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Germline mutations causing familial lung cancer.

Koichi Tomoshige1,2, Keitaro Matsumoto1, Tomoshi Tsuchiya1

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Researchers identified inherited genetic factors contributing to lung cancer susceptibility in a multi-generational family. The MAST1 gene emerged as a primary candidate oncogene driving lung cancer in both familial and sporadic cases.

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Area of Science:

  • Genetics
  • Oncology
  • Molecular Biology

Background:

  • Most lung cancers are sporadic, with limited understanding of inherited genetic factors influencing susceptibility.
  • Familial lung cancer cases offer crucial insights into the genetic underpinnings of the disease.
  • Autosomal dominant inheritance patterns are suspected in some families with high lung cancer incidence.

Purpose of the Study:

  • To identify inherited genetic alterations responsible for lung cancer in a three-generation family with suspected autosomal dominant inheritance.
  • To investigate the role of identified candidate genes in sporadic lung cancer development.
  • To pinpoint specific genes acting as oncogenic drivers in familial and sporadic lung cancer.

Main Methods:

  • Whole-exome sequencing of affected and unaffected individuals from a lung cancer-prone family.
  • Analysis of 41 genetic alterations in 40 genes identified in affected family members.
  • Exon target enrichment sequencing of 192 sporadic lung cancer patient samples to detect somatic mutations.

Main Results:

  • Identified 41 candidate mutations in 40 genes segregating with lung cancer in the affected family.
  • Detected somatic candidate mutations in sporadic lung cancer samples, with MAST1, CENPE, CACNB2, and LCT being most promising.
  • Located the MAST1 gene within a putative cancer-linked locus in the family pedigree.

Conclusions:

  • Multiple genes likely act as oncogenic drivers in familial lung cancer.
  • The MAST1 gene is strongly implicated as a causative factor in lung cancer within this family.
  • MAST1 represents a significant candidate gene for lung cancer development in both inherited and sporadic forms.