Multi-ancestry sequencing analysis in 293,141 participants identifies predisposition DNA repair genes associated with HCC risk.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Garofalo Alexis M, Chotiprasidhi Perapa, Johnson Josephine Princy, Sato-Espinoza Karina, Ma Jun, Miller Hunter, O'Brien Daniel, Guare Lindsay, Cardone Katie M, Palmiero Nicole, Rodriguez Zachary, Kaplan David E, Lynch Julie A, Tsao Philip S, Rader Daniel J, Roberts Lewis R, Debes Jose D, Odeghe Emuobor, Lesi Funmilayo, Oyeleke Ganiyat, Mattos Ângelo Z, Arrese Marco, Carrera Enrique, Prieto Jhon, Boonstra Andre, Diaz-Ferrer Javier, Okeke Edith N, Wang Jun, Hou Lifang, Agyei-Nkansah Adwoa, Afihene Mary Yeboah, Awuku Yaw Asante, Nyanga Albert, Penn Medicine Biobank, Million Veteran Program, Mayo Clinic Biobank, Chang Kyong-Mi, Antwi Samuel O, Vujković Marijana, Verma Anurag, Wangensteen Kirk J
Аннотация
METHODS: We analyzed whole exome (WES) and whole genome sequencing (WGS) data from 2,594 HCC cases and 290,547 cancer-free controls from diverse biobanks and cohorts: Penn Medicine BioBank, All of Us, Mayo Clinic, ESCALON, and the Million Veteran Program. Participants were classified into six population groups. We focused on six DNA-repair genes previously implicated in HCC: BRCA2, BRIP1, MSH6, PMS2, CHEK2, and FANCA. Gene-level burden analyses of rare predicted loss-of-function (pLoF) and damaging missense variants were performed in European and African populations, and across all six ancestry groups.
RESULTS: In the European population, MSH6, a Lynch syndrome-associated gene, had the strongest association with HCC, with a 2.75-fold increased HCC risk at 1% minor-allele frequency (MAF) (OR= 2.75 [1.50, 5.04], P=0.001, FDR q=0.02), while PMS2, showed a nominally significant association at the same MAF threshold (OR=1.90 [1.08, 3.34], P=0.03, FDR q=0.09). Combined analysis across all populations strengthened the MSH6 finding (OR=2.53 [1.43, 4.49], P=0.001, FDR q=0.01) at a MAF of 0.1%. A significant BRCA2 association was also observed in the combined analysis at a MAF of 0.1% (OR=2.26 [1.39, 3.67], P=0.001, FDR q=0.01).
CONCLUSIONS: Rare variants in MSH6 and BRCA2 are significantly associated with increased HCC risk, revealing a previously unconfirmed role for DNA repair genes in HCC susceptibility across ancestrally diverse populations. These findings may inform genetic risk stratification and surveillance strategies.
IMPACT AND IMPLICATIONS: Rare variants in MSH6 and BRCA2 genes are associated with 2.3 to 2.8-fold higher HCC risk. These findings may warrant further evaluation of liver cancer risk in individuals with MSH6-associated Lynch syndrome or BRCA2-associated hereditary cancer syndromes.