|Home | About | Journals | Submit | Contact Us | Français|
Colorectal cancer (CRC) develops within precursor lesions in the single-celled epithelial lining of the gut. The two most common epithelial lesions are the adenoma and the serrated polyp. CRC is also one of the most familial of the common cancers, and just as there are syndromes associated with increased risk of CRC arising in adenomas, there are also syndromes with increased CRC risk associated with serrated polyps. In this article, we describe the features of such a syndrome, familial serrated neoplasia, which distinguish it from the well-characterized condition Lynch syndrome (or hereditary nonpolyposis CRC), and show that the molecular pathology of tumors forms the basis for this distinction. Lynch syndrome CRC arises almost exclusively within adenomatous precursor lesions, in contrast with familial serrated neoplasia where at least half of the cancers develop in serrated polyps. Finally, rare families exist in which both conditions segregate independently, producing a difficult diagnostic picture.
Lynch syndrome, a familial cancer predisposition associated with defective DNA mismatch repair (MMR) and consequent increased risks for colorectal and endometrial malignancy in particular, was first recognized in a large family by Warthin in the early 20th Century. Clinical definitions for the recognition of Lynch syndrome, such as the Amsterdam I Criteria, had previously been based on the pattern of occurrence of cancers in multicase families [1,2]. However, it quickly became apparent that only half of the families meeting the Amsterdam Criteria demonstrated DNA MMR deficiency in their tumors [3,4]. Conversely, with both modern trends towards smaller and more scattered families, as well as the recognition of lower penetrance mutations, patients who have Lynch syndrome may not meet the clinical criteria for its recognition. Today, Lynch syndrome is largely defined by the MMR-deficient biology of its tumors, thus largely overcoming these previous limitations. Recognition of Lynch syndrome has become a paradigm for an evolving set of clinical criteria based on increasing understanding of the condition over time .
As a consequence, the definition of familial colorectal cancer (CRC) type X has emerged in recent times as an Amsterdam I familial configuration in the absence of MMR deficiency to account for the balance of Amsterdam I families who do not have Lynch syndrome . Type X CRC has become synonymous with unexplained familial CRC that is microsatellite stable, and its criteria are also likely to follow a path of evolution over time, although the retention of stringency, at least in the initial stages, may serve to limit the background noise for gene discovery. A familial CRC that fits neither of these categories, but is sometimes mistakenly included in both, was reported from New Zealand in 1996, in which the most striking feature was ‘giant hyperplastic polyps’ in multiple family members . In this landmark publication, Jass and colleagues not only prepared the ground for the recognition of the serrated pathway of CRC development at a fundamental level, but also described a novel syndrome of CRC predisposition completely distinct from our current understanding of what constitutes either Lynch syndrome [8,9] or familial CRC type X [6,10]. Importantly, it was the detailed examination of multiple tumors in this initial family that was crucial to its recognition as a separate syndrome.
The CRC-affected members of the New Zealand kindred comprised a mother and five of her ten offspring. Both the mother and one of her children developed CRC before the age of 50 years, thereby meeting the Amsterdam Criteria of the day for hereditary nonpolyposis CRC (or Lynch syndrome). However, pathology review and molecular analysis revealed several features that deviated from the accepted presentation of Lynch syndrome, specifically, multiple large hyperplastic and mixed hyperplastic/adenomatous polyps, as well as the majority of CRC demonstrating no ‘replication errors’ (now known as microsatellite instability [MSI]). One exceptional family member presented with two synchronous CRCs, and a large hyperplastic polyp, all with some evidence of MSI, although the level of the MSI was not clear. Hyperplastic polyps varied in size among affected family members, with the largest measuring 40 mm. Furthermore, two out of five offspring in the third generation of this family had multiple polyps, including ten hyperplastic, one tubular and a mixed polyp, at younger ages of onset than would be expected in the general population . Importantly, at least two members of the family in the second generation had a colonic landscape consistent with hyperplastic polyposis, demonstrating multiple large hyperplastic polyps. Details of the pedigree are given in Figure 1, and of the affected family members in Table 1.
