Cancer Risks for Relatives of Serrated Polyposis Patients
Cancer Risks for Relatives of Serrated Polyposis Patients
First- and second-degree relatives of patients with serrated polyposis had a significantly increased risk of developing CRC. In addition, first-degree relatives demonstrated a significantly increased risk of pancreatic cancer. Together these findings support an inherited component for serrated polyposis. Though increased risks for first-degree relatives could be due to shared environment, the observation that the CRC risk extended to second-degree relatives, and that relatives were also at increased risk for extracolonic cancers, increases the likelihood of a genetic etiology for serrated polyposis. Our estimate of CRC risk for first-degree relatives did not differ significantly from the relative risk estimated by Boparai et al. (P=0.86).
Extracolonic cancers in relatives of a BRAF-mutated CRC proband (implying origin in a serrated polyp) were first described in a Swedish study of familial CRC in 2006, and further extracolonic associations were seen in a Canadian study. A single anecdotal report and a clinical description reported occurrence of extracolonic cancers in serrated polyposis patients and their relatives. However, until our study, the magnitude of extracolonic cancer risk for relatives had not been estimated. A range of extracolonic cancers were observed in the study cohort but the cancer-specific numbers were too low to determine with any degree of certainty whether they occurred more often than expected. Common cancers such as those of the breast, lung, and prostate were not increased above what would be expected in the population. An apparent decreased risk for lung cancer was observed in second-degree relatives. We have no explanation for this association; however, it may be a consequence of our analysis excluding any second cancers within 1 year of the first cancer diagnosis, which was done to minimise inclusion of metastatic disease.
We observed a significantly increased risk of pancreatic cancer for first-degree relatives of patients with serrated polyposis, which is a novel finding. No cases of pancreatic cancer were seen in the serrated polyposis cases themselves, although given the young average age at diagnosis of polyposis (48 years), this is not unexpected. Pancreatic cancer occurs in familial cancer syndromes such as Peutz–Jeghers syndrome and familial atypical multiple mole melanoma syndrome where its risk ranges from 9- to132-fold that of the population. It also occurs in familial pancreatitis, with a relative risk of 50–80-fold, and in families with mutations in BRCA2 and its binding partner PALB2, where the risk varies from 3.5- to 10-fold that of the population. Our estimate for pancreatic cancer risk in serrated polyposis at 3.64 is commensurate with the lower estimates for BRCA2 families. In population terms, the pancreas is less likely to develop a malignancy than any other organ in the gastrointestinal tract, with the exception of the small intestine. Pancreatic cancer is highly age dependent, and occurs in the population around 70 years of age. The median age at diagnosis for pancreatic cancer in our study was 73 years, not indicative of an early-age of onset. Rather, the increased frequency is suggestive of an enhanced response to risk factors such as smoking, obesity, and diabetes, factors which are also associated with the development of serrated polyps. Pancreatic cancer is difficult to prevent and there are currently no robust screening tests for early detection. Endoscopic ultrasound has been trialed in very high-risk families and has shown some promise in the detection of early precursor lesions in asymptomatic individuals.
Biological explanations for the association between serrated polyposis and extracolonic cancers are not known; however, our findings support the hypothesis that this condition represents an inherited cancer predisposition in which the phenotype is most strongly expressed in the colorectum. It is also possible that environmental triggers may be interacting with the genetic predisposition to produce both colonic and extracolonic cancers. Finally, more than one condition may be segregating in these families. Jarrar et al. reported that 7 of 651 families who met the criteria of Amsterdam I, Amsterdam II, Amsterdam-like, or familial colorectal cancer, had a high prevalence of serrated polyps. One of the scenarios raised in that report was a co-occurrence of two cancer pathways: Lynch syndrome and serrated polyposis. However, our findings suggest that the cancers observed in relatives of serrated polyposis patients are unlikely to be due to co-occurring Lynch syndrome mutations as index cases with a mismatch repair gene mutation were excluded from the study.
Serrated polyposis as currently defined is likely to comprise a heterogeneous group of conditions. The pattern of inheritance in at least some serrated polyposis patients may be consistent with a recessive mode, analagous to MUTYH-associated polyposis caused by germline mutations in the MUTYH gene. Increased risks of cancer for relatives of patients with MUTYH-associated polyposis have been found for CRC, duodenal, ovary, bladder, and skin cancer for biallelic mutation carriers. Moreover, an increased risk of CRC, gastric, and endometrial cancer has been reported for monoallelic mutation carriers. Until a genetic cause is identified for serrated polyposis, studies will continue to be based on a clinical definition.
The strengths of this study are that (i) it was based, to our knowledge, on the largest sample to date of relatives of index patients with serrated polyposis; (ii) it is the first study to quantify the risks of extracolonic cancers for relatives of patients with serrated polyposis; (iii) index cases were not ascertained because of a previous family history of polyps or cancer and, therefore, the estimates from this study are less likely to be inflated owing to ascertainment bias; and (iv) we accounted for familial correlation in the risk of cancer to derive appropriate measure of estimate imprecision.
