A Case of Sporadic Multiple Colonic Polyps in a Young Woman

Round 1

Reviewer 1 Report

First of all, I would like to congratulate with authors who describe an interesting case of a considerable research topic.

The knowledge about the correlation between genes and tumours is growing up fastly. I'd instead recommend a revision of the introduction paragraph in order to clarify the epidemiological impact of APC mutation and colorectal cancer worldwide. 

Thank you.

Author Response

Thank you for your positive comment and careful review. We have added the sentence describing the epidemiological impact of APC mutation and colorectal cancer in the “Introduction” section.

Reviewer 2 Report

The authors state "The criterion that the presence of an adenomatous polyp discovered before age 40 was supposed to trigger an assessment for genetic syndromes was excluded from the revised 2004 Bethesda guidelines [12]. Thus, currently, it is unclear if young patients with colorectal adenomas have a higher propensity for colorectal cancer." And, "There was no family history of colorectal polyposis or colon cancer in her first and second-degree relatives". Still for completeness of this study, it is important to determine if a new germline APC mutation exists. Indeed, the frequency of new mutations that contribute all FAP cases is about 25% [Bisgaard, M.L., Fenger, K., Bulow, S., Niebuhr, E. and Mohr, J. (1994) Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum. Mutat., 3, 121–125].

 

The authors should discuss other studies (in addition to Powell) that evaluated APC mutations in adenomas:

Levy DB. Smith KJ. Beazer-Barclay Y. Hamilton SR. Vogelstein B. Kinzler KW. Inactivation of both APC alleles in human and mouse tumors. Cancer Res 1994; 54:5953-8.

Ichii S, Horii A, Nakatsuru S, Furuyama J, Utsunomiya J, Nakamura Y. Inactivation of both APC alleles in an early stage of colon adenomas in a patient with familial adenomatous polyposis (FAP). Human Molecular Genetics 1992; 1:387-90.

It is surprising that they didn't mention, in their introduction, the classic model of colorectal carcinogenesis that correlates specific genetic changes with evolving tissue morphology [ Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990 Jun 1;61(5):759-67. doi: 10.1016/0092-8674(90)90186-i. PMID: 2188735]

 

Author Response

Thank you for your important comment. As described in 2^nd paragraph of “Case reports” section, whole-exome sequencing of the adenomas and surrounding non-neoplastic mucosa was performed. No genetic variation of the APC gene was found in surrounding non-neoplastic mucosa, suggesting that the patient does not have germline APC mutation.

We agree with the reviewer’s comments. As the reviewer suggested, other studies that evaluated APC mutation have been included in the “Introduction” section. Please refer to the “Introduction” section in revised manuscript.

Reviewer 3 Report

Colorectal cancer is one of the most common cancers and the second leading cause of cancer deaths worldwide. Colorectal adenomas are known as precursors of colorectal  adenocarcinoma and their removal can reduce the rate of colon cancer.

The title and content of the article represent a topic of real interest worldwide. The stratification of patients with sporadic multiple colonic polyps represents an important point in their therapeutic management, respectively in the standardization of a target program. The subject of the study is topical with real interest for the future.

The introduction of the article objectively presents general aspects of colorectal pathology. The bibliographic data inserted along the article presents a qualitative chronology. The subject of the article represents a true scientific revolution in its field

The material and methods section of the article presents a quantitative and qualitative exposition of the research plan, respectively a good reproducibility in order to develop other studies with this theme. I consider it necessary to develop new studies on this subject and implement them on a population scale.

The results of the article present a logical and chronological exposition outlining qualitative aspects of a quite rare disease in young population. The figures and tables keep a specific chronology throughout their exposition, presenting qualitative aspects related to the subject of the article.

The topic of the article is a real interest for the future with major importance in this field. I consider it necessary to develop new studies on this subject and implement them on a population scale. The article presents an important research point with an optimal linguistic exposition, having an exponential potential for the future.

           This present article is written in a clear and concise manner, there by preventing or even treating this type of cancer.

           The article presents originality, with an optimal literary exposition, representing a topic of real interest for the future with objective results at the research level. The article represents a launching platform in its field and from the point of view of the characteristics it is included for publication

Author Response

Thank you for your positive comment and careful review.

Round 2

Reviewer 1 Report

I would like to congratulate with authors and I endorse paper's publication.

Author Response

Thank you for your positive comment and careful review.

Reviewer 2 Report

This case involves a 25 year-old female patient who was “incidentally” found to have colon polyps during a medical check-up for employment. The authors should explain how colonic polyps were discovered during a routine medical checkup in an apparently healthy asymptomatic individual.