Hyperplastic polyposis syndrome (HPS) is a colonic polyposis condition presenting at a wide range of ages (11–83 years) [12–15], with the bulk of patients reported to be in the sixth or seventh decades of life [16,17]. HPS has been recognized since the late 1970s but has not, until very recently, been widely considered to be a pathologic or a genetic entity. The polyposis in HPS is frequently pancolonic ; however, polyps may be concentrated in either the distal or proximal colon . Current evidence suggests that HPS , and serrated polyps in general [20,21], are more common in Europeans, and this may account for its apparent rarity in some populations. In addition, an association between current cigarette smoking and serrated polyps also increases the probability that HPS has at least one environmental modifier [21–24]. The fundamental defect in HPS has yet to be elucidated; however, the involvement of widespread DNA methylation in the normal mucosa of patients with HPS suggests deregulation of an epigenetic control mechanism .
Data from .
Clinical descriptions as well as the WHO criteria for the recognition of HPS were reported and proposed, respectively, for several important reasons. First, since HPS was once considered an innocuous condition of young males , it was important to delineate it from the clearly penetrant and clinically severe condition of familial adenomatous polyposis. Second, the foundation criteria were necessarily stringent to ensure that the diminutive hyperplastic polyps observed relatively often in the distal colon of older patients, including those that cluster around rectal cancers, were not included in the definition [29,30].
Although HPS was previously considered to have no significant clinical consequences , today, with the wider description of larger numbers of cases, it is now thought to be associated with an increased risk of CRC , although quantitation of this risk remains problematic [29,30]. In published series of more than five cases taken together, approximately 40% of HPS patients will present with synchronous CRC [15–19,26,28,31–37]. This has been recently confirmed by a large series in Europe, where 27 out of 77 (35%) of HPS patients presented with CRC . A further important clinical consequence associated with HPS is the increased risk of both CRC [7,39,31,33,36] and possibly extracolonic cancers  in the wider family setting of HPS patients. WHO Criterion 2, while at first counterintuitive, addresses the considerable evidence that HPS occurs frequently in a familial context [19,31,33,34,36,37,41], rather than simply conferring the label of HPS to an individual with a single proximal hyperplastic polyp, and elevates the significance of smaller numbers of hyperplastic polyps in a first-degree relative of an individual with HPS. The risk of CRC to relatives in the families of individuals with HPS appears to be increased; however, the penetrance for CRC is not as high as in Lynch syndrome .
As with the original Amsterdam Criteria for Lynch syndrome, families with serrated neoplasia in multiple kindred members have been described in which no affected individual meets the criteria for HPS . That serrated neoplasia families can be divided about this somewhat arbitrary delineation but share so many features suggests a need for a more expansive approach to this spectrum of presentations based on a constellation of tumor biology features, which has served so well to identify Lynch syndrome. Other problems that arise in the approach to the patient with serrated neoplasia predisposition include the historical under-reporting of hyperplastic polyps, the difficulty in obtaining accurate or cumulative polyp counts, histological subtype designation and distribution within the colon, as well as the need to obtain a detailed personal and family history of CRC and polyps in newly presenting CRC patients. Such data are not always readily available. In addition, the emphasis placed by the WHO criteria on proximal disease in HPS (Box 1)  distracts from increasing evidence that in the younger onset HPS patient, distal malignancy is more likely to occur [31,44], suggesting that in patients aged under 50 years, multiple distal neoplasia may also be worthy of notice as well as prompting investigation of family history.
The complex biology of serrated neoplasia and the plasticity of its developmental pathway, which can give rise to CRC with variable MSI status, and to small numbers of apparently traditional adenomas, in addition to multiple serrated polyps, further contribute to the difficulties in recognizing this condition, and necessitate a more tumor-focused approach. It has been estimated that adenomatous lesions, including those with villous components, are seen in up to 90% of HPS cases [16,17], raising the notion that lesser numbers of traditional adenomas are part of the syndrome. In the New Zealand family described in the opening paragraphs of this review, mixed serrated adenomatous polyps were a prominent feature. Examples of histological subtypes of colorectal polyps are given in Figure 2.
Adenomatous lesions in a serrated neoplasia predisposition may evolve from advanced serrated polyps. The first detailed histological description of HPS was published in 1977, where the observation that adenomatous foci could arise within serrated lesions was made . The presence of such mixed polyps, which demonstrate a very high rate of somatic BRAF mutation (80–90%) , and therefore by implication, origin in a serrated polyp, provides a plausible precursor lesion for the CRC that arises in HPS [12,26,46–48]. By contrast, traditional adenomas almost never harbor a BRAF mutation . CRC in HPS have shown somatic BRAF mutation in two out of six cases (33%) in a published report , and in eight out of 19 (42%) of a case series [Walsh MD & Young JP, Unpublished Data].
