title: Analysis of families with Lynch syndrome complicated by advanced serrated neoplasia: the importance of pathology review and pedigree analysis.
abstract: The identification of Lynch syndrome has been greatly assisted by the advent of tumour immunohistochemistry (IHC) for mismatch repair (MMR) proteins, and by the recognition of the role of acquired somatic BRAF mutation in sporadic MMR-deficient colorectal cancer (CRC). However, somatic BRAF mutation may also be present in the tumours in families with a predisposition to develop serrated polyps in the colorectum. In a subgroup of affected members in these families, CRCs emerge which demonstrate clear evidence of MMR deficiency with absent MLH1 staining and high-level microsatellite instability (MSI). This may result in these families being erroneously classified as Lynch syndrome, or conversely, an individual is considered "sporadic" due to the presence of a somatic BRAF mutation in a tumour. In this report, we describe two Lynch syndrome families who demonstrated several such inconsistencies. In one family, IHC deficiency of both MSH2 and MLH1 was demonstrated in tumours from different affected family members, presenting a confusing diagnostic picture. In the second family, MLH1 loss was observed in the lesions of both MLH1 mutation carriers and those who showed normal MLH1 germline sequence. Both families had Lynch syndrome complicated by an independently segregating serrated neoplasia phenotype, suggesting that in families such as these, tumour and germline studies of several key members, rather than of a single proband, are indicated to clarify the spectrum of risk.
authors.affiliation: Familial Cancer Laboratory, QIMR, Herston, QLD 4006, Australia.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Walsh
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
authors.forename: Rhiannon
authors.initials: R
authors.lastname: Walters
authors.forename: Aedan
authors.initials: A
authors.lastname: Roberts
authors.forename: Sven
authors.initials: S
authors.lastname: Arnold
authors.forename: Diane
authors.initials: D
authors.lastname: McKeone
authors.forename: Mark
authors.initials: M
authors.lastname: Clendenning
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Ruszkiewicz
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Jack
authors.initials: J
authors.lastname: Goldblatt
authors.forename: Jillian
authors.initials: J
authors.lastname: George
authors.forename: Graeme K
authors.initials: GK
authors.lastname: Suthers
authors.forename: Kerry
authors.initials: K
authors.lastname: Phillips
authors.forename: Graeme P
authors.initials: GP
authors.lastname: Young
authors.forename: Finlay
authors.initials: F
authors.lastname: Macrae
authors.forename: Musa
authors.initials: M
authors.lastname: Drini
authors.forename: Michael O
authors.initials: MO
authors.lastname: Woods
authors.forename: Susan
authors.initials: S
authors.lastname: Parry
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Jass
authors.forename: Joanne P
authors.initials: JP
authors.lastname: Young
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000236:Adenoma / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D003111:Colonic Polyps / Q000235:genetics* / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D016133:Polymerase Chain Reaction; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein