Informal Notes: Additional Research on APOE variants for Increased Risk of Late-Onset Alzheimer's Disease

[this set of notes branched out from this blog post; with 2 similar / partially identical paragraphs] 

I found it hard to find cohorts with individuals greater than 80 years of age in the AlzGene database (and 23andMe was reporting that is the age interval when onset was most likely, and risk was most increased).

To be fair, I also noticed that a recent study by Licher et al. 2019 reported Low-Risk Onset with an average age of 85.5 and High-Risk Onset with an average age of 81.3 (meaning individuals must have been over 80 at some point).  However, they grouped both E3/E4 individuals (like myself) with E4/E4 individuals (who should be at noticeably higher risk) in the "High-Risk" group.  The CDC also provides a short review here.

There is an earlier paper by Corder et al. 1993 reports "mean age at onset decreased from 84 to 68 years," but here were less than a dozen E4/E4 individuals for each gender in that paper (and the maximum risk of 90% seems high compared to other studies).  To be fair, Farrer et al. 1997 also reports an earlier age of onset with more samples (closer to 755 Caucasian E4/E4 individuals from meta-analysis; 14.8% of 5107 cases).  However, with that later study, I would kind of like to see some error bars (and ideally see individual points and/or be able to download an Excel / tab-delimited text / comma-separated text file with APOE genotype, disease status, age of onset, gender, ethnicity, and cohort / batch / family ID).

Myers et al. 1996 report an E4/E4 age of onset closer to 80 years (for 55% of E4/E4 individuals); however, the total percent of individuals developing Alzheimer's Disease is noticeably lower for E3/E4 and E3/E3 (27% and 9%, respectively) as well as having a later onset of closer to 85 years than 80 years.  Unfortunately, I don't have access to that later information, to check additional details.  It also doesn't look like 23andMe directly cites these papers (but I think these are what are discussed in review articles), but they report something more similar to Myers et al. 1996 (and Genin et al. 2011, which I do have access to).

Also, to be fair, my 23andMe Report says "Approximately 40-65% of Alzheimer's patients have one or two copies of the APOE ε4 variant. However, many people with the APOE ε4 variant will not develop late-onset Alzheimer's disease" (citing Alzheimer's Association 2016).  This probably matches the 55% APOE E4/E4 onset (and an indication that E3/E4 individuals like myself are increased risk, but are still more likely not to get the disease).

There are also different genes (such as APP / PSEN1 / PSEN2) which are more associated with early-onset Alzheimer's disease (which I found from this CDC link).

While a slightly different topic, my understanding is that the previous content from the 23andMe forums will be deleted.  So, to copy over some of the main points here, the 23andMe scientific report describes the "General population" risk estimates for individuals over 85 to be 11% for males and 14% from females.  I noticed that the overall risk estimates for individuals over 85 from other sources were numbers like 25%, 50%, and 50%.  Another member of the 23andMe community passed along a link to a PDF of the World Alzheimer Report 2018 from Alzheimer's Disease International; while a bit hard to find that same document, I do see the prevalence values that I mention in this article (which is "3% of people age 65-74, 17% of people age 75-84 and 32% of people age 85 or older have Alzheimer's dementia.").  If you check the reference in this CDC post, then Hebert et al. 2013 indicate previous and projected frequencies of 32% to 37% in Table 1.  I think this leaves some questions unanswered, but I think also the younger age estimates are more similar (and I would guess it is easier to collect data from those younger than 85).  So, I thought the feedback and discussion was helpful.

Change Log:

9/14/2019 - public post date
10/3/2019 - add link for CDC review

8/21/2021 - add overall frequency notes from 23andMe forum

Informal Notes: Pathogenic Variant Risk for BRCA1/2 Mutations

[this set of notes branched out from this blog post] 

I think the estimates of 50% risk for breast cancer and 30% risk of ovarian cancer (in this infographic from the CDC) are in line with that I was expecting (although that doesn't capture mutations in BRCA1 being higher risk than BRCA2).  There is also this page with 60-75% risk for BRCA1 carriers and 50-70% risk for BRCA2 carriers (which I learned about from this Twitter reply).

Importantly, because of that Twitter communication, I read the book "Resurrection Lily" by Amy Byer Shainman.  I think this provides a very poignant perspective of what is like for yourself and/or your friends to go through either breast cancer treatment or prevention strategies (including up to preventive surgeries).  There are also multiple pages for risk estimates at the end of the book (pages 253 and 262-263 in my copy of the book).

Before I learned about that book, I think I would mostly typically refer to the Stanford BRCA Decision Tool (Kurian et al. 2012) that provides the variance of risk with a few options (although I'm not sure about the the intervals of screening, I don't know what is the relative effectiveness of hormonal therapies, and these estimates are at the gene level when I would expect some specific variants are higher risk than others).

While it is probably not going to be a problem in the future, there was a few days when the website was down.  So, I have attached some screenshots below (for BRCA1, and then BRCA2):

There was a recommendation for BRCA screening with a "B" grade in individuals with family histories, but a recommendation against BRCA screening with a "D" grade for individuals that didn't already have an increased risk of getting breast cancer (which I think is shown most clearly on the US Preventive Services website).  While the context is different, I think this figure from Biesecker 2019 shows one example of how filtering for prior risk may help (although not specifically for BRCA1/2).