Our study has several limitations, including the presence of unverified cancers, unaccounted for time and geographic variation. These might increase the imprecision of estimates more than indicated by the reported CIs. Estimates from this study should be generalizable to relatives of symptomatic patients with serrated polyposis identified in a clinical setting. As all index cases were recruited from genetics clinics, this raises the possibility that relatives of symptomatic patients may represent a more aggressive phenotype associated with a higher "familial risk profile" compared with other asymptomatic patients. However, symptoms such as abdominal pain or change in bowel habit, which first brought the index patients to their primary care clinician, are also very common outside the setting of serrated polyposis, and may have had nothing to do with their serrated polyposis condition. Therefore, it is not possible to state at this time that an aggressive phenotype should be inferred. A further limitation of the study is that it is not possible to know whether an endoscopist referred the patient to a genetics clinic because of polyp burden or because of family history. As the family history data used in this study were determined using genetics clinic pedigree records, we do not know the extent of family history recorded by the endoscopists. However, it has been observed that even in high-risk patients diagnosed at age <50 years, family history was not noted in 49–83% of cases.
Our findings suggest that relatives of patients with serrated polyposis could benefit from appropriate colonoscopic surveillance. Current practice for first-degree relatives is usually five-yearly colonoscopy from the age of 40–50 years or from an age 5 years younger than the age at which serrated polyposis was diagnosed in the family. The median age at which CRC was diagnosed in first-degree relatives in our study (55 years old) supports these guidelines for surveillance. Further independent studies are required to confirm the risks of extracolonic cancers for relatives of patients with serrated polyposis. Also, given the arbitrary nature of the current criteria for the identification of serrated polyposis and the initial observation of extracolonic cancers in relatives of index cases whose CRC arose from a serrated polyp, the implications of this finding may be applicable beyond the stringent criteria for diagnosis of serrated polyposis, identifying some families with both CRC and pancreatic cancer (in which Lynch syndrome is excluded) as having a serrated neoplasia predisposition.
This large, international study has observed that relatives of serrated polyposis patients are at significantly increased risks of colorectal and pancreatic cancer. These findings add to the accumulating evidence that serrated polyposis has an inherited component, while also highlighting the need for surveillance in relatives of patients with serrated polyposis.
Discussion
First- and second-degree relatives of patients with serrated polyposis had a significantly increased risk of developing CRC. In addition, first-degree relatives demonstrated a significantly increased risk of pancreatic cancer. Together these findings support an inherited component for serrated polyposis. Though increased risks for first-degree relatives could be due to shared environment, the observation that the CRC risk extended to second-degree relatives, and that relatives were also at increased risk for extracolonic cancers, increases the likelihood of a genetic etiology for serrated polyposis. Our estimate of CRC risk for first-degree relatives did not differ significantly from the relative risk estimated by Boparai et al. (P=0.86).
Extracolonic cancers in relatives of a BRAF-mutated CRC proband (implying origin in a serrated polyp) were first described in a Swedish study of familial CRC in 2006, and further extracolonic associations were seen in a Canadian study. A single anecdotal report and a clinical description reported occurrence of extracolonic cancers in serrated polyposis patients and their relatives. However, until our study, the magnitude of extracolonic cancer risk for relatives had not been estimated. A range of extracolonic cancers were observed in the study cohort but the cancer-specific numbers were too low to determine with any degree of certainty whether they occurred more often than expected. Common cancers such as those of the breast, lung, and prostate were not increased above what would be expected in the population. An apparent decreased risk for lung cancer was observed in second-degree relatives. We have no explanation for this association; however, it may be a consequence of our analysis excluding any second cancers within 1 year of the first cancer diagnosis, which was done to minimise inclusion of metastatic disease.
We observed a significantly increased risk of pancreatic cancer for first-degree relatives of patients with serrated polyposis, which is a novel finding. No cases of pancreatic cancer were seen in the serrated polyposis cases themselves, although given the young average age at diagnosis of polyposis (48 years), this is not unexpected. Pancreatic cancer occurs in familial cancer syndromes such as Peutz–Jeghers syndrome and familial atypical multiple mole melanoma syndrome where its risk ranges from 9- to132-fold that of the population. It also occurs in familial pancreatitis, with a relative risk of 50–80-fold, and in families with mutations in BRCA2 and its binding partner PALB2, where the risk varies from 3.5- to 10-fold that of the population. Our estimate for pancreatic cancer risk in serrated polyposis at 3.64 is commensurate with the lower estimates for BRCA2 families. In population terms, the pancreas is less likely to develop a malignancy than any other organ in the gastrointestinal tract, with the exception of the small intestine. Pancreatic cancer is highly age dependent, and occurs in the population around 70 years of age. The median age at diagnosis for pancreatic cancer in our study was 73 years, not indicative of an early-age of onset. Rather, the increased frequency is suggestive of an enhanced response to risk factors such as smoking, obesity, and diabetes, factors which are also associated with the development of serrated polyps. Pancreatic cancer is difficult to prevent and there are currently no robust screening tests for early detection. Endoscopic ultrasound has been trialed in very high-risk families and has shown some promise in the detection of early precursor lesions in asymptomatic individuals.
Biological explanations for the association between serrated polyposis and extracolonic cancers are not known; however, our findings support the hypothesis that this condition represents an inherited cancer predisposition in which the phenotype is most strongly expressed in the colorectum. It is also possible that environmental triggers may be interacting with the genetic predisposition to produce both colonic and extracolonic cancers. Finally, more than one condition may be segregating in these families. Jarrar et al. reported that 7 of 651 families who met the criteria of Amsterdam I, Amsterdam II, Amsterdam-like, or familial colorectal cancer, had a high prevalence of serrated polyps. One of the scenarios raised in that report was a co-occurrence of two cancer pathways: Lynch syndrome and serrated polyposis. However, our findings suggest that the cancers observed in relatives of serrated polyposis patients are unlikely to be due to co-occurring Lynch syndrome mutations as index cases with a mismatch repair gene mutation were excluded from the study.
Serrated polyposis as currently defined is likely to comprise a heterogeneous group of conditions. The pattern of inheritance in at least some serrated polyposis patients may be consistent with a recessive mode, analagous to MUTYH-associated polyposis caused by germline mutations in the MUTYH gene. Increased risks of cancer for relatives of patients with MUTYH-associated polyposis have been found for CRC, duodenal, ovary, bladder, and skin cancer for biallelic mutation carriers. Moreover, an increased risk of CRC, gastric, and endometrial cancer has been reported for monoallelic mutation carriers. Until a genetic cause is identified for serrated polyposis, studies will continue to be based on a clinical definition.
The strengths of this study are that (i) it was based, to our knowledge, on the largest sample to date of relatives of index patients with serrated polyposis; (ii) it is the first study to quantify the risks of extracolonic cancers for relatives of patients with serrated polyposis; (iii) index cases were not ascertained because of a previous family history of polyps or cancer and, therefore, the estimates from this study are less likely to be inflated owing to ascertainment bias; and (iv) we accounted for familial correlation in the risk of cancer to derive appropriate measure of estimate imprecision.
Our study has several limitations, including the presence of unverified cancers, unaccounted for time and geographic variation. These might increase the imprecision of estimates more than indicated by the reported CIs. Estimates from this study should be generalizable to relatives of symptomatic patients with serrated polyposis identified in a clinical setting. As all index cases were recruited from genetics clinics, this raises the possibility that relatives of symptomatic patients may represent a more aggressive phenotype associated with a higher "familial risk profile" compared with other asymptomatic patients. However, symptoms such as abdominal pain or change in bowel habit, which first brought the index patients to their primary care clinician, are also very common outside the setting of serrated polyposis, and may have had nothing to do with their serrated polyposis condition. Therefore, it is not possible to state at this time that an aggressive phenotype should be inferred. A further limitation of the study is that it is not possible to know whether an endoscopist referred the patient to a genetics clinic because of polyp burden or because of family history. As the family history data used in this study were determined using genetics clinic pedigree records, we do not know the extent of family history recorded by the endoscopists. However, it has been observed that even in high-risk patients diagnosed at age <50 years, family history was not noted in 49–83% of cases.
Our findings suggest that relatives of patients with serrated polyposis could benefit from appropriate colonoscopic surveillance. Current practice for first-degree relatives is usually five-yearly colonoscopy from the age of 40–50 years or from an age 5 years younger than the age at which serrated polyposis was diagnosed in the family. The median age at which CRC was diagnosed in first-degree relatives in our study (55 years old) supports these guidelines for surveillance. Further independent studies are required to confirm the risks of extracolonic cancers for relatives of patients with serrated polyposis. Also, given the arbitrary nature of the current criteria for the identification of serrated polyposis and the initial observation of extracolonic cancers in relatives of index cases whose CRC arose from a serrated polyp, the implications of this finding may be applicable beyond the stringent criteria for diagnosis of serrated polyposis, identifying some families with both CRC and pancreatic cancer (in which Lynch syndrome is excluded) as having a serrated neoplasia predisposition.
This large, international study has observed that relatives of serrated polyposis patients are at significantly increased risks of colorectal and pancreatic cancer. These findings add to the accumulating evidence that serrated polyposis has an inherited component, while also highlighting the need for surveillance in relatives of patients with serrated polyposis.
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