The recognition of familial predisposition to CRC is an important factor in the prevention of morbidity and mortality in both the proband and their relatives. MSI and IHC analysis in a single tumour from the proband, followed by mutation testing in the proband and subsequently in at-risk relatives, is usually adequate to identify those individuals in Lynch syndrome families who carry deleterious mutations in an MMR gene. However, in a small number of Lynch syndrome families the CRC risk is likely due to two independent germline factors. This is particularly important when one susceptibility is for advanced serrated polyps which can produce both somatic BRAF
mutation-bearing CRC, which may be MSI-H due to MLH1 deficiency, and mixed serrated-adenomatous polyps, which may also demonstrate IHC loss of MLH124
Families with a mixed lineage disorder involving Lynch syndrome have been reported previously25
. Skoglund et al described a family where both Lynch syndrome, due to a deleterious mutation in MSH2
, as well as a second predisposition linked to a region on 9q concurred26 27
. A further family report detailed the counterintuitive findings of adenomatous polyposis in the presence of an MSH6
germline mutation also suggesting two co-occurring predispostions28
. Mixed lineage families have also been described where MUTYH
. Given the recent findings regarding individuals with advanced serrated polyps presenting with biallelic mutations in MUTYH30
, both families were screened for the two common variants of MUTYH
found in northern Europeans (data not shown)31
, and all sixty-five individuals who underwent testing were wild-type for both G382D and Y165C. Our findings regarding MUTYH
are not unexpected as the lesions in both families demonstrated somatic BRAF
rather than KRAS
. In this case report, we describe another factor which may complicate the management of a Lynch syndrome family, namely a co-existing susceptibility to develop advanced serrated polyps.
It is important to be aware of these mixed lineage families because of the risk of confounding both diagnosis and management. The identification of an MSI-H CRC demonstrating IHC absence of MLH1 in an individual at a relatively young age and with a family history of CRC is likely to result in a diagnosis of Lynch syndrome. The individual in whom the tumour is found will be designated as the family proband, and mutation testing will proceed in their germline tissue. In the majority of cases, this will result in diagnostic confirmation through the ascertainment of a pathogenic germline MMR gene mutation. However, should this tumour be the result of a serrated neoplasia predisposition, a search for a germline mutation in MLH1 may prove fruitless if this individual is in fact a Lynch syndrome phenocopy.
In this report we describe two families where advanced serrated polyps coincided with Lynch syndrome. In Family 1, an individual with hyperplastic polyposis syndrome (HPS) developed several neoplasms where MLH1 was absent. Given her family history, including multiple CRCs and endometrial cancer, it would be reasonable to suspect that this person also, had Lynch syndrome. Though the multiple CRC in this family indeed resulted from Lynch syndrome, specifically due to a germline defect in MSH2, the individual with HPS did not carry this mutation. Instead, she was at increased risk for CRC due to her predisposition to develop multiple serrated polyps. In Family 2, a CRC demonstrated a somatic BRAF mutation in a young-onset female mutation carrier. This was an unexpected finding, however, serrated polyps, including multiple sessile serrated adenomas and traditional serrated adenomas were detected in several of her first-degree relatives, and advanced serrated polyps, including traditional serrated adenomas and mixed polyps were observed in three female relatives in her maternal generation. In two of these relatives, the family germline mutation was not detected, suggesting independent segregation. Importantly, in one of these relatives, the serrated polyp demonstrated IHC loss of MLH1 in the absence of a germline mutation.
Though small serrated polyps, especially those occurring in the distal colon, are relatively common in the population, available evidence suggests that serrated polyps which are large, proximal, and of atypical histological appearance (advanced serrated polyps), especially if multiple, may be associated with a genetic predisposition32
. Such predispositions are thought to be relatively rare, however recent evidence suggests that they may be prevalent in some populations33
, specifically more common in Europeans21
, and in Anglo-Celtic populations in particular34
. The mode of inheritance in families with serrated neoplasia predisposition ranges from isolated individuals with numerous serrated polyps reminiscent of a recessive condition, exemplified by family 1, to families with multiple affected members where polyp numbers are relatively low but where advanced serrated polyps are frequent as seen in family 2. There is currently no robust clinical test which can discriminate serrated polyps with malignant potential from innocuous serrated lesions, nor is there any robust germline genetic test available which can definitively identify individuals at risk for high-risk serrated polyps. Histological examination remains the best available technique. This report does not conflict with the conventional wisdom that diminutive serrated polyps in the distal colon are unlikely to be of clinical concern. In both families, the serrated polyps are multiple and advanced, and therefore are likely to be associated with an increased risk for colorectal cancer, though precise risk estimates are not able to be derived from currently available data35
CRC in Lynch syndrome develops from traditional adenomas, and studies of Lynch syndrome families have observed that IHC absence of an MMR protein is not observed in serrated or hyperplastic polyps in MMR mutation carriers36
, in contrast to this alteration being demonstrated in 70% of traditional adenomas37
. The occurrence of the somatic BRAF
mutation in tumours in Lynch syndrome families is rare8 9 38-42
and, consistent with this finding, advanced serrated polyps are also rare in Lynch syndrome43
. Confirmed Lynch syndrome families in which somatic BRAF
mutation is detected in a tumour therefore warrant closer investigation, especially when detected in a young-onset individual, as this may indicate that other family members are at risk for CRC independent of their carrier status for MMR mutations. The clinical team managing these mixed lineage families, in whom advanced serrated polyps are observed, need to build a model for dealing with the co-existing genetic predispositions, and update the risk status of the family when each new result becomes available. This management model depends on the study of more than one affected individual in the diagnostic strategy28
and examination of the pathology of pre-malignant lesions developing in the colon. The recognition of a serrated neoplasia predisposition originally came about in the family cancer clinic attended by the authors because multiple tumours from each family were routinely characterised during Lynch syndrome triage, allowing for detection of a pattern of observations delineating serrated neoplasia families from those with Lynch syndrome13
In summary, we have reported two mixed lineage families in whom tumours have arisen from both Lynch syndrome and serrated neoplasia predispositions, overlapping in some but not all affected individuals. Such families will likely come to light as tumour BRAF mutation testing becomes more widespread as a screening test to exclude Lynch syndrome. The finding of incongruous occurrences of young-onset CRC in a Lynch syndrome family should suggest consideration of mixed lineage and prompt further investigations, including detailed pedigree analysis, namely segregation of phenotypes, somatic BRAF mutation testing, and pathology review, especially in families with European ancestry.