While the topic of treatment strategies is a little different, I did notice some different number on an NCI Prevention Tweet (going back to topic of the range of risk estimates).  For example, that number seemed noticeably different for BRCA2, and the total risk reduction (particularly if you focus on death from breast cancer) also seemed different that the text in that Tweet (compared to what I see in the BRCA Decision Tool).

I also think I had another interesting conversation on Twitter here, some of which was converted into notes as a blog post (in terms of the overall prevalence of cancers where variants in moderate-to-high risk genes could be found).

There are some NCCN guidelines, although I thought those were more clear for criteria for screening versus recommendation for surgery in a BRCA-positive individual (which supports use on a "case-by-case basis").  Nevertheless, there is a lot of information available if you register for an account in this document, where some details for the "Bilateral Total Mastectomy" are on page MS-24.  Nevertheless, if this implies that people who don't qualify for the NCCN screening criteria (but had a test result, for some reason) are less likely to benefit from surgery, then perhaps that is helpful for making decisions.

The CDC has guidelines to define "average," "moderate," and "high" hereditary breast cancer risk.  I think their guidelines for genetic testing are similar to the NCCN and USPSTF (but you might find that website easier to read, and this page mentions that the USPSTF recommendations may affect health care coverage).  They also have an additional link for mammogram screenings that I didn't previously know about (on this page).

While I think there are some specific things that can be improved (for communication with non-scientists and communicating ranges for estimates of risk for specific variants, for example), I believe free, publicly-available resources like BRCAExchange.org should play an important roles in helping patients learn more about their results.  ClinVar also provides some information, for variants in general.

For example, I believe these are the 3 BRCA1/BRCA2 variants covered by 23andMe: rs386833395, rs80357906, and rs80359550.

The mutation described by the author of "Resurrection Lily" was referred to as "BRCA1 #5385 insC" as well as "BRCA1 #5382".  The book includes some references to ClinVar, but I don't believe I saw the rsID.  However, I believe those names refer to this variant in BRCA Exchange and this variant in ClinVar (based upon this Hamel et al. 2011 paper, and the synonyms in the database listings).  That makes this is second of the 3 variants tested by 23andMe above.

I am not sure about other available estimates.  However, there are selected genes with high (or highest?) lifetime risk variants for 7 cancer types (including breast and ovarian cancer) on this page from JScreen.

You can listen to some personal perspectives from a patient advocate in this podcast from DNA Today.  One statistic that caught my attention was that 1 in 40 Ashkenazi Jewish women have a mutation in the BRCA1 or BRCA2 genes.  I would also find that statistic on this page from the CDC.  I believe that page is combining pathogenic variants from the BRCA1 and BRCA2 genes when reporting "About 50 out of 100 women with a BRCA gene mutation will get breast cancer by the time they turn 70 years old".

There are also various ways to see the influence of ENIGMA on BRCA1 and BRCA2 variant annotations.  For example, BRCA Exchange includes pathogenic variant annotations from ENIGMA and ClinVar.  This page provides information for ENIGMA annotations in ClinVar, and there is also an ENIGMA BRCA1/BRCA2 expert panel in ClinGen (related to "Variant Pathogenicity" for BRCA1 and BRCA2).

Change Log:

9/14/2019 - public post date
11/12/2019 - add link to BRCA decision tool paper; website not currently working, but I will add some screenshots later (to show substantial difference in risk at the gene level for BRCA1 versus BRCA2)
11/20/2019 - add screenshots for BRCA Decision Tool.
12/2/2019 - add prior risk venn diagram link

7/6/2020 - add "breast cancer" label

8/16/2020 - add additional Penn/Basser link for risk estimates

8/22/2020 - add BRCAExchange link

10/25/2020 - add Resurrection Lily link

2/23/2022 - correct typo

12/1/2023 - add JScreen link (after listening to this podcast)

1/21/2024 - add additional DNA Today link as well as CDC Link for BRCA variants in women with Ashkenazi Jewish ancestry.

1/22/2024 - after receiving helpful feedback from GenomeConnect / ClinGen staff, add links for various types of ENIGMA annotations.

Informal Notes: Collection of References Regarding the Frequency of Pathogenic Mutations in Moderate-to-High Cancer Risk Genes

While I typically prefer to keep Twitter responses less formal than blog posts (which in turn are less formal than pre-prints or peer-reviewed journal articles), I feel kind of bad continuing to add citations to an earlier discussion thread.

So, I thought I would copy the notes here, and provide information for those that are interested (without having all the notices go to the person with the original response):

BRCA Exchange tries to provide some variant information (for BRCA1 / BRCA2)

data.color.com also provides some information about specific variants (but counts are often low).  Color also has this page for Breast Cancer Awareness Month (October).

