2231O - Pan-cancer assessment of the impact of intronic variants on cancer development and progression

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 MSK-IMPACT 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 – inf], p < 0.001), APC in 87% of colorectal cancers (CRC) (OR 197.23 [123.7 – inf], p < 0.001), and RB1 in 9% of small cell lung cancer (SCLC) (OR 32.3 [15.06 – 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 – 18.2], p= 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 = < 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.

Clinical trial identification

NCT01775072 First Posted: January 24, 2013 Last Update Posted: May 6, 2023.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

L. Norton: Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: Agenus Inc., Celgene, Cold Spring Harbor Laboratory; Non-Financial Interests, Personal, Speaker, Consultant, Advisor, Provision of services (Uncompensated): ASCO, Breast Cancer Research Foundation, Cure Breast Cancer Foundation, NewStem Ltd., Springer Nature Limited, Translational Breast Cancer Research Consortium; Financial Interests, Personal and Institutional, Ownership Interest: Codagenix, Inc., Immix Biopharma, Inc., Martell Diagnostic Laboratories, Inc.; Financial Interests, Personal and Institutional, Licencing Fees or royalty for IP: Cure Breast Cancer Foundation; Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor, Provision of services (Uncompensated): QLS Advisors, LLC; Financial Interests, Personal and Institutional, Ownership Interest, Ownership Role and Fiduciary Role: Samus Therapeutics LLC; Financial Interests, Personal, Speaker, Consultant, Advisor, Provision of services (Uncompensated): US Department of Justice. D. Solit: Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: American Association for Cancer Research, Apple Tree Life Sciences, Inc., BridgeBio Inc., Pfizer, Inc.; Financial Interests, Personal and Institutional, Ownership Interest, Ownership Interests and Provision of Services: NovellusDx Ltd., Scorpion Therapeutics, Inc., Vividion Therapeutics. S. Chandarlapaty: Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: Breast Cancer Research Foundation, Eli Lilly and Company, Inivata, Inc., Korean Society for Medical Oncology, Novartis, Sanofi US Services Inc., Targeted Oncology, The Japanese Breast Cancer Society; Non-Financial Interests, Personal, Speaker, Consultant, Advisor, Provision of services (Uncompensated): Global Breast Cancer Conference; Financial Interests, Personal and Institutional, Ownership Interest: Totus Medicines Inc. P. Razavi: Financial Interests, Institutional, Research Funding: Grail, Illumina, Novartis, AstraZeneca, Epic Sciences, Invitae/Archer DX, Biotheranostics, Tempus, Inivata, Biovica, Guardant; Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: Novartis, AstraZeneca, Pfizer, Lilly/Loxo, Prelude Therapeutics, Epic Sciences, Foundation Medicine, Inivata, Natera, Tempus, SAGA Diagnostics, Paige.ai, Guardant; Financial Interests, Personal and Institutional, Member of Board of Directors, Co-Founder and Board Member: Odyssey Biosciences; Financial Interests, Personal and Institutional, Leadership Role, Co-Founder and Board Member: Odyssey Biosciences. M. Robson: Non-Financial Interests, Personal, Speaker, Consultant, Advisor, Provision of Services (Uncompensated): Artios Pharma Limited, Pfizer, Inc., Tempus Labs, Inc.; Non-Financial Interests, Personal, Speaker, Consultant, Advisor, Provision of services (Uncompensated): AstraZeneca; Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: Change Healthcare Inc., Clinical Education Alliance, LLC, Genome Quebec, MJH Associates. M. Berger: Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: AstraZeneca, Eli Lilly and Company, PetDx, Inc.; Non-Financial Interests, Personal, Speaker, Consultant, Advisor, Provision of services (Uncompensated): JCO Precision Oncology, Journal of Molecular Diagnostics, Journal of Visualized Experiments. M. Ladanyi: Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: ADC Therapeutics, AstraZeneca, Merck Sharp & Dohme; Financial Interests, Personal and Institutional, Ownership Interest, Ownership Interests and Provision of Services: Paige.AI, Inc. J.S. Reis-Filho: Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: Belgian Volition, Goldman Sachs, Personalis, Inc.; Financial Interests, Personal and Institutional, Ownership Interest, Ownership/Equity Interests and Fiduciary Role/Position: Oncoclinicas do Brasil Servicos Medicos S.A.; Financial Interests, Personal and Institutional, Ownership Interest, Ownership Interest and Provision of Services: Paige.AI, Inc., Repare Therapeutics. All other authors have declared no conflicts of interest.