Further colonoscopic examination revealed multiple sessile colonic polyps which were found to be tubular adenomas and to have a heterozygous deletion mutation of c.1331-1332del in exon 11 in the APC gene.

The author states in the discussion: “Samples from the patient’s family members were not available. Thus, we could not completely exclude the possibility that germline mutations were inherited by the patient.” Still, the paper concludes that the adenomas are sporadic in nature.

However, there is a high likelihood that these multiple adenomas arose because of a germline APC mutation for several reasons.

1. Their patient is at an unusually young age (25 years) to be developing multiple (dozens) of colonic adenomas.

2. It is now well established that about 25-30% of FAP patients will have de novo APC mutations and a negative family history.

3. In their patient, all of the adenomas at different anatomic locations were found to have the same APC mutation.

If this patient does not have a germline mutation that is predisposing her to adenoma development in the colon, the authors need to provide a logical mechanism that explains the reason for presence of the same APC mutation in these multiple adenomas.

In any case, the paper should clearly state that this patient needs to be closely monitored for recurrent colon adenomas and possible carcinomas. If additional colonic tumors are subsequently found, then testing for a germline mutation should be recommended.

Still, whether the adenomas are hereditary or sporadic in nature is really mute and should not detract from the main take home conclusion of their paper that a single truncating mutation of the APC gene can initiate adenoma formation

Author Response

This case involves a 25-year-old female patient who was “incidentally” found to have colon polyps during a medical check-up for employment.

The authors should explain how colonic polyps were discovered during a routine medical checkup in an apparently healthy asymptomatic individual.
Answer: The patient visited local clinic for medical check-up including physical examination and endoscopy (gastroscope and colonofiberscope) as an obligation for employment like chest x-ray examnation in some companies of our country. Multiple polyps were found with colonoscopic examination and she was transferred to our hospital for further evaluation.   

Further colonoscopic examination revealed multiple sessile colonic polyps which were found to be tubular adenomas and to have a heterozygous deletion mutation of c.1331-1332del in exon 11 in the APC gene.

The author states in the discussion: “Samples from the patient’s family members were not available. Thus, we could not completely exclude the possibility that germline mutations were inherited by the patient.” Still, the paper concludes that the adenomas are sporadic in nature.

However, there is a high likelihood that these multiple adenomas arose because of a germline APC mutation for several reasons.

1. Their patient is at an unusually young age (25 years) to be developing multiple (dozens) of colonic adenomas.
2. It is now well established that about 25-30% of FAP patients will have de novo APC mutations and a negative family history.
3. In their patient, all of the adenomas at different anatomic locations were found to have the same APC mutation.

If this patient does not have a germline mutation that is predisposing her to adenoma development in the colon, the authors need to provide a logical mechanism that explains the reason for presence of the same APC mutation in these multiple adenomas.

In any case, the paper should clearly state that this patient needs to be closely monitored for recurrent colon adenomas and possible carcinomas. If additional colonic tumors are subsequently found, then testing for a germline mutation should be recommended.

Still, whether the adenomas are hereditary or sporadic in nature is really mute and should not detract from the main take home conclusion of their paper that a single truncating mutation of the APC gene can initiate adenoma formation.

Answer: Thank you for this insightful comment. As the reviewer indicated, we cannot completely rule out the possibility of germline mutation or de novo APC mutation. The same APC mutation in three adenomas (page 2, line 78-81) at different anatomic locations led us to hypothesize that the mutation detected in this patient be germline. However, as described in “Case Report” section, sequencing and Western blot analysis showed the mutation in only adenoma tissues but not in surrounding non-neoplastic colonic mucosa (Figure 3A & 3B). Because the patients who are born with an APC mutation have the mutation in every cells in their colon, it is likely that the APC mutation detected in this patient is sporadic. Unfortunately, we did not examine the mutation in other adenomas, due to small size of the polyps. Additional studies towards understanding the same APC mutation in adenomas at different locations are needed to address such question and we believe this is out of the scope of the case report.

As the reviewer recommended, the patient is still under follow-up and there was no visible colon polyps 6 months after polypectomy, as described in the “Case Reports” section (page 2, line 69-70). If additional colonic tumors are found in this patient, it will be interesting to study germline or de novo mutation in this patient and family members.

We have revised the last paragraph of the “Discussion” and “Conclusion” section.

Author Response File: Author Response.docx

Round 3

Reviewer 2 Report

Looks good - no further comments