Ambry provides an Interactive Prevalence Tool (in collaboration with Mayo)

Stanford BRCA Decision Tool provides some statistics to guide discussions about risk prevention options (although that relates more to risk than total frequency; however, this with total numbers is essentially what I want to see)

MSKCC lists total inherited breast cancer rate at 5-10%

There is a link from the CDC website listing the BRCA1+BRCA2 rate for hereditary breast cancer as 3% for breast cancer and 10% for ovarian cancer.  If you sum the frequencies, that is somewhat close to LaDuca et al. 2019.

There is also a different source of information from the CDC, mentioning for all hereditary breast and ovarian cancer (which must be greater than the sum of BRCA1+BRCA2), which was 5-10% and 10-15% respectively.

Offit 2006 

• Editorial about BRCA mutation frequency and risk

Hu et al. 2018

• Table 2 shows some percentages per gene

LaDuca et al. 2019

• Learned about from @kristinclift
• GenomeWeb review mentions "13.8 percent of ovarian cancer patients carried germline pathogenic variants in at least one of the 32 genes tested"
• Supplemental Table S7 also shows a higher BRCA1/2 ovarian cancer percent (3-5%, OC) than breast cancer percent (1-2%, BC)
• There are all high-risk patients 
• Total numbers are fairly different: 66,954 BC, 9,106 OC, 1,087 BC+OV.
• Supplemental Table S6 has gnomAD control frequencies, but I think variant calls may need to be more specialized for targeted gene panels.
• In other words, those percentages look low compared to that matched control study, but they do provide those details.
• I also think they used results from the reports from different Ambry panels, rather than obtaining and re-analyzing raw data independently.  So, I wonder how much of an effect that had.

Unpublished (?) CARRIER Study Data

• In a CARRIERS plot (a PDF from a Clinical Cancer Genomics Conference presentation that I don't know if I have permission to post), getting control variants for BRCA1/2 below 0.4% puts BRCA1/2 case mutation rates at under 1.4%.
• I think that is for breast cancer.
• Plots for 14 individual studies (for a total of 10,000s of samples, with matched controls) were shown for 21 genes of with overall case rate of ~6% and control rate of ~2.5%, as well as 17 higher-risk genes with overall case rate of ~5% and control rate of ~2% (which I guess could up to a 30% “false positive” rate either way).

Variability in Variant Calling

• May need more specialized variant calling for targeted gene panels - Warden et al. 2014
• For example, notice the difference in scale for the y-axis in Figure 9, where the relative “novel” variants in controls is a proxy for false positives:
• You may get better concordance between variants with reprocessing (in this case, using a more typical processing strategy for WGS and Exome Data) - blog post on custom scripts and precisionFDA comparisons.
• In addition to data.color.com, I think cBioPortal can be a useful research to look at mutation information across different cancer types and studies
• cBioPortal has some tutorials that can be viewed here
• For example, I think I could see results more similar to what I read elsewhere (with BRCA2 being found at higher frequencies) if I removed variants of unknown significance
• I think 47:45 - 51:55 of this webinar also gives some useful caveats to mutation and copy number calling that might be worth taking into consideration (where a region that is supposed to have a homozygous deletion has a variant with an allele frequency that you would normally consider a match for a heterozgyous variant, when a true homozygous deletion call shouldn't have any variants)

Polygenic Risk Scores

These are arguably more for risk assessment rather than frequency (although the risk estimate vary across the population).

Nevertheless, I would also be interested in seeing more results from Myriad myRisk and AmbryScore-Breast Polygenic Risk Scores (PRS).  This is in part because I haven't been highly satisfied with the polygenic scores that I was able to apply to myself, but I should note that clinical features are included in the calculation for these scores (beyond just the genetic information).

For example, I noticed that some more information Myriad myRisk was provided in these slides, which I believe reference this announcement.  I believe that is a reference to the Hughes et al. 2020 and Gallagher et al. 2020 papers.  However, what caught my eye was this figure, which I don't think it is directly from those publications?

I am not sure if I am correctly understanding that both Myriad myRisk and AmbryScore-Breast use "clinical history" information?

As a possibly separate point, I thought Figure 2 of Fahed et al. 2020 was interesting because of the difference in the range of risk estimates by PRS with versus without a BRCA1 or BRCA2 mutation.  The stratification without being a BRCA1/2 carrier was more limited.  However, I would be interested to get a better sense of how PRS stratification compares to variants in or near the BRCA1 or BRCA2 genomic footprint.  I think the later more along the goals of resources like BRCA Exchange.

Those interested in these notes may also be interested in this post with notes on the range of risk estimates.

Change Log:

9/9/2019 - public post date
9/10/2019 - add "informal note" category, along with link to original response
9/13/2019 - add CDC links, as well as some extra information not previously copied over from earlier Twitter discussion
10/10/2019 - add Color link for BRCA1/2 mutation frequencies
11/12/2019 - add link to other blog post
5/8/2020 - add cBioPortal notes

7/6/2020 - add "breast cancer" label
7/7/2020 - add note about interest in hearing about a range of PRS experiences.

8/14/2020 - add additional PRS links

8/16/2020 - minor change

3/9/2021 - add link for Ambry Prevalence Table

4/23/2021 - move link from earlier blog post to this blog post

6/26/2022 - add link to PRS within BRCA1/2 carriers