The balance of CRC in HPS demonstrates either somatic KRAS mutation or is oncogene-mutation null, and may arise, in the manner of common CRC, from the traditional adenomas that frequently co-exist in patients with HPS [17,18]. Indeed, in reporting the first autosomal dominant family with serrated neoplasia, Jass and colleagues made note of an adenomatous precursor in contiguity with a small CRC, and concluded that the CRC in HPS arises through both the development of dysplasia in serrated polyps, as well as through co-incident traditional adenomas .
Somatic KRAS mutation straddles the divide between serrated and adenomatous polyps and is mutually excluded in lesions bearing a BRAF mutation . It is observed in goblet cell hyper-plastic polyps , which rarely undergo malignant transformation; however, its presence, albeit less common, in advanced serrated polyps , in rare contiguous serrated polyps attached to CRC [Young JP, Unpublished Data] and in the lesions present in bi-allelic mutation carriers for MUTYH  suggest that serrated lesions with KRAS mutations are not completely devoid of malignant potential. However, KRAS mutation exerts its strongest effects on the development of CRC within the adenoma–carcinoma developmental sequence through its acquisition by villous components of adenomas [49,54], ultimately giving rise to approximately a third of all CRC .
KRAS-mutated serrated polyps are less frequently observed among lesions removed for histological examination in the general population . Consistent with this finding, HPS patients with predominantly KRAS-mutated polyps constitute a minor subgroup of HPS and have been reported on at least two previous occasions [19,56]. Current evidence suggests that in at least some [31,53], but not all , of these patients, bi-allelic common germline mutation of MUTYH may be responsible. Importantly, these cases can be distinguished from the bulk of HPS patients by the demonstration of numbers of adenomas well in excess of those observed in the majority of HPS patients (>25 adenomas). Although germline bi-allelic mutation in MUTYH accounts for only 1% of all HPS cases , when bi-allelic MUTYH mutation carriers are assessed, 18% meet the WHO criteria for HPS . The question now arises as to whether patients such as these are segregating more than one disorder, with concomitant clinical implications.
In contrast to HPS, where first-degree relatives are at increased risk for CRC, the risk to MUTYH single-mutation carriers is not substantial, and colonoscopic surveillance is not generally advised for their parents or children. A recent report from Parry et al. presents some evidence that individuals with both MUTYH-associated polyposis (MAP) and HPS may be segregating two conditions with differing modes of inheritance . In this particular report, they describe a 56-year-old Caucasian male with more than 100 colonic polyps, (10–15-mm adenomas predominating in the proximal colon and <5-mm serrated polyps in the distal colon and rectum) who was demonstrated to be a bi-allelic mutation carrier for the two common European mutations in MUTYH . His mother had CRC of the sigmoid colon at the age of 70 years. Interestingly, his 17-year-old symptomatic son had multiple 4-mm hyperplastic polyps in the rectosigmoid, suggesting that an independently segregating predisposition to serrated neoplasia may be present in this family, and that screening therefore needs to also consider the risk to first-degree relatives that serrated neoplasia can present in this setting. For this reason, detailed pathological examination of the polyps in patients with MAP is warranted.
An additional scenario that is likely to arise in northern European populations, albeit infrequently, is that of a family with independent segregation of both serrated neoplasia and Lynch syndrome [59,60]. The identification of Lynch syndrome has been greatly assisted by the advent of tumor MSI testing and immunohistochemistry for MMR proteins. More recently, the presence of acquired somatic BRAF mutation has been used as a negative predictive test for Lynch syndrome, since the CRC in Lynch syndrome arises within traditional adenomas, a lesion that almost never demonstrates this mutation .
However, somatic BRAF mutation is not only present in sporadic MMR-deficient CRC but may also be present in the tumors of families with a serrated neoplasia predisposition. Such families have been reported previously [39,43,62], and in a subset of these probands, high-level MSI tumors arise where MLH1 is methylated and therefore absent on immunohistochemical tests. Such findings may increase the probability that the family could be incorrectly diagnosed as having Lynch syndrome . Furthermore, the presence of a somatic BRAF mutation in a tumor from an individual family member could result in their CRC being designated ‘sporadic’ . Therefore, any family in which Lynch syndrome is suspected or confirmed, but in which a BRAF mutation is detected in a young-onset CRC patient, is likely to be segregating two independent CRC predispositions and would benefit from expanded surveillance. Although not all high-level MSI CRC occurring outside Lynch syndrome are sporadic, those which occur in individuals older than 70 years are less likely to be associated with a familial risk of CRC .
