^–5). Furthermore, the results suggested a high risk of colorectal, urinary tract, and basal-cell skin cancer for homozygous individuals, supporting NTHL1 as a recessive multi-tumour susceptibility gene. No significant association with BC risk was detected for SERPINA3 or any other evaluated gene.

Original language	English
Article number	21127
Journal	Scientific Reports
Volume	13
Issue	1
Number of pages	14
ISSN	2045-2322
DOIs	https://doi.org/10.1038/s41598-023-47441-w
Publication status	Published - Dec 2023
Externally published	Yes

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@article{881682cb68b0475bacb37db861eed56c,

title = "NTHL1 is a recessive cancer susceptibility gene",

abstract = "In search of novel breast cancer (BC) risk variants, we performed a whole-exome sequencing and variant analysis of 69 Finnish BC patients as well as analysed loss-of-function variants identified in DNA repair genes in the Finns from the Genome Aggregation Database. Additionally, we carried out a validation study of SERPINA3 c.918-1G>C, recently suggested for BC predisposition. We estimated the frequencies of 41 rare candidate variants in 38 genes by genotyping them in 2482–4101 BC patients and in 1273–3985 controls. We further evaluated all coding variants in the candidate genes in a dataset of 18,786 BC patients and 182,927 controls from FinnGen. None of the variants associated significantly with cancer risk in the primary BC series; however, in the FinnGen data, NTHL1 c.244C>T p.(Gln82Ter) associated with BC with a high risk for homozygous (OR = 44.7 [95% CI 6.90–290], P = 6.7 × 10–5) and a low risk for heterozygous women (OR = 1.39 [1.18–1.64], P = 7.8 × 10–5). Furthermore, the results suggested a high risk of colorectal, urinary tract, and basal-cell skin cancer for homozygous individuals, supporting NTHL1 as a recessive multi-tumour susceptibility gene. No significant association with BC risk was detected for SERPINA3 or any other evaluated gene.",

author = "Nurmi, {Anna K.} and Pelttari, {Liisa M.} and Kiiski, {Johanna I.} and Sofia Khan and Mika Nurmikolu and Maija Suvanto and Niina Aho and Tiina Tasmuth and Eija Kalso and Johanna Schleutker and Anne Kallioniemi and P{\"a}ivi Heikkil{\"a} and Aarno Palotie and Mark Daly and Bridget Riley-Gillis and Howard Jacob and Dirk Paul and Slav{\'e} Petrovski and Heiko Runz and Sally John and George Okafo and Nathan Lawless and Heli Salminen-Mankonen and Robert Plenge and Joseph Maranville and Mark McCarthy and Ehm, {Margaret G.} and Kirsi Auro and Simonne Longerich and Anders M{\"a}larstig and Katherine Klinger and Clement Chatelain and Matthias Gossel and Karol Estrada and Robert Graham and Robert Yang and Chris O{\textquoteright}Donnell and M{\"a}kel{\"a}, {Tomi P.} and Jaakko Kaprio and Petri Virolainen and Antti Hakanen and Terhi Kilpi and Markus Perola and Jukka Partanen and Anne Pitk{\"a}ranta and Taneli Raivio and Hao Chen and Aoxing Liu and Shuang Luo and FinnGen",

year = "2023",

month = dec,

doi = "10.1038/s41598-023-47441-w",

language = "English",

volume = "13",

journal = "Scientific Reports",

issn = "2045-2322",

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T1 - NTHL1 is a recessive cancer susceptibility gene

AU - Nurmi, Anna K.

AU - Pelttari, Liisa M.

AU - Kiiski, Johanna I.

