Identifying Lynch syndrome in people with sebaceous skin lesions

Ingrid Winship1,2, Michael Wlash3, Mark Clendenning4,5, Khalid Mahmood4,6, Peter Georgeson4,5, Ryan Hutchinson4,5, Julia Como4,5, Susan Preston4,5, Magda Kloc4,5, Sharelle Joseland4,5, Jihoon Joo4,5, Harindra Jayasekara4,5, Liz Donaldson1, Joanne Isbister1, Jessica Taylor1, Kirsty Storey1, Aung Win7,5, Mark Jenkins7,5, Daniel Buchanan4,1,5

1Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Australia. 2Department of Medicine, The University of Melbourne, Parkville, Australia. 3Sullivan Nicolaides Pathology, Brisbane, Australia. 4Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Australia. 5University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Australia. 6Melbourne Bioinformatics, The University of Melbourne, Parkville, Australia. 7Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Australia


Objectives: A subset of people with Lynch syndrome develop sebaceous skin lesions.  Mismatch repair (MMR) deficiency is frequently observed in sebaceous lesions, but is not diagnostic for Lynch syndrome.  An effective tool to aid clinical decision making for germline MMR gene testing for people with sebaceous lesions is needed.

Methods: We studied 255 sebaceous lesions from 225 people recruited from Sullivan Nicolaides Pathology (n=168), where pathologist-initiated MMR IHC is performed on sebaceous lesions, or via Family Cancer Clinics across Australia (n=57).  Germline MMR gene testing and MMR IHC was performed on all participants and lesions, respectively.  Immune cell (CD3, CD8, CD20, FOXP3) infiltration and checkpoint (PD-1, PD-L1) expression was determined by IHC on a subset of 38 sebaceous lesions from 36 participants.

Results: 255 sebaceous lesions comprised 179 (70.2%) adenomas, 49 (19.2%) carcinomas and 27 (10.6%) sebaceomas; 79% of all lesions occurred on the head and neck region.  MMR-deficiency was identified in 49% of 213 lesions tested.  Of the 135 participants with germline MMR gene testing completed, 29/59 (49.2%) participants who had a MMR-deficient lesion and 1/76 (1.3%) who had a MMR-proficient lesion carried a MMR gene mutation.  MMR mutation carriers showed an inflamed immune infiltration phenotype (67%), defined as strong infiltration of CD3+ and CD8+ T-cells within the peritumoral and invasive front, compared with participants with MMR-deficient non-Lynch (17%) and MMR-proficient (15%) sebaceous lesions.

Conclusions: Further elucidation of the genotype-phenotype correlations, immune contexture and somatic mutation landscape in sebaceous neoplasia will help to improve triaging for identifying Lynch syndrome.