Colorectal cancer is one of the most familial of the common cancers . It has been estimated that 15% of all CRC is associated with familial aggregation. However, we can definitively identify the underlying genetic cause in only 2% of CRC cases. Just as there are syndromes associated with increased risk of CRC arising in adenomas (Lynch syndrome), there are also syndromes with increased CRC risk associated with serrated polyps. Subsequent to the first report of familial serrated neoplasia, other families have been reported, including 11 from Australia , 26 from Sweden  and seven from the USA . Further examples of families with serrated neoplasia from the Genetics of Serrated Neoplasia (GSN) study are given in Figures 3 & 4 . Characterization of the genetic basis of serrated neoplasia predisposition is a necessary requirement for assessment of risk to both patients and their relatives. Until a genetic mechanism for HPS is uncovered, with subsequent penetrance and risk assessment studies at a population level, the minimal requirements of what constitutes a serrated neoplasia predisposition will remain undefined. In the interim, the role of genetics departments in assembling the clinical picture of families such as these is likely to become increasingly important . A more complete assessment, including pedigree analysis, pathology review and molecular and immunohistochemical phenotyping on multiple cases, may be of benefit to the diagnosis and management of some families, rather than the diagnosis of a family being based on assessment of a single individual. This is especially true in families with serrated neoplasia where the presence of MSI or immunohistochemical absence of MLH1, coupled with an Amsterdam-like pedigree structure, can erroneously lead to a diagnosis of Lynch syndrome .
The lack of recognition that accompanies serrated neoplasia and its ability to complicate the presentation of at least MYH-associated polyposis  and Lynch syndrome  constitutes a potential problem in the management of CRC families. Importantly, patients with multiple or advanced serrated polyps may originate from CRC families who fall short of the WHO criteria. Some of these familial configurations are currently included by default under familial CRC type X, and the inclusion of these families within this category is likely to introduce further heterogeneity , thus hampering efforts to find the underlying genetic cause of both type X families and those with serrated neoplasia predisposition. The recognition of familial serrated neoplasia as a concept in its own right, and its distinction from Lynch syndrome  and MAP (Table 2) is an important step in the wider understanding and characterization of its genetics and biology.
Approximately two-thirds of familial CRC has neither an identified genetic basis nor a defined mode of inheritance, making the management of families particularly difficult. An under-recognized syndrome, familial serrated neoplasia, is associated with northern European ancestry and can present alone or in combination with other syndromes. Important in its recognition is a detailed analysis of both its pathology and molecular features in multiple affected family members, since the plasticity of the familial serrated neoplasia phenotype does not lead to characteristic presentations in individuals, unless the proband has hyperplastic polyposis. With the advances in mutation-finding technologies, it is likely that the genetic basis for familial serrated neoplasia will be identified in the next 5 years, allowing population studies of genetic penetrance, personal and familial risk of CRC, and interactions with environmental agents such as cigarette smoking, all of which will contribute to optimal management for patients with this condition and their families.
The authors acknowledge the significant contribution of the late Professor Jeremy Jass to the foundations of this paper, and thank the patients enrolled in the Genetics of Serrated Neoplasia (GSN) study (http://gsn.qimr.edu.au/index.html) who have generously contributed to the understanding of this condition.
For reprint orders, please contact: moc.enicidemerutuf@stnirper
Financial & competing interests disclosure
Joanne Young is supported by a Cancer Council Queensland Senior Research Fellowship and by a grant from the National Cancer Institute 1R01CA123010 (Genetics of Serrated Neoplasia). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Daniel D Buchanan, Familial Cancer Laboratory, QIMR, Herston Q 4006, Australia, Tel.: +61 733 620 498.
Aedan Roberts, Familial Cancer Laboratory, QIMR, Herston Q 4006, Australia, Tel.: +61 733 620 493.
Michael D Walsh, Familial Cancer Laboratory, QIMR, Herston Q 4006, Australia, Tel.: +61 738 453 775.
Susan Parry, Genetic Services, Auckland City Hospital, & Department of Gastroenterology & Hepatology, Middlemore Hospital, Auckland, New Zealand, Tel.: +64 930 749 49.
Joanne P Young, Associate Professor, Familial Cancer Laboratory, QIMR, Herston Q 4006, Australia, Tel.: +61 733 620 490, Fax: +61 733 620 108.
Papers of special note have been highlighted as:
of considerable interest