AU - Khan, Sofia

AU - Nurmikolu, Mika

AU - Suvanto, Maija

AU - Aho, Niina

AU - Tasmuth, Tiina

AU - Kalso, Eija

AU - Schleutker, Johanna

AU - Kallioniemi, Anne

AU - Heikkilä, Päivi

AU - Palotie, Aarno

AU - Daly, Mark

AU - Riley-Gillis, Bridget

AU - Jacob, Howard

AU - Paul, Dirk

AU - Petrovski, Slavé

AU - Runz, Heiko

AU - John, Sally

AU - Okafo, George

AU - Lawless, Nathan

AU - Salminen-Mankonen, Heli

AU - Plenge, Robert

AU - Maranville, Joseph

AU - McCarthy, Mark

AU - Ehm, Margaret G.

AU - Auro, Kirsi

AU - Longerich, Simonne

AU - Mälarstig, Anders

AU - Klinger, Katherine

AU - Chatelain, Clement

AU - Gossel, Matthias

AU - Estrada, Karol

AU - Graham, Robert

AU - Yang, Robert

AU - O’Donnell, Chris

AU - Mäkelä, Tomi P.

AU - Kaprio, Jaakko

AU - Virolainen, Petri

AU - Hakanen, Antti

AU - Kilpi, Terhi

AU - Perola, Markus

AU - Partanen, Jukka

AU - Pitkäranta, Anne

AU - Raivio, Taneli

AU - Chen, Hao

AU - Liu, Aoxing

AU - Luo, Shuang

AU - FinnGen

PY - 2023/12

Y1 - 2023/12

N2 - In search of novel breast cancer (BC) risk variants, we performed a whole-exome sequencing and variant analysis of 69 Finnish BC patients as well as analysed loss-of-function variants identified in DNA repair genes in the Finns from the Genome Aggregation Database. Additionally, we carried out a validation study of SERPINA3 c.918-1G>C, recently suggested for BC predisposition. We estimated the frequencies of 41 rare candidate variants in 38 genes by genotyping them in 2482–4101 BC patients and in 1273–3985 controls. We further evaluated all coding variants in the candidate genes in a dataset of 18,786 BC patients and 182,927 controls from FinnGen. None of the variants associated significantly with cancer risk in the primary BC series; however, in the FinnGen data, NTHL1 c.244C>T p.(Gln82Ter) associated with BC with a high risk for homozygous (OR = 44.7 [95% CI 6.90–290], P = 6.7 × 10–5) and a low risk for heterozygous women (OR = 1.39 [1.18–1.64], P = 7.8 × 10–5). Furthermore, the results suggested a high risk of colorectal, urinary tract, and basal-cell skin cancer for homozygous individuals, supporting NTHL1 as a recessive multi-tumour susceptibility gene. No significant association with BC risk was detected for SERPINA3 or any other evaluated gene.

AB - In search of novel breast cancer (BC) risk variants, we performed a whole-exome sequencing and variant analysis of 69 Finnish BC patients as well as analysed loss-of-function variants identified in DNA repair genes in the Finns from the Genome Aggregation Database. Additionally, we carried out a validation study of SERPINA3 c.918-1G>C, recently suggested for BC predisposition. We estimated the frequencies of 41 rare candidate variants in 38 genes by genotyping them in 2482–4101 BC patients and in 1273–3985 controls. We further evaluated all coding variants in the candidate genes in a dataset of 18,786 BC patients and 182,927 controls from FinnGen. None of the variants associated significantly with cancer risk in the primary BC series; however, in the FinnGen data, NTHL1 c.244C>T p.(Gln82Ter) associated with BC with a high risk for homozygous (OR = 44.7 [95% CI 6.90–290], P = 6.7 × 10–5) and a low risk for heterozygous women (OR = 1.39 [1.18–1.64], P = 7.8 × 10–5). Furthermore, the results suggested a high risk of colorectal, urinary tract, and basal-cell skin cancer for homozygous individuals, supporting NTHL1 as a recessive multi-tumour susceptibility gene. No significant association with BC risk was detected for SERPINA3 or any other evaluated gene.

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DO - 10.1038/s41598-023-47441-w

M3 - Journal article

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AN - SCOPUS:85178178393

SN - 2045-2322

VL - 13

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 21127

ER -

NTHL1 is a recessive cancer susceptibility gene

Abstract

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