Peer-reviewed article

A follow-up cohort study on secondary findings in cancer predisposition genes from 20,205 Chinese individuals.

Jiaqi Xu, Jin Sun, Jie Tang, Wan Huai, Yijin Gao et al. · 7 Jul 2026

Abstract

BACKGROUND: With the increasing use of next-generation sequencing, secondary findings (SFs) in cancer predisposition genes (CPGs) are being detected more frequently. However, evidence on clinical follow-up, cascade testing, and psychosocial impact in pediatric referral settings remains limited. METHODS: We retrospectively analyzed whole-exome sequencing data from 20,205 non-cancer individuals who underwent testing at Shanghai Children's Medical Center between 2014 and 2025 to identify SFs in 28 predefined CPGs. Probands with SFs received confirmatory testing and family-based cascade testing, then clinical follow-up including family health assessment and a structured psychosocial counseling questionnaire. RESULTS: A total of 67 pathogenic or likely pathogenic (P/LP) variants were identified in 84 probands, yielding an SFs frequency of 0.42% (84/20,205). The cohort included 76 minors and eight adults (median age 10 years; range 1-56). SFs involved nine genes, predominantly BRCA2 (35%), PALB2 (22%), BRCA1 (20%), and Lynch syndrome genes PMS2 (13%) and MSH6 (6%). Most variants were loss-of-function (78%) and inherited (99%, 68/69). Among 47 probands completing follow-up, 26 reported family cancer history, with 15 potentially concordant with the SFs. Of 33 questionnaire respondents, 13 reported anxiety, yet all perceived health management benefits. CONCLUSION: Disclosing SFs enabled genetic counseling, cascade testing, and risk-informed management for probands and at-risk relatives. The germline P/LP variant spectrum and curated pedigrees provide resources for penetrance research and may inform pediatric SF return strategies.