ROS1 Gene Rearrangement

Overview

The ROS1 gene (proto-oncogene 1, receptor tyrosine kinase) is located on chromosome 6q22 and encodes a receptor tyrosine kinase (RTK) involved in cell growth and differentiation. Although its exact physiologic ligand is not fully defined, ROS1 becomes clinically significant when it undergoes gene rearrangement, resulting in fusion oncogenes that cause uncontrolled proliferation.

ROS1 gene rearrangement was first described in glioblastoma and has since been identified in a subset of non-small cell lung cancers (NSCLC), accounting for about 1–2% of cases. It is also observed in other malignancies including cholangiocarcinoma, gastric cancer, colorectal cancer, spitzoid melanoma, ovarian tumors, and angiosarcoma.

The most common fusion partner in lung cancer is the CD74 gene, though others like SLC34A2, TPM3, EZR, FIG, LRIG3, and SDC4 are also documented. These fusions constitutively activate signaling pathways such as MAPK, PI3K/AKT, and JAK/STAT, driving cancer growth and survival.

Symptoms

ROS1 gene rearrangements do not directly cause symptoms; instead, symptoms depend on the associated cancer:

1. NSCLC (Non-Small Cell Lung Cancer): Persistent cough, chest pain, hemoptysis, shortness of breath, and unexplained weight loss.
2. Glioblastoma: Headaches, seizures, neurological deficits, and behavioral changes.
3. Cholangiocarcinoma: Jaundice, abdominal pain, fatigue, and loss of appetite.
4. Gastric or Colorectal Cancer: Abdominal bloating, altered bowel habits, blood in stool, and unexplained weight loss.
5. Other Tumors: Localized swelling, pain, or organ-specific dysfunction depending on the site of cancer.

Patients with ROS1-positive cancers often present with rapid disease progression, making early molecular testing essential.

Causes

The primary cause of ROS1-positive cancers is chromosomal rearrangement leading to fusion oncogenes.

1. Gene Fusions:
   1. Common fusion partners include CD74, SLC34A2, TPM3, EZR, FIG, LRIG3, and SDC4.
   2. These fusions create constitutively active ROS1 proteins that bypass normal regulatory signals.
2. Oncogenic Pathways Activated:
   1. MAPK Pathway: Promotes abnormal cell proliferation.
   2. PI3K/AKT Pathway: Increases cell survival and resistance to apoptosis.
   3. JAK/STAT Pathway: Supports tumor progression and immune evasion.

Such persistent activation of signaling cascades contributes to tumor growth, spread, and poor prognosis.

Risk Factors

ROS1 rearrangements are not inherited but arise from somatic genetic events. Still, some groups have a higher likelihood of harboring ROS1-positive cancers:

1. Patients with NSCLC: Especially younger, non-smokers with adenocarcinoma subtype.
2. Individuals with Glioblastoma or Cholangiocarcinoma: Where ROS1 fusions were first reported.
3. Patients with Rare Tumors: Including ovarian, angiosarcoma, gastric, and colorectal cancers.
4. Aggressive Disease Presentations: Patients with rapidly spreading cancers unresponsive to conventional chemotherapy.
5. Geographical and Diagnostic Limitations: Lack of access to advanced molecular diagnostics can delay recognition and treatment of ROS1-positive cases.

Prevention

ROS1 gene rearrangements themselves cannot be prevented, but early detection and targeted therapy can significantly improve outcomes:

1. Diagnostic Testing:
   1. Next-Generation Sequencing (NGS): Comprehensive analysis for ROS1 fusions.
   2. Fluorescence In Situ Hybridization (FISH): Reliable confirmation of rearrangements.
   3. Sample Requirements:
      1. Bone marrow aspiration (≥2.5 mL)
      2. Blood in EDTA tubes (≥6 mL)Tissue in Hank’s fluid or formalin-fixed paraffin blocks
      3. Plasma for ctDNA testing, transported within 8 hours at ambient temperature
2. Targeted Therapies:
   1. Crizotinib: The first FDA-approved ROS1 inhibitor for NSCLC.
   2. Entrectinib: Effective with CNS penetration, useful in brain metastases.Lorlatinib and Repotrectinib: Effective against resistant mutations.
   3. Compared with chemotherapy, targeted therapy improves survival and quality of life though it is not curative.
3. Prognostic Monitoring:
   1. ROS1-positive lung cancers are aggressive and fast-growing.
   2. Regular follow-ups ensure timely detection of resistance and therapy adjustments.