Comparative molecular profiling of aLEGH and GAS in a mother-daughter pair with Peutz-Jeghers syndrome

Peutz-Jeghers syndrome (PJS) is caused by germline STK11 mutations and increases the risk of gastric-type endocervical adenocarcinoma (GAS). The molecular differences between its precursor, atypical lobular endocervical glandular hyperplasia (aLEGH), and invasive GAS are incompletely defined. In this family-based cross-sectional comparison, we used targeted next-generation sequencing and immunohistochemistry to profile a mother with invasive GAS and her daughter with aLEGH, who share the same germline STK11 splice-site variant (c.735-1G>A). Both lesions showed gastric differentiation and loss of detectable STK11 protein expression. No somatic variants were reported for the daughter’s aLEGH sample, whereas the maternal GAS harbored KRAS p. G12C, a truncating ARID1A alteration, FBXW7 , and LZTR1 alterations. ARID1A protein expression was lost in the GAS but showed patchy positivity in the aLEGH. These findings identify molecular differences associated with the two observed pathological states and support further investigation of additional somatic alterations in PJS-associated cervical lesions. This family-based cross-sectional comparison provides a hypothesis-generating framework, but does not establish temporal acquisition, clonal relatedness, or causal progression from aLEGH to GAS.