Pan-cancer assessment of the impact of intronic variants on cancer development and progression

Safonov, A, Mehine, M, Ceyhan-Birsoy, O, Brown, D, Bandlamudi, C, Forbes, A, Gazzo, A, Selenica, P, Shen, R, Khurana, E, Norton, L, Solit, D, Chandarlapaty, S, Razavi, P, Robson, M, Weigelt, B, Berger, M, Ladanyi, M, Reis-Filho, JS, Mandelker, D (2023) Pan-cancer assessment of the impact of intronic variants on cancer development and progression. In: UNSPECIFIED.

DOI: 10.1016/j.annonc.2023.09.1259


Background: Despite advancements in cancer genomics, the contribution of intronic somatic mutations to cancer development and progression remains to be fully established. Here we systematically investigated the functional significance of intronic variants in a pan-cancer cohort with >30,000 tumor/normal samples subjected to an FDA-authorized multi-gene assay. Methods: Patients who underwent tumor and matched normal sequencing by MSKIMPACT from 2014 to Sept 2021 were included. We first defined histology-specific gene enrichments incorporating pathogenic somatic variants (PVs). Similar analyses consisting exclusively of non-coding variants (NCVs) were subsequently performed. The rates of concordance between NCV and PV-based gene-histology enrichment as a function of tumor suppressor (TSGs) vs. oncogene (OG) status were investigated. We defined the patterns of mutual exclusivity and co-occurrence between PVs and NCVs, as well as loss of heterozygosity (LOH) status of TSGs affected by these variants. Results: We analyzed 33,106 tumors from 25,418 patients across 22 cancer types. NCVs were enriched in specific cancer types, matching the enrichment of PVs. NCVs significantly affected cases with no PV identified in the known driver gene: CDH1 in 14% of invasive lobular carcinomas (ILC) (OR 109.7 [26.5 e inf], p < 0.001), APC in 87% of colorectal cancers (CRC) (OR 197.23 [123.7 e inf], p < 0.001), and RB1 in 9% of small cell lung cancer (SCLC) (OR 32.3 [15.06 e inf], p < 0.001) with no PV identified in the known driver gene. NCVs in TSGs followed lineage-specific patterns vs. OGs (OR 5.5 [1.6-29.6], p < 0.001) and vs. genes not enriched in the PV analysis (OR 9.5 [5.0 e 18.2], p¼ 2.87 e-12). NCV in TSGs occurred in tumors with mono-allelic loss of the TSG: 100.0% of CDH1 in ILC (p < 0.001), 87.3% of APC in CRC (p < 0.001), and 100.0% of RB1 in SCLC (p ¼ < 0.001). Immunohistochemistry of select cases with NCVs in RB1, CDH1, and other select TSGs showed loss of protein expression. Conclusions: We report the frequent detection of intronic variants that are not reported by clinical tumor sequencing assays. Such variants followed expected histology and zygosity patterns, strongly suggesting intronic variants may be consequential and constitute the second hit in a lineage-specific manner.

Item Type: Conference or Workshop Item (Paper)
Subjects: diseases & disorders > cancer
diseases & disorders
CSHL Authors:
Communities: CSHL labs > Wigler lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 2023
Date Deposited: 20 Dec 2023 19:13
Last Modified: 20 Dec 2023 19:13
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