Diffuse expression of MUC6 defines a distinct clinicopathological subset of pulmonary invasive mucinous adenocarcinoma

Abstract

Invasive mucinous adenocarcinoma (IMA) of the lung is a unique variant of lung adenocarcinoma.Aberrant mucin expression is associated with cancer development and metastasis. However, the clinicopathological significance of mucin expression in IMA is not fully understood. Herein, we evaluated the clinicopathological, immunohistochemical, and molecular characteristics of 70 IMA tumors. EGFR, KRAS, GNAS, and TP53 mutations were assessed by PCR-based sequencing.Next-generation sequencing was used to assess cases without EGFR/KRAS mutations. A NanoString-based screening for fusions was performed in all IMAs without mitogenic driver mutations. Expression of mucins (MUC1, MUC2, MUC4, MUC5AC, and MUC6) was evaluated by immunohistochemistry and categorized as follows: negative (<10% of tumor cells), patchy expression (<90% of tumor cells), or diffuse expression (≥90% of tumor cells).Immunohistochemical testing for transcription factors (TTF-1, CDX-2, HNF1β, HNF3α, HNF3β, and HNF4α) was also performed. As expected, KRAS mutations were the most common (in 67% of cases), followed by small numbers of other alterations. Patchy or diffuse expression of MUC1, MUC2, MUC4, MUC5AC, and MUC6 was observed in 52% or 6%, 3% or 0%, 30% or 3%, 26% or 73%, and 59% or 27% of cases, respectively. Furthermore, all IMAs were generally positive for HNF1β (100%), HNF3α (100%), HNF3β (100%), and HNF4α (99%) but were positive less often for TTF-1 (6%) and CDX2 (9%). Overall, there was no significant correlation between mucin expression and transcription factor expression. Unexpectedly, diffuse expression of MUC6 was significantly associated with KRAS-wild type tumors (p=0.0008), smaller tumor size (p=0.0073), and tumors in female patients (p=0.0359) in multivariate analyses. Furthermore, patients with tumors exhibiting diffuse MUC6 expression had significantly favorable outcomes. Notably, none of these patients died of the disease. Our data suggested that diffuse expression of MUC6 defines a distinct clinicopathological subset of IMA characterized by wild-type KRAS and possibly less aggressive clinical course.

Comprehensive Molecular and Clinicopathologic Analysis of 200 Pulmonary Invasive Mucinous Adenocarcinomas Identifies Distinct Characteristics of Molecular Subtypes

“…5) or anchored multiplex PCR (6), previous studies failed to reveal a mitogenic driver alteration in the majority of such cases. Notably, the early studies frequently used molecular techniques with limited analytical sensitivity for KRAS mutation detection (3,7,8), and more recent studies using next-generation sequencing (NGS) techniques only examined mutations and fusions, but not copy-number alterations (5,6,10).…”

Glycosylation of MUC6 by α1,4‐linked N‐acetylglucosamine enhances suppression of pancreatic cancer malignancy

“…Moreover, accumulating results indicate that MUC6‐positive or higher‐expressing cases showed preferable prognosis in gastric cancer, 36 colorectal cancer, 37 and pulmonary invasive mucinous adenocarcinoma. 38 We also examined MUC6 mRNA expression and prognosis of pancreatic ductal adenocarcinoma patients and found that higher mRNA levels were significantly correlated with favorable prognosis as compared with lower levels (Figure 5B ). The present study also strongly supports the idea that α4GnT and MUC6 exert tumor‐suppressive effects on two pancreatic cancer cell lines and suggests that α4GnT, or αGlcNAc, and MUC6 may also be good prognostic markers in pancreatic cancer.…”

Use of a highly sensitive lung cancer compact panel to detect KRAS G12D in the wash fluid from a lung tumor: A case report

“…KRAS mutations have been linked to the clinicopathological, immunohistochemical and molecular characteristics of pulmonary invasive mucinous adenocarcinoma. 7 Because metastatic NSCLC harboring KRAS G12C can be treated with KRAS-targeting agents (e.g., sotorasib), the detection of KRAS subtypes using methods such as the Lung Cancer Compact Panel is essential for therapeutic decision-making. We strongly suspected lung cancer because of this finding, and recommended surgical resection.…”