Molecular markers

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• STK11 somatic mutations occur in ~15 - 35% of non-small cell lung carcinomas (NSCLCs) and are enriched in KRAS mutant and KEAP1 mutant lung adenocarcinoma, often mutually exclusive with EGFR mutations (Nature 2008;455:1069)
  • STK11 mutant NSCLCs show lower PDL1 expression and patients have worse response to PDL1 targeted immunotherapies (Cancer Discov 2018;8:822, BMC Cancer 2024;24:491)
  • STK11 mutant NSCLCs have worse overall survival compared with STK11 wild type patients and worse response to radiotherapy (Clin Cancer Res 2021;27:1720)
  • Decreased STK11 expression is significantly associated with larger tumor size, lymph node metastasis and higher pathological tumor stage (PLoS One 2016;11:e0152674)
• STK11 germline alterations associated with autosomal dominant Peutz-Jeghers syndrome
  • Characterized by hamartomatous polyps of the GI tract (particularly the small intestines), mucocutaneous pigmentation and predisposition to benign and malignant tumors
    • Mucocutaneous pigmentation includes bluish black macules and papules of the perioral region, lips, buccal mucosa, fingers and vaginal region (Cureus 2024;16:e58887)
    • GI hamartomas are typically multiple and may present in childhood secondary to intussusception (J Clin Med 2021;10:473)
    • GI polyps frequently involve small intestines but also the stomach and colon (Cureus 2024;16:e58887)
    • Tumors involve pancreas, breast, uterus, cervix (cervical adenocarcinoma of gastric type), ovary (sex cord tumors with annular tubules [SCTAT], STK11 associated adnexal tumor), stomach, thyroid, testis (intratubular large cell hyalinizing Sertoli cell tumor) or colon (Nature 1998;391:184, Pediatr Dev Pathol 2023;26:486, Am J Surg Pathol 2021;45:1061, Virchows Arch 2024;484:723)
    • Relative risk of developing cancer estimated between 6 - 9x compared with normal population, generally by 30s - 40s (Dig Liver Dis 2013;45:606)

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• Immunohistochemistry not currently used in routine practice by pathologists
• Identification of hamartomatous polyps of GI tract or STK11 associated malignancy (e.g., STK11 adnexal tumor or intratubular large cell hyalinizing Sertoli cell tumor of testis) should prompt diagnostic comment about genetic counseling
• See Clinical features

Contributed by David Kolin, M.D., Ph.D.

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STK11 is altered in 10 - 30% of lung cancers and associated with a worse prognosis. Which of the following is a common mechanism of STK11 alteration in lung cancer?

1. Kinase domain activating mutation
2. Kinase domain duplication
3. Oncogenic fusion
4. Truncating mutations

D. Truncating mutations. STK11 is a tumor suppressor gene and biallelic inactivation has been reported in up to 30% of non-small cell lung cancers. Truncating mutations are a frequent cause of inactivation. Answers A, B and C are incorrect because the mutations described are activating and would not be associated with biallelic inactivation.

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Reference: STK11

Following presentation for intussusception, a 9 year old boy undergoes a polypectomy showing multiple hamartomatous polyps (see image above). His history is otherwise notable for freckles noted around his mouth and lips, a family history of polyps in his older sister and ovarian cancer in his mother. In your pathology report, you recommend genetic counseling to test for mutations in which gene and its associated genetic presentation?

1. MUTYH / Gardner syndrome
2. PRKAR1A / juvenile polyposis syndrome
3. PTEN / Cowden syndrome
4. STK11 / Peutz-Jeghers syndrome

D. STK11 / Peutz-Jeghers syndrome. The clinical features described (mucocutaneous pigmentation and small intestinal hamartomatous polyp in a child with family history of hamartomatous polyps and ovarian cancer) are a classic presentation of Peutz-Jeghers syndrome, which is caused by autosomal dominant mutations in the gene STK11. Answer C is incorrect because mutations in PTEN are associated with hamartoma syndromes (e.g., Cowden) with skin manifestations but do not typically show mucocutaneous pigmentation and ovarian cancer. Answer B is incorrect because although PRKAR1A mutations are associated with cancer predisposition and cutaneous growth and pigmentation, the genetic association is with Carney complex and not juvenile polyposis syndrome. Answer A is incorrect because although both MUTYH gene mutations and Gardner syndrome are associated with cancer predisposition and polyposis, they do not represent a gene syndrome dyad.

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Reference: STK11